Synaptic nanomodules underlie the organization and plasticity of spine synapses.

Experience results in long-lasting changes in dendritic spine size, yet how the molecular architecture of the synapse responds to plasticity remains poorly understood. Here a combined approach of multicolor stimulated emission depletion microscopy (STED) and confocal imaging in rat and mouse demonstrates that structural plasticity is linked to the addition of unitary synaptic nanomodules to spines. Spine synapses in vivo and in vitro contain discrete and aligned subdiffraction modules of pre- and postsynaptic proteins whose number scales linearly with spine size. Live-cell time-lapse super-resolution imaging reveals that NMDA receptor-dependent increases in spine size are accompanied both by enhanced mobility of pre- and postsynaptic modules that remain aligned with each other and by a coordinated increase in the number of nanomodules. These findings suggest a simplified model for experience-dependent structural plasticity relying on an unexpectedly modular nanomolecular architecture of synaptic proteins

Geometric limits of Mandelbrot and Julia sets under degree growth

First, for the family P_{n,c}(z) = z^n + c, we show that the geometric limit of the Mandelbrot sets M_n(P) as n tends to infinity exists and is the closed unit disk, and that the geometric limit of the Julia sets J(P_{n,c}) as n tends to infinity is the unit circle, at least when the modulus of c is not one. Then we establish similar results for some generalizations of this family; namely, the maps F_{t,c} (z) = z^t+c for real t>= 2, and the rational maps R_{n,c,a} (z) = z^n + c + a/z^n.Comment: 29 pages, 16 figures (34 pic files), submitte

Assessing the quality of ionogram interpretation using the HF Doppler technique

International audienceThe first joint common volume measurements by the Digisonde Portable Sounder (DPS-4) and a new Doppler type system has been run at the Pruhonice ionospheric observatory (49.99° N, 14.54° E) since January 2004. The measurement of the Doppler shift is carried out continuously on a frequency of 3.6 MHz, thus the radio wave is reflected predominantly from the ionospheric F layer. To compare digisonde measurements with the Doppler data, a phase path was calculated from both Doppler and digisonde records. Under stormy conditions and in the case where a sporadic E layer was present, a significant disagreement between both measurements has been found. The discrepancies could be related to the uncertainties of the observational inputs and to the interpretation of the digisonde data. The comparison of the phase paths shows that during geomagnetically quiet days, in the absence of the sporadic E layer, and when high quality ionograms are available and correctly scaled, the electron density N(h) profiles, calculated by the Automatic Real Time Ionogram Scaler with True height algorithm (ARTIST), can be considered reliable

Bedrock weathering and stream water chemistry in felsic and ultramafic forest catchments

Abstract not availablePavel Krám, Juraj Farkaš, Anna Pereponova, Chukwudi Nwaogu, Veronika Štědrá, Jakub Hrušk

Retargeting the \u3ci\u3eClostridium botulinum\u3c/i\u3e C2 toxin to the neuronal cytosol

Many biological toxins are known to attack specific cell types, delivering their enzymatic payloads to the cytosol. This process can be manipulated by molecular engineering of chimeric toxins. Using toxins with naturally unlinked components as a starting point is advantageous because it allows for the development of payloads separately from the binding/translocation components. Here the Clostridium botulinum C2 binding/translocation domain was retargeted to neural cell populations by deleting its non-specific binding domain and replacing it with a C. botulinum neurotoxin binding domain. This fusion protein was used to deliver fluorescently labeled payloads to Neuro-2a cells. Intracellular delivery was quantified by flow cytometry and found to be dependent on artificial enrichment of cells with the polysialoganglioside receptor GT1b. Visualization by confocal microscopy showed a dissociation of payloads from the early endosome indicating translocation of the chimeric toxin. The natural Clostridium botulinum C2 toxin was then delivered to human glioblastoma A172 and synchronized HeLa cells. In the presence of the fusion protein, native cytosolic enzymatic activity of the enzyme was observed and found to be GT1b-dependent. This retargeted toxin may enable delivery of therapeutics to peripheral neurons and be of use in addressing experimental questions about neural physiology

Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone-vascular paradox, a therapeutic target, and a biomarker

The chronic kidney disease-mineral bone disorder (CKD-MBD) is a complex multi-component syndrome occurring during kidney disease and its progression. Here, we update progress in the components of the syndrome, and synthesize recent investigations, which suggest a potential mechanism of the bone-vascular paradox. The discovery that calcified arteries in chronic kidney disease inhibit bone remodeling lead to the identification of factors produced by the vasculature that inhibit the skeleton, thus providing a potential explanation for the bone-vascular paradox. Among the factors produced by calcifying arteries, sclerostin secretion is especially enlightening. Sclerostin is a potent inhibitor of bone remodeling and an osteocyte specific protein. Its production by the vasculature in chronic kidney disease identifies the key role of vascular cell osteoblastic/osteocytic transdifferentiation in vascular calcification and renal osteodystrophy. Subsequent studies showing that inhibition of sclerostin activity by a monoclonal antibody improved bone remodeling as expected, but stimulated vascular calcification, demonstrate that vascular sclerostin functions to brake the Wnt stimulation of the calcification milieu. Thus, the target of therapy in the chronic kidney disease-mineral bone disorder is not inhibition of sclerostin function, which would intensify vascular calcification. Rather, decreasing sclerostin production by decreasing the vascular osteoblastic/osteocytic transdifferentiation is the goal. This might decrease vascular calcification, decrease vascular stiffness, decrease cardiac hypertrophy, decrease sclerostin production, reduce serum sclerostin and improve skeletal remodeling. Thus, the therapeutic target of the chronic kidney disease-mineral bone disorder may be vascular osteoblastic transdifferentiation, and sclerostin levels may be a useful biomarker for the diagnosis of the chronic kidney disease-mineral bone disorder and the progress of its therapy

CAT(0) spaces with polynomial divergence of geodesics

We construct a family of finite 2-complexes whose universal covers are CAT(0) and have polynomial divergence of desired degree. This answers a question of Gersten, namely whether such CAT(0) complexes exist

Patterns of co-occurring addictions, PTSD, and MDD in detoxification treatment seekers: Implications for improving detoxification treatment outcomes

Background and objectives Poly-substance use and psychiatric comorbidity are common among individuals receiving substance detoxification services. Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are the most common co-occurring psychiatric disorders with substance use disorder (SUD). Current treatment favors a one-size-fits-all approach to treating addiction focusing on one substance or one comorbidity. Research examining patterns of substance use and comorbidities can inform efforts to effectively identify and differentially treat individuals with co-occurring conditions. Methods Using latent class analysis, the current study identified four patterns of PTSD, MDD, and substance use among 375 addiction treatment seekers receiving medically supervised detoxification. Results The four identified classes were: 1) a PTSD-MDD-Poly SUD class characterized by PTSD and MDD occurring in the context of opioid, cannabis, and tobacco use disorders; 2) an MDD-Poly SUD class characterized by MDD and alcohol, opioid, tobacco, and cannabis use disorders; 3) an alcohol-tobacco class characterized by alcohol and tobacco use disorders; and 4) an opioid-tobacco use disorder class characterized by opioid and tobacco use disorders. The observed classes differed on gender and clinical characteristics including addiction severity, trauma history, and PTSD/MDD symptom severity. Discussion and conclusions The observed classes likely require differing treatment approaches. For example, people in the PTSD-MDD-Poly SUD class would likely benefit from treatment approaches targeting anxiety sensitivity and distress tolerance, while the opioid-tobacco class would benefit from treatments that incorporate motivational interviewing. Appropriate matching of treatment to class could optimize treatment outcomes for polysubstance and comorbid psychiatric treatment seekers. These findings also underscore the importance of well-developed referral networks to optimize outpatient psychotherapy for detoxification treatment-seekers to enhance long-term recovery, particularly those that include transdiagnostic treatment components