Summary
Background
Worldwide, dengue is the most prevalent human arbovirus disease. Dengue infection may cause a range of clinical manifestations from self‐limiting febrile illness through to a ...life‐threatening syndrome accompanied by both bleeding and shock. Thrombocytopenia is frequently observed in mild and severe disease; however, the mechanisms involved in DENV‐induced platelet activation and thrombocytopenia are incompletely understood.
Patients and methods
Freshly isolated platelets from patients with dengue were evaluated for markers of activation, mitochondrial alteration and activation of cell death pathways. In parallel, we examined direct DENV‐induced activation and apoptosis of platelets obtained from healthy subjects.
Results
We found that platelets from DENV‐infected patients exhibited increased activation by comparison to control subjects. Moreover, platelets from DENV‐infected patients exhibited classic signs of the intrinsic pathway of apoptosis that include increased surface phosphatidylserine exposure, mitochondrial depolarization and activation of caspase‐9 and ‐3. Indeed, thrombocytopenia was shown to strongly associate with enhanced platelet activation and cell death in DENV‐infected patients. Platelet activation, mitochondrial dysfunction and caspase‐dependent phosphatidylserine exposure on platelets were also observed when platelets from healthy subjects were directly exposed to DENV in vitro. DENV‐induced platelet activation was shown to occur through mechanisms largely dependent on DC‐SIGN.
Conclusions
Together our results demonstrate that platelets from patients with dengue present signs of activation, mitochondrial dysfunction and activation of the apoptosis caspase cascade, which may contribute to the development of thrombocytopenia in patients with dengue. Our results also suggest the involvement of DC‐SIGN as a critical receptor in DENV‐dependent platelet activation.
In the late 1960s, numerous investigators independently demonstrated that platelets are capable of synthesizing proteins. Studies continued at a steady pace over the next 30 years and into the 21st ...century. Collectively, these investigations confirmed that platelets synthesize proteins and that the pattern of protein synthesis changes in response to cellular activation. More recent studies have characterized the mechanisms by which platelets synthesize proteins and have shown that protein synthesis alters the phenotype and functions of platelets. Here, we chronologically review our increased understanding of protein synthetic responses in platelets and discuss how the field may evolve over the next decade.
Background
It is often stated that loose seton drainage results in distal migration of a fistula tract in perianal fistula. The aim of the present study was to assess this distalization of trans- and ...suprasphincteric perianal fistulas after a silicone seton has been inserted.
Methods
Consecutive patients who underwent loose seton placement for the management of a transsphincteric or suprasphincteric fistula between January 2016 and December 2021 with a pre- and postoperative magnetic resonance imaging (MRI) were included in the present retrospective study. The height of the external anal sphincter (EAS) and the level of penetration of perianal fistula through the EAS or puborectal muscle (PRM) were determined on MRI. Primary outcome was migration of the fistula tract through the EAS and PRM.
Results
Thirty-eight patients with perianal fistulas were included. Median height of the EAS was 28 (IQR 25–34) mm before seton placement and 27 (IQR 24–33) mm afterward. Median level of perforation was 32 (IQR 17–40) mm before seton placement and 28 (IQR 17–40) mm afterward (
p
= 0.37). One fistula (3%) was downgraded from mid to low transsphincteric and was laid open after 14.9 months of loose seton drainage.
Conclusions
No statistically significant distalization of complex fistula tracts after loose silicone seton drainage was found. Some complex fistulas may downgrade to a less complex fistula after long-term seton drainage. However, loose silicone seton drainage should not be offered to patients as a treatment option to downgrade a complex fistula to a simple one or even have the hope to heal it.
Wear of articular cartilage is not well understood. We hypothesize that cartilage wears due to fatigue failure in repetitive compression instead of reciprocating friction.
This study compares ...reciprocating sliding of immature bovine articular cartilage against glass in two testing configurations: (1) a stationary contact area configuration (SCA), which results in static compression, interstitial fluid depressurization, and increasing friction coefficient during reciprocating sliding, and (2) a migrating contact area configuration (MCA), which maintains pressurization and low friction while producing repetitive compressive loading in addition to reciprocating sliding. Contact pressure, sliding duration, and sliding distance were controlled to be similar between test groups.
SCA tests exhibited an average friction coefficient of μ=0.084±0.032, while MCA tests exhibited a lower average friction coefficient of μ=0.020±0.008 (p<10
). Despite the lower friction, MCA cartilage samples exhibited clear surface damage with a significantly greater average surface deviation from a fitted plane after wear testing (R
=0.125±0.095 mm) than cartilage samples slid in a SCA configuration (R
=0.044±0.017 mm, p=0.002), which showed minimal signs of wear. Polarized light microscopy confirmed that delamination damage occurred between the superficial and middle zones of the articular cartilage in MCA samples.
The greatest wear was observed in the group with lowest friction coefficient, subjected to cyclical instead of static compression, implying that friction is not the primary driver of cartilage wear. Delamination between superficial and middle zones implies the main mode of wear is fatigue failure under cyclical compression, not fatigue or abrasion due to reciprocating frictional sliding.
Primaquine, an 8-aminoquinoline, is the only medication approved by the World Health Organization to treat the hypnozoite stage of
and
malaria. Relapse, triggered by activation of dormant hypnozoites ...in the liver, can occur weeks to years after primary infection, and provides the predominant source of transmission in endemic settings. Hence, primaquine is essential for individual treatment and
elimination efforts. However, primaquine use is limited by the risk of life-threatening acute hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. More recently, studies have demonstrated decreased efficacy of primaquine due to cytochrome P450 2D6 (
) polymorphisms conferring an impaired metabolizer phenotype. Failure of standard primaquine therapy has occurred in individuals with decreased or absent CYP2D6 activity. Both G6PD and CYP2D6 are highly polymorphic genes, with considerable geographic and interethnic variability, adding complexity to primaquine use. Innovative strategies are required to overcome the dual challenge of G6PD deficiency and impaired primaquine metabolism. Further understanding of the pharmacogenetics of primaquine is key to utilizing its full potential. Accurate
genotype-phenotype translation may optimize primaquine dosing strategies for impaired metabolizers and expand its use in a safe, efficacious manner. At an individual level the current challenges with G6PD diagnostics and CYP2D6 testing limit clinical implementation of pharmacogenetics. However, further characterisation of the overlap and spectrum of G6PD and CYP2D6 activity may optimize primaquine use at a population level and facilitate region-specific dosing strategies for mass drug administration. This precision public health approach merits further investigation for
elimination.
Platelet-activating factor (PAF) is a phospholipid with potent, diverse
physiological actions, particularly as a mediator of inflammation. The
synthesis, transport, and degradation of PAF are tightly ...regulated, and the
biochemical basis for many of these processes has been elucidated in recent
years. Many of the actions of PAF can be mimicked by structurally related
phospholipids that are derived from nonenzymatic oxidation, because such
compounds can bind to the PAF receptor. This process circumvents much of the
biochemical control and presumably is regulated primarily by the rate of
degradation, which is catalyzed by PAF acetylhydrolase. The isolation of cDNA
clones encoding most of the key proteins involved in regulating PAF has allowed
substantial recent progress and will facilitate studies to determine the
structural basis for substrate specificity and the precise role of PAF in
physiological events.
Celotno besedilo
Dostopno za:
CMK, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Intraspecific competition is a pervasive phenomenon with important ecological and evolutionary consequences in ants. However, its effect at population level remains less known. We investigated the ...effect of intraspecific competition on the demography of the leaf-cutting ant
Acromyrmex lobicornis
using a stochastic matrix demographic model parameterized with 3 years of census data. Given that competition is a negative interaction with potential consequences on fitness, we expected that nests that share their foraging area with conspecific nests would have a lower population growth rate than nests that did not. The stochastic growth rate of all sampled nests showed positive values, but with differences according to their competitive condition. Nests that did not share their foraging area showed a 34% annual growth, while nests that shared their foraging area with another conspecific nest showed only 13%. This difference appears to be related to a reduced probability that small nests grow to medium size in the competitive condition, this transition being the one that contributes the most to the population growth rate. These results suggest that competitive interactions often restrict the growth of small nest sizes, supporting previous evidence that proposed young ant colonies as the most vulnerable demographic stage. The known pattern of low overlap in ant foraging areas could be a consequence of a lower population growth rate of nests under competitive conditions. This illustrates how selective pressures on individuals (e.g., ant nests) can influence demography, emphasizing the role of intraspecific competition at population level and the potential consequences for species density and geographical ranges.
The increased use of veterinary antibiotics in modern agriculture for therapeutic uses and growth promotion has raised concern regarding the environmental impacts of antibiotic residues in soil and ...water. The mobility and transport of antibiotics in the environment depends on their sorption behavior, which is typically predicted by extrapolating from an experimentally determined soil-water distribution coefficient (K
d
). Accurate determination of K
d
values is important in order to better predict the environmental fate of antibiotics. In this paper, we examine different analytical approaches in assessing K
d
of two major classes of veterinary antibiotics (sulfonamides and macrolides) and compare the existing literature data with experimental data obtained in our laboratory. While environmental parameters such as soil pH and organic matter content are the most significant factors that affect the sorption of antibiotics in soil, it is important to consider the concentrations used, the analytical method employed, and the transformations that can occur when determining K
d
values. Application of solid phase extraction and liquid chromatography/mass spectrometry can facilitate accurate determination of K
d
at environmentally relevant concentrations. Because the bioavailability of antibiotics in soil depends on their sorption behavior, it is important to examine current practices in assessing their mobility in soil.
Essentials
Platelets express retinoic acid receptor (RAR)α protein, specifically binding target mRNAs.
mRNAs under RARα control include MAP1LC3B2, SLAIN2, and ANGPT1.
All‐trans retinoic acid (atRA) ...releases RARα from its target mRNA.
RARα expressed in human platelets exerts translational control via direct mRNA binding.
Summary
Background
Translational control mechanisms in platelets are incompletely defined. Here, we determined whether the nuclear transcription factor RARα controls protein translational events in human platelets.
Methods
Isolated human platelets were treated with the pan‐RAR agonist all‐trans‐retinoic acid (atRA). Global and targeted translational events were examined.
Results
Stimulation of platelets with atRA significantly increased global protein expression. RARα protein bound to a subset of platelet mRNAs, as measured by next‐generation RNA‐sequencing. In‐depth analyses of 5′ and 3′‐untranslated regions of the RARα‐bound mRNAs revealed consensus RARα binding sites in microtubule‐associated protein 1 light chain 3 beta 2 (MAP1LC3B2), SLAIN motif‐containing protein 2 (SLAIN2) and angiopoietin‐1 (ANGPT1) transcripts. When platelets were treated with atRA, binding interactions between RARα protein and mRNA for MAP1LC3B2, SLAIN2 and ANGPT1 were significantly decreased. Consistent with the release of bound RARα protein from MAP1LCB2mRNA, we observed an increase in the synthesis of MAP1LC3B2 protein.
Conclusions
These findings provide the first evidence that RARα, a nuclear transcriptional factor, regulates synthetic events in anucleate human platelets. They also reveal an additional non‐genomic role for RARα in platelets that may have implications for the vitamin A‐dependent signaling in humans.
PDF
