Conformational dynamics of the human serotonin transporter during substrate and drug binding

The serotonin transporter (SERT) is responsible for re-uptake of serotonin into the presynaptic neuron and plays a key role in synaptic transmission. Here, the authors use hydrogen-deuterium exchange mass spectrometry to probe the conformational dynamics of human SERT in the absence and presence of known substrates and targeted drugs

Work-related psychosocial events as triggers of sick leave - results from a Swedish case-crossover study

<p>Abstract</p> <p>Background</p> <p>Although illness is an important cause of sick leave, it has also been suggested that non-medical risk factors may influence this association. If such factors impact on the period of decision making, they should be considered as triggers. Yet, there is no empirical support available.</p> <p>The aim was to investigate whether recent exposure to work-related psychosocial events can trigger the decision to report sick when ill.</p> <p>Methods</p> <p>A case-crossover design was applied to 546 sick-leave spells, extracted from a Swedish cohort of 1 430 employees with a 3-12 month follow-up of new sick-leave spells. Exposure in a case period corresponding to an induction period of one or two days was compared with exposure during control periods sampled from workdays during a two-week period prior to sick leave for the same individual. This was done according to the matched-pair interval and the usual frequency approaches. Results are presented as odds ratios (OR) with 95% confidence intervals (CI).</p> <p>Results</p> <p>Most sick-leave spells happened in relation to acute, minor illnesses that substantially reduced work ability. The risk of taking sick leave was increased when individuals had recently been exposed to problems in their relationship with a superior (OR 3.63; CI 1.44-9.14) or colleagues (OR 4.68; CI 1.43-15.29). Individuals were also more inclined to report sick on days when they expected a very stressful work situation than on a day when they were not under such stress (OR 2.27; CI 1.40-3.70).</p> <p>Conclusions</p> <p>Exposure to problems in workplace relationships or a stressful work situation seems to be able to trigger reporting sick. Psychosocial work-environmental factors appear to have a short-term effect on individuals when deciding to report sick.</p

Invasive cutaneous malignant melanoma in Sweden, 1990-1999 - A prospective, population-based study of survival and prognostic factors

BACKGROUND. The objective of the current study was to compile prospective, population-based data on cutaneous invasive melanomas in Sweden during the period from 1990 to 1999, to describe and analyze survival data and prognostic factors, and to make comparisons with previously published Swedish and international data. METHODS. Twelve thousand five hundred thirty-three patients, which included 97% of all registered melanomas in Sweden, were included and described. Among these, 9515 patients with clinical Stage I and II melanoma were included in an analysis of survival and in a univariate analysis, and 6191 patients were included in a multivariate analysis of prognostic factors. RESULTS. There was no significant change in melanoma incidence during 1990-1999. Favorable prognostic factors were found, especially in younger and female patients, resulting in a relative 5-year survival rate of 91.5%. In the multivariate analysis, significant factors that had a negative effect on survival were Clark level of invasion, Breslow thickness, ulceration, older patient age, trunk location, greatest tumor dimension, nodular histogenetic type, and male gender. CONCLUSIONS. During the period from 1990 to 1999, the 5-year survival of patients with malignant melanoma in Sweden was better compared with the previously reported rates in published, population-based studies from Sweden, probably as a result of better secondary prevention due to better knowledge and awareness by both patients and the medical profession. The more favorable prognostic factors and the change in melanoma location found in younger patients, compared with earlier reports, may reflect changes in clothing as well as tanning habits; however, a decrease also was found in Clark Level II and thin melanomas for the same patient group. The authors concluded that further improvements can be achieved with better access to health care and with the use of early melanoma detection campaigns. (C) 2004 American Cancer Society

A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene

International audienceDNA damage triggers chromatin remodeling by mechanisms that are poorly understood. The oncogene and chromatin remodeler ALC1/CHD1L massively decompacts chromatin in vivo yet is inactive prior to DNA-damage-mediated PARP1 induction. We show that the interaction of the ALC1 macrodomain with the ATPase module mediates auto-inhibition. PARP1 activation suppresses this inhibitory interaction. Crucially, release from auto-inhibition requires a poly-ADP-ribose (PAR) binding macrodomain. We identify tri-ADP-ribose as a potent PAR-mimic and synthetic allosteric effector that abrogates ATPase-macrodomain interactions, promotes an ungated conformation, and activates the remodeler’s ATPase. ALC1 fragments lacking the regulatory macrodomain relax chromatin in vivo without requiring PARP1 activation. Further, the ATPase restricts the macrodomain’s interaction with PARP1 under non-DNA damage conditions. Somatic cancer mutants disrupt ALC1’s auto-inhibition and activate chromatin remodeling. Our data show that the NAD+-metabolite and nucleic acid PAR triggers ALC1 to drive chromatin relaxation. Modular allostery in this oncogene tightly controls its robust, DNA-damage-dependent activation