Dupuytren’s disease (DD) is a common, progressive fibroproliferative disease affecting the palmar fascia of the hands, causing fingers to irreversibly flex toward the palm with significant loss of ...function. Surgical treatments are limited; therefore, effective new therapies for DD are urgently required. To identify the key cellular and molecular pathways driving DD, we employed single-cell RNA sequencing, profiling the transcriptomes of 35,250 human single cells from DD, nonpathogenic fascia, and healthy dermis. We identify a DD-specific population of pathogenic PDPN+/FAP+ mesenchymal cells displaying an elevated expression of fibrillar collagens and profibrogenic genes. In silico trajectory analysis reveals resident fibroblasts to be the source of this pathogenic population. To resolve the processes governing DD progression, genes differentially expressed during fibroblast differentiation were identified, including upregulated TNFRSF12A and transcription factor SCX. Knockdown of SCX and blockade of TNFRSF12A inhibited the proliferation and altered the profibrotic gene expression of cultured human FAP+ mesenchymal cells, demonstrating a functional role for these genes in DD. The power of single-cell RNA sequencing is utilized to identify the major pathogenic mesenchymal subpopulations driving DD and the key molecular pathways regulating the DD-specific myofibroblast phenotype. Using this precision medicine approach, inhibition of TNFRSF12A has shown potential clinical utility in the treatment of DD.
Neurons that fire in relation to licking, in the ventral part of the dorsolateral striatum (DLS), were studied during acquisition and performance of a licking task in rats for 14 sessions (2 h/d). ...Task learning was indicated by fewer errors of omission of licking and improved movement efficiency (i.e., shorter lick duration) over sessions. Number of licks did not change over sessions. Overtraining did not result in habit formation, as indicated by similar reductions of licking responses following devaluation by satiety in both early and late sessions. Twenty-nine lick neurons recorded and tracked over sessions exhibited a significant linear decrease in average firing rate across all neurons over sessions, correlating with concurrent declines in lick duration. Individually, most neurons (86%) exhibited decreased firing rates, while a small proportion (14%) exhibited increased firing rates, during lick movements that were matched over sessions. Reward manipulations did not alter firing patterns over sessions. Aside from the absence of habit formation, striatal processing during unconditioned movements (i.e., licking) was characterized by high activity of movement-related neurons during early performance and decreased activity of the same neurons during overtraining, similar to our previous report of head movement neurons during acquired, skilled, instrumental head movements that ultimately became habitual (Tang et al., 2007). Decreased activity in DLS neurons may reflect a common neural mechanism underlying improvement in movement efficiency with overtraining. Nonetheless, the decreased striatal firing in relation to a movement that did not become habitual demonstrates that not all DLS changes reflect habit formation.
The rhizosphere microbiome is considered to play a key role in determining crop health. However, current understanding of the factors which shape assembly and composition of the microbiome is heavily ...biased toward bacterial communities, and the relevance for other microbial groups is unclear. Furthermore, community assembly is determined by a variety of factors, including host genotype, environment and agricultural management practices, and their relative importance and interactions remain to be elucidated. We investigated the impact of nitrogen fertilization on rhizosphere bacterial, fungal, nematode and protist communities of 10 contrasting oilseed rape genotypes in a field experiment. We found significant differences in the composition of bacteria, fungi, protist and nematode communities between the rhizosphere and bulk soil. Nitrogen application had a significant but weak effect on fungal, bacterial, and protist community composition, and this was associated with increased relative abundance of a complex of fungal pathogens in the rhizosphere and soil, including
Mycosphaerella
sp. and
Leptosphaeria
sp. Network analysis showed that nitrogen application had different effects on microbial community connectivity in the soil and rhizosphere. Crop genotype significantly affected fungal community composition, with evidence for a degree of genotype specificity for a number of pathogens, including
L. maculans, Alternaria sp., Pyrenopeziza brassicae, Olpidium brassicae
, and
L. biglobosa
, and also potentially beneficial Heliotales root endophytes. Crop genotype had no significant effect on assembly of bacteria, protist or nematode communities. There was no relationship between genetic distance of crop genotypes and the extent of dissimilarity of rhizosphere microbial communities. Field disease assessment confirmed infection of crops by
Leptosphaeria sp., P. brassicae
, and
Alternaria
sp., indicating that rhizosphere microbiome sequencing was an effective indicator of plant health. We conclude that under field conditions soil and rhizosphere nutrient stoichiometry and crop genotype are key factors determining crop health by influencing the infection of roots by pathogenic and mutualistic fungal communities, and the connectivity and stability of rhizosphere microbiome interaction networks.
To sustain native species in managed forests, landowners need silvicultural strategies that retain habitat elements often eliminated during traditional harvests such as clearcut logging. One ...alternative is green-tree or variable retention. We investigated the response of terrestrial small mammals to experimental harvests that retained large live trees in varying amounts (approximately 100, 75, 40, and 15% of original basal area) and patterns (aggregated versus dispersed) in mature coniferous forests of western Oregon and Washington. Treatments were applied in 36, 13-ha experimental units. We used pitfall traps to sample small mammals for 4 weeks each autumn during 2 years before and 2 years after treatments. We captured 21,351 individuals of 32 species. We analyzed effects of treatments on relative abundance of 12 species. As level of retention declined, we expected species associated with closed-canopy forests to decrease (
Sorex trowbridgii,
Neurotrichus gibbsii,
Peromyscus keeni,
Myodes
Clethrionomys
californicus, and
M. gapperi); species associated with early successional habitats to increase (
S. vagrans,
P. maniculatus,
Microtus longicaudus, and
Microtus oregoni); and habitat generalists to show little response (
S. monticolus,
S. pacificus, and
S. sonomae). As expected,
M. californicus declined after harvest, and
P. maniculatus and
M. longicaudus increased.
Sorex sonomae showed an unpredicted decrease. Other species did not show consistent changes. Responses of
S. monticolus,
S. sonomae, and
M. gapperi varied among study areas. For
M. gapperi, this variation was not explained by differences in habitat structure among areas. For all species, capture rates were similar in dispersed- and aggregated-retention units. Similarity in species composition between harvested sites and controls decreased with decreasing retention. Future sampling of these treatments is needed to assess long-term responses. Based on our initial results, green-tree retention strategies need to be sensitive to regional variation in environmental characteristics and small mammal community composition.
To investigate striatal mechanisms underlying the acute effects of stimulants on motor behavior, firing rates (FRs) of striatal neurons related specifically to vertical head movement were studied ...exclusively during vertical head movements. Precocaine FRs were recorded after intraperitoneal saline injection (time 1; T1), and rats performed conditioned vertical head movements (>10,000) similar to those induced by stimulants. After cocaine injection (0, 5, 10, or 20 mg/kg; T2), animals continued in the task. The proportion of long head movements was increased by low doses but decreased by the high dose, which induced stereotypic head movements. Comparing each neuron's FR during movements that were matched between T1 and T2 (e.g., regarding direction, distance), cocaine's effects depended on predrug FR and dose. Plots regressing T2FR on T1FR showed dose-dependent, "clockwise" rotations of regression lines in plots of all the neurons' average FRs and of individual neurons' FRs during different movements. All three doses elevated normally low FRs; the high dose also suppressed many higher FRs. Enhancement of a neuron's FR associated with weak and suppression of FR associated with strong corticostriatal inputs contradict several current theories of dopamine (DA) function. Induction of stereotypy by a single, high-dose injection suggests that this cocaine level exceeded that in other studies using cocaine self-administration, in which stereotypy develops only after several sessions. Suppressive effects observed only at the high dose and in numerous electrophysiological studies of DA agonist effects may be unrepresentative of uniform elevations in lateral striatal firing related to movement observed at lower cocaine levels.
To compare the frequency and extent of Troponin I and late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) defined injury following PCI compared with CABG in patients with multivessel ...and/or left main coronary artery disease (CAD), and interpret these finding in light of the new ESC/ACCF/AHA/WHF Task Force definitions for necrosis and infarction.
Prospective, registered, single centre randomised controlled trial. Eighty patients with 3 vessel CAD (≥ 50% stenoses), or 2 vessel CAD including a type C lesion in the LAD, and/or left main disease were enrolled. Mean SYNTAX and EuroSCOREs were similar for both groups. Forty patients underwent PCI with drug eluting stents and 39 underwent CABG (one died prior to CABG). In the PCI group 6/38 (15.8%) patients had LGE, compared with 9/32 (28.1%) CABG patients (p = 0.25). Using the new Task Force definitions, necrosis occurred in 30/40 (75%) PCI patients and 35/35 (100%) CABG patients (p = 0.001), whilst infarction occurred in 30/40 (75%) PCI patients and 9/32 (28.1%) CABG patients (p = 0.0001).
Periprocedural necrosis according to the Task Force definition was significantly lower in the PCI group, and universal in the CABG group. The incidence and extent of CMR defined infarction following PCI did not differ compared with CABG. This demonstrates that PCI can achieve revascularisation in complex patients without increased procedural myocardial damage.
The rat dorsolateral striatum (DLS) has been implicated in habit formation. Previous studies in our laboratory found that as animals acquired a motor habit or remained goal-directed, tested by reward ...devaluation, the vast majority of DLS neurons decreased firing rates during the same responses over training days. However, mixed results have been reported in the literature regarding whether DLS neurons exhibit cue reactivity. In the present study, we reanalyzed a sample of DLS neurons in a task in which habitual behavior was acquired (dataset of Tang et al., 2007
45) and found that somatic sensorimotor as well as nonsomatomotor neurons of the DLS exhibited no cue-evoked firing. A second sample of DLS neurons related to licking in a task in which goal-directed behavior occurred (dataset of Tang et al., 2009
46) was also reanalyzed for cue-evoked correlates. Although behavior was cue guided, lick neurons did not exhibit cue-evoked firing. Given the complete absence of cue-related firing during habitual or goal-directed behavior, adaptations in DLS firing patterns may be regulated by movement-related learning rather than nonsomatosensory cues, consistent with convergent S1 and M1 afferents to the region. Striatal cue reactivity in the rat is likely mediated within the dorsomedial and ventromedial striatum, in line with associative and limbic afferents to these regions, respectively.
•Consistency, stability and confidence are three indicators of opinion quality.•We compare opinion quality after focus groups and information-choice questionnaires.•Information-choice questionnaires ...result in higher-quality opinions than focus groups.
Both focus group discussions and information-choice questionnaires (ICQs) have previously been used to examine informed public opinions about carbon dioxide capture and storage (CCS). This paper presents an extensive experimental study to systematically examine and compare the quality of opinions created by these two research techniques. Depending on experimental condition, participants either participated in a focus group meeting or completed an ICQ. In both conditions participants received identical factual information about two specific CCS options. After having processed the information, they indicated their overall opinion about each CCS option. The quality of these opinions was determined by looking at three outcome-oriented indicators of opinion quality: consistency, stability, and confidence. Results for all three indicators showed that ICQs yielded higher-quality opinions than focus groups, but also that focus groups did not perform poor in this regard. Implications for the choice between focus group discussions and ICQs are discussed.
Recent analyses of sediment samples from "black mat" sites in outh merica and urope support previous interpretations of an impact event that reversed the Late Glacial demise of ice during the Bølling ...Allerød warming, resulting in a resurgence of ice termed the Younger Dryas (YD) cooling episode. The breakup or impact of a cosmic vehicle at the boundary coincides with the onset of a 1-kyr long interval of glacial resurgence, one of the most studied events of the Late Pleistocene. New analytical databases reveal a corpus of data indicating that the cosmic impact was a real event, most possibly a cosmic airburst from Earth's encounter with the Taurid Complex comet or unknown asteroid, an event that led to cosmic fragments exploding interhemispherically over widely dispersed areas, including the northern ndes of enezuela and the Alps on the Italian/French frontier. While the databases in the two areas differ somewhat, the overall interpretation is that microtextural evidence in weathering rinds and in sands of associated paleosols and glaciofluvial deposits carry undeniable attributes of melted glassy carbon and e spherules, planar deformation features, shock-melted and contorted quartz, occasional transition and platinum metals, and brecciated and impacted minerals of diverse lithologies. In concert with other black mat localities in the Western , the etherlands, coastal rance, yria, entral sia, eru, rgentina and exico, it appears that a widespread cosmic impact by an asteroid or comet is responsible for deposition of the black mat at the onset of the glacial event. Whether or not the impact caused a 1-kyr interval of glacial climate depends upon whether or not the Earth had multiple centuries-long episodic encounters with the Taurid Complex or asteroid remnants; impact-related changes in microclimates sustained climatic forcing sufficient to maintain positive mass balances in the reformed ice; and/or inertia in the Atlantic thermohaline circulation system persisted for 1-kyr.
Previous research has shown that public knowledge and awareness of carbon dioxide capture and storage (CCS) is very limited. As a result, traditional surveys designed to collect public opinions about ...CCS do in fact assess so-called pseudo opinions. Pseudo-opinions are of very low quality because they are mostly unstable and inconsistent. Therefore, they are not predictive for actual and future public support for or opposition against CCS. As compared to pseudo opinions, opinions expressed after the public has been provided with factual information about CCS are likely to be of higher quality. Focus group discussions and Information-Choice Questionnaires (ICQs) are two research techniques frequently used in the CCS literature that aim to collect such informed public opinions. In this study, we examined which of these two research technique leads to the highest quality opinions (i.e., to opinions that are consistent, stable, and that people are confident about). Our results showed that ICQs yielded higher-quality opinions than focus group discussions. Practical implications and recommendations are discussed.
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