The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice

MiR-221 and miR-222 are two highly homologous microRNAs whose upregulation has been recently described in several types of human tumors, for some of which their oncogenic role was explained by the discovery of their target p27, a key cell cycle regulator. We previously showed this regulatory relationship in prostate carcinoma cell lines in vitro, underlying the role of miR-221/222 as inducers of proliferation and tumorigenicity

Impact of Serotonin 2C Receptor Null Mutation on Physiology and Behavior Associated with Nigrostriatal Dopamine Pathway Function

The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT2CR) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT2CRs produces marked alterations in the activity and functional output of this pathway. 5-HT2CR mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of D-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D1 receptor agonist SKF 81297. Differences in DSt D1 or D2 receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT2CRs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt

The α5 Subunit Regulates the Expression and Function of α4*-Containing Neuronal Nicotinic Acetylcholine Receptors in the Ventral-Tegmental Area

Human genetic association studies have shown gene variants in the α5 subunit of the neuronal nicotinic receptor (nAChR) influence both ethanol and nicotine dependence. The α5 subunit is an accessory subunit that facilitates α4* nAChRs assembly in vitro. However, it is unknown whether this occurs in the brain, as there are few research tools to adequately address this question. As the α4*-containing nAChRs are highly expressed in the ventral tegmental area (VTA) we assessed the molecular, functional and pharmacological roles of α5 in α4*-containing nAChRs in the VTA. We utilized transgenic mice α5+/+(α4YFP) and α5-/-(α4YFP) that allow the direct visualization and measurement of α4-YFP expression and the effect of the presence (α5+/+) and absence of α5 (-/-) subunit, as the antibodies for detecting the α4* subunits of the nAChR are not specific. We performed voltage clamp electrophysiological experiments to study baseline nicotinic currents in VTA dopaminergic neurons. We show that in the presence of the α5 subunit, the overall expression of α4 subunit is increased significantly by 60% in the VTA. Furthermore, the α5 subunit strengthens baseline nAChR currents, suggesting the increased expression of α4* nAChRs to be likely on the cell surface. While the presence of the α5 subunit blunts the desensitization of nAChRs following nicotine exposure, it does not alter the amount of ethanol potentiation of VTA dopaminergic neurons. Our data demonstrates a major regulatory role for the α5 subunit in both the maintenance of α4*-containing nAChRs expression and in modulating nicotinic currents in VTA dopaminergic neurons. Additionally, the α5α4* nAChR in VTA dopaminergic neurons regulates the effect of nicotine but not ethanol on currents. Together, the data suggest that the α5 subunit is critical for controlling the expression and functional role of a population of α4*-containing nAChRs in the VTA

Fever episodes in early life and the development of atopy in children with asthma

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Dynamics of the Hubbard model: a general approach by time dependent variational principle

We describe the quantum dynamics of the Hubbard model at semi-classical level, by implementing the Time-Dependent Variational Principle (TDVP) procedure on appropriate macroscopic wavefunctions constructed in terms of su(2)-coherent states. Within the TDVP procedure, such states turn out to include a time-dependent quantum phase, part of which can be recognized as Berry's phase. We derive two new semi-classical model Hamiltonians for describing the dynamics in the paramagnetic, superconducting, antiferromagnetic and charge density wave phases and solve the corresponding canonical equations of motion in various cases. Noticeably, a vortex-like ground state phase dynamics is found to take place for U>0 away from half filling. Moreover, it appears that an oscillatory-like ground state dynamics survives at the Fermi surface at half-filling for any U. The low-energy dynamics is also exactly solved by separating fast and slow variables. The role of the time-dependent phase is shown to be particularly interesting in the ordered phases.Comment: ReVTeX file, 38 pages, to appear on Phys. Rev.

Resonance- and Chaos-Assisted Tunneling

We consider dynamical tunneling between two symmetry-related regular islands that are separated in phase space by a chaotic sea. Such tunneling processes are dominantly governed by nonlinear resonances, which induce a coupling mechanism between ``regular'' quantum states within and ``chaotic'' states outside the islands. By means of a random matrix ansatz for the chaotic part of the Hamiltonian, one can show that the corresponding coupling matrix element directly determines the level splitting between the symmetric and the antisymmetric eigenstates of the pair of islands. We show in detail how this matrix element can be expressed in terms of elementary classical quantities that are associated with the resonance. The validity of this theory is demonstrated with the kicked Harper model.Comment: 25 pages, 5 figure

Resonance-assisted tunneling in near-integrable systems

Dynamical tunneling between symmetry related invariant tori is studied in the near-integrable regime. Using the kicked Harper model as an illustration, we show that the exponential decay of the wave functions in the classically forbidden region is modified due to coupling processes that are mediated by classical resonances. This mechanism leads to a substantial deviation of the splitting between quasi-degenerate eigenvalues from the purely exponential decrease with 1 / hbar obtained for the integrable system. A simple semiclassical framework, which takes into account the effect of the resonance substructure on the KAM tori, allows to quantitatively reproduce the behavior of the eigenvalue splittings.Comment: 4 pages, 2 figures, gzipped tar file, to appear in Phys. Rev. Lett, text slightly condensed compared to first versio

Sometimes it is better to just make it simple. De-escalation of oncoplastic and reconstructive procedures

© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Simple breast conservation surgery (sBCS) has technically advanced onto oncoplastic breast procedures (OBP) to avoid mastectomy and improve breast cancer patients' psychosocial well-being and cosmetic outcome. Although OBP are time-consuming and expensive, we are witnessing an increase in their use, even for cases that could be managed with sBCS. The choice between keeping it simple or opting for more complex oncoplastic procedures is difficult. This review proposes a pragmatic approach in assisting this decision. Medical literature suggests that OBP and sBCS might be similar regarding local recurrence and overall survival, and patients seem to have higher satisfaction levels with the aesthetic outcome of OBP when compared to sBCS. However, the lack of comprehensive high-quality research assessing their safety, efficacy, and patient-reported outcomes hinders these supposed conclusions. Postoperative complications after OBP may delay the initiation of adjuvant RT. In addition, precise displacement of the breast volume is not effectively recorded despite surgical clips placement, making accurate dose delivery tricky for radiation oncologists, and WBRT preferable to APBI in complex OBP cases. With a critical eye on financial toxicity, patient satisfaction, and oncological outcomes, OBP must be carefully integrated into clinical practice. The thoughtful provision of informed consent is essential for decision-making between sBCS and OBP. As we look into the future, machine learning and artificial intelligence can potentially help patients and doctors avoid postoperative regrets by setting realistic aesthetic expectations.Eduard-Alexandru Bonci’s work has been supported by a UICC Technical Fellowship [grant number UICC-TF/2022-1429].info:eu-repo/semantics/publishedVersio

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here