Exact simulation of pigment-protein complexes unveils vibronic renormalization of electronic parameters in ultrafast spectroscopy.

The primary steps of photosynthesis rely on the generation, transport, and trapping of excitons in pigment-protein complexes (PPCs). Generically, PPCs possess highly structured vibrational spectra, combining many discrete intra-pigment modes and a quasi-continuous of protein modes, with vibrational and electronic couplings of comparable strength. The intricacy of the resulting vibronic dynamics poses significant challenges in establishing a quantitative connection between spectroscopic data and underlying microscopic models. Here we show how to address this challenge using numerically exact simulation methods by considering two model systems, namely the water-soluble chlorophyll-binding protein of cauliflower and the special pair of bacterial reaction centers. We demonstrate that the inclusion of the full multi-mode vibronic dynamics in numerical calculations of linear spectra leads to systematic and quantitatively significant corrections to electronic parameter estimation. These multi-mode vibronic effects are shown to be relevant in the longstanding discussion regarding the origin of long-lived oscillations in multidimensional nonlinear spectra.

RNF11 is a GGA protein cargo and acts as a molecular adaptor for GGA3 ubiquitination mediated by Itch.

Ring finger protein 11 (RNF11) is a RING (really interesting new gene)-H2 E3 ligase that is overexpressed in several human tumor tissues. The mature protein, which is anchored to membranes via a double acylation, localizes to early endosome and recycling compartments. Apart from its subcellular localization, additional lines of evidence implicate RNF11 in the mechanisms underlying vesicle traffic. Here we identify two acidic-cluster dileucine (Ac-LL) motifs, which are recognized by the VHS domains of Golgi-localized, gamma adaptin era-containing, ADP-ribosylation factor-binding protein (GGA) adaptors, as the molecular determinants governing RNF11 sorting at the trans-Golgi network and its internalization from the plasma membrane. We also show that RNF11 recruits itch to drive the ubiquitination of GGA3. This function is experimentally detectable only in cells overexpressing an RNF11 variant that is inactivated in the RING domain, indicating that RNF11 recruits GGA3 and controls its ubiquitination by regulating itch activity. Accordingly, our data demonstrate the involvement of itch in regulating GGA3 stability. Indeed, we observe that the endogenous levels of GGA3 are increased in cells knocked down for itch and endogenous GGA3 is hyperubiquitinated in an itch-dependent manner in a cell line expressing catalytically inactive RNF11. Our data are consistent with a model whereby the RING E3 ligase RNF11 is a novel GGA cargo actively participating in regulating the ubiquitination of the GGA protein family. The results that we are presenting put RNF11 at the center of a finally regulated system where it acts both as an adaptor and a modulator of itch-mediated control of ubiquitination events underlying membrane traffic.

Production of brain-derived neurotrophic factor by mononuclear cells of patients with multiple sclerosis treated with glatiramer acetate, interferon-beta 1a, and high doses of immunoglobulins.

Sixty, relapsing remitting (RR) multiple sclerosis (MS) patients, who underwent treatment with glatiramer acetate (GA), interferon (IFN)-beta 1a, and immunoglobulins (Igs) (20 per treatment group), were assessed for levels of brain-derived neurotrophic factor (BDNF) in the supernatants of unstimulated and stimulated peripheral blood mononuclear cells (PBMCs) in the first year of treatment. Phytohemagglutinin (PHA), anti-OKT3 antibody, myelin basic protein (MPB) and GA were used as stimuli. Cytokine responses by ELISPOT and lymphoproliferative responses were also assessed. The GA-treated MS patient group showed a progressive increase in BDNF levels, from baseline to month three; thereafter, the levels remained stable and significantly greater compared with baseline and controls (ANOVA=P<0.001). IFN-beta 1a had no effect on BDNF production, whereas Igs induced a slight decrease (ANOVA=P<0.04). ELISPOT analysis revealed a significant decrease of IFN-gamma, an increase of interleukin (IL)-4 and IL-5 in GA-treated MS patients, and an increase of IL-10 in patients treated with IFN-beta 1a and GA. No significant correlation was found between BDNF secretion in the supernatants of PBMCs and cytokine response, lesional load, and measures of atrophy. Increased BDNF production related to GA treatment can have implications for understanding the mechanism of action of this immunomodulatory agent, in light of evidence suggesting its effects in promoting neuroprotective immunity in MS patients; however, a clinically measurable effect, especially in terms of an impact on actual disease progression, remains to be established.

The role of neuroimaging in the diagnosis of headache in childhood and adolescence: a multicentre study.

Following the diagnostic indications of the Guidelines for the diagnosis and therapy of juvenile headache, we present the results of a prospective, multicentre study of headache patients aimed at evaluating the utility of neuroradiologic testing in the diagnosis of headache. A total of 6535 subjects up to age 18 were studied, and 1485 underwent neuroimaging testing based on the indications of the diagnostic Flow-Chart. Abnormal results were observed in 273 (18.5%) subjects. Incidental findings were observed in 138 (9.3%) subjects, not correlated with the headache pathology, whereas alterations that led to the diagnosis of secondary headache were observed in 135 (9.1%) subjects. In conclusion, our data support a greater incidence of positive neuroimaging examinations among patients who underwent testing based on suspicion of a secondary headache pathology when compared with the low percentages observed in study populations.

Delayed loss of residual hearing in Clarion cochlear implant users.

Hearing threshold has been measured in a group of patients following cochlear implantation with a Clarion device for the last eight years. The patients had received either a pre-curved carrier or the Hi-Focus I plus Electrode Positioner System (EPS). The assessment was carried out within the first post-operative week as well as at a later stage, between six and 87 months, post-operatively. Residual hearing thresholds were still measurable early after surgery in 24.5 per cent of the patients, without differences between the two different Clarion models. However, the number of subjects with measurable hearing dropped to 16.3 per cent as observed when hearing was measured at a later stage, with an equal distribution between the two groups of patients. From this study it has been possible to observe that only a limited number of patients maintain residual hearing after Clarion cochlear implantation, and that this tends to decrease further over time. Nevertheless, the performance of these patients for speech tests did not appear to be affected by deterioration of the pure-tone auditory threshold.

[Ethical problems in dialysis in elderly patients]. / L'etica nel paziente anziano in dialisi. Un'interpretazione del Centro Dialisi di Aosta.

The incidence and prevalence of elderly patients are progressively increasing in most dialysis facilities with consequent medical assistance difficulties and the need to find a suitable care unit. Particularly in this age group, the clinical assessment is often difficult and the selection criteria vary widely, not only from country to country, but also from one dialysis unit to another unit in the same area. The authors discuss some of the more complex arguments for and against dialysis in elderly patients. For some of the more difficult cases, Kantian deontology and its three ethical principles of beneficence, non-maleficence and autonomy can facilitate the decision-making process regarding the acceptance or refusal of the therapy. The central role of the patients themselves, the involvement of the family, the discussion of the individual case within the dialysis team, and the good performance of the pre-dialysis program are particularly important. In certain cases it is possible to actually discontinue the treatment, or not initiate it, by using different arguments in competent or incompetent patients. In conclusion, the difficult choice of whether to treat or turn down an elderly patient must depend exclusively on the medical clinical assessment of each case, whereas economical considerations can incorrectly influence that choice.

Auditory evoked potentials for the assessment of noise induced hearing loss.

As it has been demonstrated in many animal experiments, noise can damage the cochlea and the central auditory pathways. It is very difficult in clinical studies to separate the relative contribution of both these sites. Auditory evoked potentials ABR, MLR and SVR study retrocochlear nervous conduction and collectively the results of these techniques proved an objective evaluation of the cochlear function. The Authors have studied a group of 130 sport shooters with high frequency hearing loss and found that in 38 ears a clear retrocochlear component could be recognised. Correlation with intensity, frequency and length of exposure to the traumatic noise demonstrates that explosive noise is an agent for NIHL. However athletes exposed to similar noises did not suffer from similar hearing loss, probably because of the well known individual noise susceptibility.