Hitting the wall: Human sperm velocity recovery under ultra-confined conditions.

Infertility is a common medical condition encountered by health systems throughout the world. Despite the development of complex in vitro fertilization techniques, only one-third of these procedures are successful. New lab-on-a-chip systems that focus on spermatozoa selection require a better understanding of sperm behavior under ultra-confined conditions in order to improve outcomes. Experimental studies combined with models and simulations allow the evaluation of the efficiency of different lab-on-a-chip devices during the design process. In this work, we provide experimental evidence of the dynamics of sperm interacting with a lateral wall in a shallow chamber. We observe a decrease in average sperm velocity during initial wall interaction and partial recovery after the alignment of the trajectory of the cell. To describe this phenomenon, we propose a simple model for the sperm alignment process with a single free parameter. By incorporating experimental motility characterization into the model, we achieve an accurate description of the average velocity behavior of the sperm population close to walls. These results will contribute to the design of more efficient lab-on-a-chip devices for the treatment of human infertility.

Self-assembly of Pseudo-Dipolar Nanoparticles at Low Densities and Strong Coupling.

Nanocolloids having directional interactions are highly relevant for designing new self-assembled materials easy to control. In this article we report stochastic dynamics simulations of finite-size pseudo-dipolar colloids immersed in an implicit dielectric solvent using a realistic continuous description of the quasi-hard Coulombic interaction. We investigate structural and dynamical properties near the low-temperature and highly-diluted limits. This system self-assembles in a rich variety of string-like configurations, depicting three clearly distinguishable regimes with decreasing temperature: fluid, composed by isolated colloids; string-fluid, a gas of short string-like clusters; and string-gel, a percolated network. By structural characterization using radial distribution functions and cluster properties, we calculate the state diagram, verifying the presence of string-fluid regime. Regarding the string-gel regime, we show that the antiparallel alignment of the network chains arises as a novel self-assembly mechanism when the characteristic interaction energy exceeds the thermal energy in two orders of magnitude, ud/kBT ≈ 100. This is associated to relevant structural modifications in the network connectivity and porosity. Furthermore, our results give insights about the dynamically-arrested nature of the string-gel regime, where we show that the slow relaxation takes place in minuscule energy steps that reflect local rearrangements of the network.

The prokineticin receptor antagonist PC1 rescues memory impairment induced by ß amyloid administration through the modulation of prokineticin system.

Growing evidences demonstrate that chemokines and chemokine receptors are up-regulated in resident central nervous system cells during Alzheimer's disease contributing to neuroinflammation and neurodegeneration. Prokineticin 2 belongs to a new family of chemokines which recently emerged as a critical player in immune system and inflammatory diseases. Since pharmacological blockade in vitro of the prokineticin system is able to antagonize Amyloid ß-induced neurotoxicity, the aim of the present study was to investigate in vivo effects of prokineticin receptor antagonist PC1 on memory impairment in a rodent model of Alzheimer's disease. Rats were intracerebroventricular infused with Aß1-42 and behavioral responses as well as the expression profile in hippocampus of prokineticin 2 and its receptors were investigated. Results demonstrated that Aß1-42-infused rats developed significant memory impairments together with a marked up-regulation of both prokineticin 2 and its receptors in hippocampal neurons and astrocytes. Treatment with PC1 significantly improved learning capability of Aß1-42-infused rats restoring the balance of prokineticin system. This study pointed to a neuroprotective role of PC1 on Aß1-42-induced memory deficits that could be ascribed to the ability of PC1 to modulate rat hippocampal prokineticin system and to recover the impaired Aß1-42-induced neurogenesis. This suggests that prokineticin system antagonism could be considered as a new approach for the study of AD etiopathology.

Maternal exposure to low levels of corticosterone during lactation protects adult rat progeny against TNBS-induced colitis: A study on GR-mediated anti-inflammatory effect and prokineticin system.

The early phase of life represents a critical period for the development of an organism. Interestingly, early life experiences are able to influence the development of the gastrointestinal tract and the reactivity to colonic inflammatory stress. We recently demonstrated that adult male rats exposed to low doses of corticosterone during lactation (CORT-nursed rats) are protected against experimental colitis induced by the intracolonic infusion of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Based on these interesting results, we wanted to better investigate which cellular actors could be involved in the protection of CORT-nursed rats from TNBS-induced experimental colitis. Therefore, in the present work, we focused our attention on different factors implicated in GR-mediated anti-inflammatory effect. To address this issue, colonic tissues, collected from control and CORT-nursed healthy animals and from control and CORT-nursed colitic rats, were processed and the following inflammatory factors were evaluated: the expression of (i) glucocorticoid receptors (GR), (ii) glucocorticoid-induced leucine zipper (GILZ), (iii) phospho-p65NF-κB, (iv) the pro-inflammatory cytokines IL-1ß and TNF-α, (v) the prokineticins PK2 and PK2L and (vi) their receptors PKR1 and PKR2. We found that adult CORT-nursed rats, in comparison to controls, showed increased expression of colonic GR and reduced expression of pro-inflammatory molecules (IL-1ß, TNF-α, PK2 and PK2L) in response to inflammatory colitis. The observed changes were associated with an increase in GILZ colonic expression and with a reduction in phospo-p65NF-κB colonic expression.

Swimming performance of Bradyrhizobium diazoefficiens is an emergent property of its two flagellar systems.

Many bacterial species use flagella for self-propulsion in aqueous media. In the soil, which is a complex and structured environment, water is found in microscopic channels where viscosity and water potential depend on the composition of the soil solution and the degree of soil water saturation. Therefore, the motility of soil bacteria might have special requirements. An important soil bacterial genus is Bradyrhizobium, with species that possess one flagellar system and others with two different flagellar systems. Among the latter is B. diazoefficiens, which may express its subpolar and lateral flagella simultaneously in liquid medium, although its swimming behaviour was not described yet. These two flagellar systems were observed here as functionally integrated in a swimming performance that emerged as an epistatic interaction between those appendages. In addition, each flagellum seemed engaged in a particular task that might be required for swimming oriented toward chemoattractants near the soil inner surfaces at viscosities that may occur after the loss of soil gravitational water. Because the possession of two flagellar systems is not general in Bradyrhizobium or in related genera that coexist in the same environment, there may be an adaptive tradeoff between energetic costs and ecological benefits among these different species.

Bv8/prokineticin 2 is involved in Aß-induced neurotoxicity.

Bv8/Prokineticin 2 (PROK2) is a bioactive peptide initially discovered as a regulator of gastrointestinal motility. Among multiple biological roles demonstrated for PROK2, it was recently established that PROK2 is an insult-inducible endangering mediator for cerebral damage. Aim of the present study was to evaluate the PROK2 and its receptors' potential involvement in amyloid beta (Aß) neurotoxicity, a hallmark of Alzheimer's disease (AD) and various forms of traumatic brain injury (TBI). Analyzing primary cortical cultures (CNs) and cortex and hippocampus from Aß treated rats, we found that PROK2 and its receptors PKR1 and PKR2 mRNA are up-regulated by Aß, suggesting their potential involvement in AD. Hence we evaluated if impairing the prokineticin system activation might have protective effect against neuronal death induced by Aß. We found that a PKR antagonist concentration-dependently protects CNs against Aß(1-42)-induced neurotoxicity, by reducing the Aß-induced PROK2 neuronal up-regulation. Moreover, the antagonist completely rescued LTP impairment in hippocampal slices from 6 month-old Tg2576 AD mice without affecting basal synaptic transmission and paired pulse-facilitation paradigms. These results indicate that PROK2 plays a role in cerebral amyloidosis and that PROK2 antagonists may represent a new approach for ameliorating the defining pathology of AD.

Prokineticin 2 upregulation in the peripheral nervous system has a major role in triggering and maintaining neuropathic pain in the chronic constriction injury model.

The new chemokine Prokineticin 2 (PROK2) and its receptors (PKR1 and PKR2) have a role in inflammatory pain and immunomodulation. Here we identified PROK2 as a critical mediator of neuropathic pain in the chronic constriction injury (CCI) of the sciatic nerve in mice and demonstrated that blocking the prokineticin receptors with two PKR1-preferring antagonists (PC1 and PC7) reduces pain and nerve damage. PROK2 mRNA expression was upregulated in the injured nerve since day 3 post injury (dpi) and in the ipsilateral DRG since 6 dpi. PROK2 protein overexpression was evident in Schwann Cells, infiltrating macrophages and axons in the peripheral nerve and in the neuronal bodies and some satellite cells in the DRG. Therapeutic treatment of neuropathic mice with the PKR-antagonist, PC1, impaired the PROK2 upregulation and signalling. This fact, besides alleviating pain, brought down the burden of proinflammatory cytokines in the damaged nerve and prompted an anti-inflammatory repair program. Such a treatment also reduced intraneural oedema and axon degeneration as demonstrated by the physiological skin innervation and thickness conserved in CCI-PC1 mice. These findings suggest that PROK2 plays a crucial role in neuropathic pain and might represent a novel target of treatment for this disease.

A new convenient synthetic method and preliminary pharmacological characterization of triazinediones as prokineticin receptor antagonists.

A new efficient synthetic method to obtain prokineticin receptor antagonists based on the triazinedione scaffold is described. In this procedure the overall yield improves from 13% to about 54%, essentially for two factors: 1) N-(chlorocarbonyl) isocyanate is no more used, it represents the yield limiting step with an average yield not exceeding 30%. 2) The Mitsunobu reaction is not involved in the new synthetic scheme avoiding the use of time and solvent consuming column chromatography. All synthesized triazinediones were preliminary pharmacologically screened in vivo for their ability to reduce the Bv8-induced thermal hyperalgesia. In this assay all compounds displayed EC50 values in the picomolar-subpicomolar range, some triazinediones containing a 4-halogen substituted benzyl group in position 5 showed the best activity. The analogues containing a 4-fluorine atom (PC-7) and a 4-bromobenzyl group (PC-25) resulted 10 times more potent than the reference PC-1 that bears a 4-ethylbenzyl group. While the 4-trifluoromethylbenzyl substituted analog (PC-27) was 100 times more potent as compared to PC1.

Age-related changes of protein SUMOylation balance in the AßPP Tg2576 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a complex disorder that affects the central nervous system causing a severe neurodegeneration. This pathology affects an increasing number of people worldwide due to the overall aging of the human population. In recent years SUMO protein modification has emerged as a possible cellular mechanism involved in AD. Some of the proteins engaged in the physiopathological process of AD, like BACE1, GSK3-ß tau, AßPP, and JNK, are in fact subject to protein SUMO modifications or interactions. Here, we have investigated the SUMO/deSUMOylation balance and SUMO-related proteins during the onset and progression of the pathology in the Tg2576 mouse model of AD. We examined four age-stages (1.5, 3, 6, 17 months old) and observed shows an increase in SUMO-1 protein conjugation at 3 and 6 months in transgenic mice with respect to WT in both cortex and hippocampus. Interestingly this is paralleled by increased expression levels of Ubc9 and SENP1 in both brain regions. At 6 months of age also the SUMO-1 mRNA resulted augmented. SUMO-2-ylation was surprisingly decreased in old transgenic mice and was unaltered in the other time windows. The fact that alterations in SUMO/deSUMOylation equilibrium occur from the early phases of AD suggests that global posttranslational modifications may play an important role in the mechanisms underlying disease pathogenesis, thus providing potential targets for pharmacological interventions.

Kinetics of string-gel formation in a system of dipolar colloidal particles.

The formation of string-gels of dipolar colloidal particles is investigated using molecular dynamics simulations. The characteristic gelation time consistently increases as the temperature of the system increases; it also increases as the density of the system increases. This latter result suggests that the gel formation is not a simple nucleation process. In particular, the energy barriers separating the embryonic nuclei from the final phase appear to be lower for the low-density system, suggesting an important entropic contribution.

Rocking ratchets in two-dimensional Josephson networks: collective effects and current reversal.

A detailed numerical study on the directed motion of ac-driven vortices and antivortices in 2D Josephson junction arrays with an asymmetric periodic pinning potential is reported. dc-voltage rectification shows a strong dependence on vortex density as well as an inversion of the vortex flow direction with ac amplitude for a wide range of vortex density around f = 1/2 (f = Ha(2)/Phi(0)), in good agreement with recent experiments by Shalóm and Pastoriza [Phys. Rev. Lett. 94, 177001 (2005)10.1103/PhysRevLett.94.177001]. The study of vortex structures, spatial and temporal correlations, and vortex-antivortex pairs formation gives insight into a purely collective mechanism behind the current reversal effect.