Macrophages promote tissue remodeling but few mechanisms exist to modulate their activity during tissue fibrosis. Serum amyloid P (SAP), a member of the pentraxin family of proteins, signals through ...Fcgamma receptors which are known to affect macrophage activation. We determined that IPF/UIP patients have increased protein levels of several alternatively activated pro-fibrotic (M2) macrophage-associated proteins in the lung and monocytes from these patients show skewing towards an M2 macrophage phenotype. SAP therapeutically inhibits established bleomycin-induced pulmonary fibrosis, when administered systemically or locally to the lungs. The reduction in aberrant collagen deposition was associated with a reduction in M2 macrophages in the lung and increased IP10/CXCL10. These data highlight the role of macrophages in fibrotic lung disease, and demonstrate a therapeutic action of SAP on macrophages which may extend to many fibrotic indications caused by over-exuberant pro-fibrotic macrophage responses.
A class of Langevin stochastic differential equations is shown to converge in the small-mass limit under very weak assumptions on the coefficients defining the equation. The convergence result is ...applied to three physically realizable examples where the coefficients defining the Langevin equation for these examples grow unboundedly either at a boundary, such as a wall, and/or at the point at infinity. This unboundedness violates the assumptions of previous limit theorems in the literature. The main result of this paper proves convergence for such examples.
We study a system of Skorokhod stochastic differential equations modeling the pairwise dispersion (in spatial dimension
d
=
2
) of inertial particles transported by a rough turbulent flow with Hölder ...exponent
h
∈
(
0
,
1
)
. Under the assumption that
h
>
0
is sufficiently small, we use Lyapunov methods and control theory to show that the Markovian system is nonexplosive and has a unique, exponentially attractive invariant probability measure. Furthermore, our Lyapunov construction is radially sharp and gives partial confirmation on a predicted asymptotic behavior with respect to the Hölder exponent
h
of the invariant probability measure. A physical interpretation of the asymptotics is that intermittent clustering is weakened when the carrier flow is sufficiently rough.
Numerous studies throughout North America allege deleterious associations among invasive Asian Carp and native fishes; however, no empirical evidence on a system-wide scale exists. We used ...Mississippi River Basin fish community data collected by the Long Term Resource Monitoring program and the Missouri Department of Conservation to evaluate possible interaction between Asian Carp and native fishes. Results from two decades of long-term monitoring throughout much of the Mississippi River suggest that Silver Carp relative abundance has increased while relative abundance (Bigmouth Buffalo F 3, 8240 = 6.44, P<0.01 and Gizzard Shad F 3, 8240 = 31.04, P<0.01) and condition (Bigmouth Buffalo slope = -0.11; t = -1.71; P = 0.1014 and Gizzard Shad slope = -0.39; t = -3.02; P = 0.0073) of native planktivores have declined. Floodplain lake qualitative evaluations yielded similar results; floodplain lake fish communities were likely altered (i.e., reductions in native species) by Silver Carp. Furthermore, laboratory experiments corroborated field evidence; Silver Carp negatively influence native planktivores through competition for prey (all comparisons, P > 0.05). To this end, this study provides evidence that Silver Carp are likely adversely influencing native fishes; however, mere presence of Silver Carp in the system does not induce deleterious effects on native fishes. To the best of our knowledge, this evaluation is the first to describe the effects of Asian Carp throughout the Mississippi River Basin and could be used to reduce the effects of Asian Carp on native biota through an integrated pest management program as suggested by congressional policy. Despite the simplicity of the data analyzed and approach used, this study provides a framework for beginning to identify the interactions of invasive fish pests on native fishes (i.e., necessary first step of integrated pest management). However, knowledge gaps remain. We suggest future efforts should conduct more in depth analyses (i.e., multivariate statistical approaches) that investigate the influence on all native species.
Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and ...effective delivery has proved unsuccessful.
Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF CERE-110). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert.
AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity.
This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.
We apply Gamma calculus to the hypoelliptic and non-symmetric setting of Langevin dynamics under general conditions on the potential. This extension allows us to provide explicit estimates on the ...convergence rate (which is exponential) to equilibrium for the dynamics in a weighted
H
1
(
μ
)
sense,
μ
denoting the unique invariant probability measure of the system. The general result holds for singular potentials, such as the well-known Lennard–Jones interaction and confining well, and it is applied in such a case to estimate the rate of convergence when the number of particles
N
in the system is large.
Understanding linkages between natal and nursery habitats is critical for conservation of riverine fishes.
Scaphirhynchus
sturgeons inhabiting the middle Mississippi River may originate from the ...Missouri or Mississippi rivers, although relative importance of these recruitment sources is unknown. We characterized the relationship between water and sturgeon fin ray Sr:Ca, verified shifts in water Sr:Ca are recorded in age-0 sturgeon fin rays, and determined whether age-0 sturgeons from the Mississippi and Missouri rivers exhibited distinct fin ray Sr:Ca signatures. Fin ray Sr:Ca of laboratory-reared fish reflected transfer from water with elevated Sr:Ca to ambient water 1 day posthatch, indicating that short-term residency in environments can be detected. Nine of 30 age-0 fish captured in the middle Mississippi River were Missouri River emigrants. Four of these emigrants originated in the upper portion of the lower Missouri River (≥589 km upstream from its mouth), where water Sr:Ca is higher compared with the lowermost section of the Missouri River and the Mississippi River. Twenty-five of 30 fish collected from the lowermost section of the Missouri River originated within this river segment; the remainder originated upriver. Fin ray Sr:Ca enables identification of natal river segment for age-0 sturgeons and contributions of river segments to sturgeon recruitment.
Major depressive disorder (MDD) is a highly heterogeneous disorder, which may partly explain why treatment outcome using antidepressants is unsatisfactory. We investigated the onset of depression as ...a possible clinical marker for therapy response prediction in the context of somatic biomarkers blood pressure and plasma electrolyte concentration. 889 MDD patients were divided into early (EO, n = 226), intermediate (IO, n = 493), and late onset (LO, n = 169) patients and were analyzed for differences in socio-demographic and clinical parameters, comorbidities and treatment outcome as well as systolic blood pressure and electrolytes. EO patients more often suffered from a recurrent depression, had more previous depressive episodes, a higher rate of comorbid axis I and II disorders, and more often reported of suicidality (p < 0.001) compared to IO and LO patients. Treatment outcome was not different from IO and LO patients, although LO patients responded faster. EO patients who showed an early non-improvement of depression after 2 weeks of therapy (<20% improvement) had a 4.3-fold higher likelihood to become non-remitter as compared to LO patients with an early improvement. EO patients had significantly lower systolic blood pressure than patients with IO or LO and electrolytes in EO patients were significantly correlated with depression severity. Our results confirm other studies showing an association of an early onset of depression with a slower treatment response. The worse treatment outcome in patients with an additional early non-improvement to antidepressant therapy opens perspectives to develop and test individualized treatment approaches for EO and LO patients in the future, which may be based on differences in autonomic regulation.
Response to antidepressant treatment in major depressive disorder (MDD) cannot be predicted currently, leading to uncertainty in medication selection, increasing costs, and prolonged suffering for ...many patients. Despite tremendous efforts in identifying response-associated genes in large genome-wide association studies, the results have been fairly modest, underlining the need to establish conceptually novel strategies. For the identification of transcriptome signatures that can distinguish between treatment responders and nonresponders, we herein submit a novel animal experimental approach focusing on extreme phenotypes. We utilized the large variance in response to antidepressant treatment occurring in DBA/2J mice, enabling sample stratification into subpopulations of good and poor treatment responders to delineate response-associated signature transcript profiles in peripheral blood samples. As a proof of concept, we translated our murine data to the transcriptome data of a clinically relevant human cohort. A cluster of 259 differentially regulated genes was identified when peripheral transcriptome profiles of good and poor treatment responders were compared in the murine model. Differences in expression profiles from baseline to week 12 of the human orthologues selected on the basis of the murine transcript signature allowed prediction of response status with an accuracy of 76% in the patient population. Finally, we show that glucocorticoid receptor (GR)-regulated genes are significantly enriched in this cluster of antidepressant-response genes. Our findings point to the involvement of GR sensitivity as a potential key mechanism shaping response to antidepressant treatment and support the hypothesis that antidepressants could stimulate resilience-promoting molecular mechanisms. Our data highlight the suitability of an appropriate animal experimental approach for the discovery of treatment response-associated pathways across species.
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