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CDC7 kinase is crucial for DNA replication initiation and is involved in fork processing and replication stress response. Human CDC7 requires the binding of either DBF4 or DRF1 for its activity. However, it is unclear whether the two regulatory subunits target CDC7 to a specific set of substrates, thus having different biological functions, or if they act redundantly. Using genome editing technology, we generated isogenic cell lines deficient in either DBF4 or DRF1: these cells are viable but present signs of genomic instability, indicating that both can independently support CDC7 for bulk DNA replication. Nonetheless, DBF4-deficient cells show altered replication efficiency, partial deficiency in MCM helicase phosphorylation, and alterations in the replication timing of discrete genomic regions. Notably, we find that CDC7 function at replication forks is entirely dependent on DBF4 and not on DRF1. Thus, DBF4 is the primary regulator of CDC7 activity, mediating most of its functions in unperturbed DNA replication and upon replication interference. [ABSTRACT FROM AUTHOR]

Background/ObjectivesSharing the bed with a partner is common among adults and impacts sleep quality with potential implications for mental health. However, hitherto findings are contradictory and particularly polysomnographic data on co-sleeping couples are extremely rare. The present study aimed to investigate the effects of a bed partner's presence on individual and dyadic sleep neurophysiology.MethodsYoung healthy heterosexual couples underwent sleep-lab-based polysomnography of two sleeping arrangements: individual sleep and co-sleep. Individual and dyadic sleep parameters (i.e., synchronization of sleep stages) were collected. The latter were assessed using cross-recurrence quantification analysis. Additionally, subjective sleep quality, relationship characteristics, and chronotype were monitored. Data were analyzed comparing co-sleep vs. individual sleep. Interaction effects of the sleeping arrangement with gender, chronotype, or relationship characteristics were moreover tested.ResultsAs compared to sleeping individually, co-sleeping was associated with about 10% more REM sleep, less fragmented REM sleep (p = 0.008), longer undisturbed REM fragments (p = 0.0006), and more limb movements (p = 0.007). None of the other sleep stages was significantly altered. Social support interacted with sleeping arrangement in a way that individuals with suboptimal social support showed the biggest impact of the sleeping arrangement on REM sleep. Sleep architectures were more synchronized between partners during co-sleep (p = 0.005) even if wake phases were excluded (p = 0.022). Moreover, sleep architectures are significantly coupled across a lag of ± 5min. Depth of relationship represented an additional significant main effect regarding synchronization, reflecting a positive association between the two. Neither REM sleep nor synchronization was influenced by gender, chronotype, or other relationship characteristics.ConclusionDepending on the sleeping arrangement, couple's sleep architecture and synchronization show alterations that are modified by relationship characteristics. We discuss that these alterations could be part of a self-enhancing feedback loop of REM sleep and sociality and a mechanism through which sociality prevents mental illness.

Checkpoint kinases control cell cycle progression via the regulation of many key regulators. Here the authors demonstrate how HDAC1 and HDAC2 modulate checkpoint kinase signalling via the suppression of PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2.

Type I/II interferons (IFNα,β/IFNɣ) are cytokines that activate signal-transducer-and-activator-of-transcription-1 (STAT1). The STAT1 N-terminal domain (NTD) mediates dimerization and cooperative DNA-binding. The STAT1 DNA-binding domain (DBD) confers sequence-specific DNA-recognition. STAT1 has been connected to growth inhibition, replication stress and DNA-damage. We investigated how STAT1 and NTD/DBD mutants thereof affect fibrosarcoma cells. STAT1 and indicated mutants do not affect proliferation of resting and IFNα-treated cells as well as checkpoint kinase signaling, and phosphorylation of the tumor-suppressive transcription factor p53 ensuing ɣ-irradiation. Of the STAT1 reconstituted U3A cells those with STAT1 NTD mutants accumulate the highest levels of the replication stress/DNA-damage marker S139-phosphorylated histone H2AX (ɣH2AX). This is similarly seen with a STAT1 NTD/DBD double mutant, indicating transcription-independent effects. Furthermore, U3A cells with STAT1 NTD mutants are most susceptible to apoptotic DNA fragmentation and cleavage of the DNA repair protein PARP1. These data provide novel insights into the relevance of the STAT1 NTD.

[This corrects the article DOI: 10.1371/journal.pone.0198890.].

Sleep's relevance for long-term social functioning in psychiatric disorders has been widely overlooked so far. Here, we investigate social functioning in a transdiagnostic sample of 31 patients with severe mental illness, namely schizophrenia (n = 15) or major depression (n = 16), in relation to their polysomnographic sleep characteristics 6 (± 2.4) years earlier. In addition, cognitive performance at follow-up and clinical characteristics (i.e., severity of disorder-related symptoms and number of hospitalizations between baseline and follow-up) are assessed. Multiple regression analysis results in a model with slow-wave sleep (SWS) and number of hospitalizations as significant predictors accounting for 50% (R2 = 0.507; p

Depression is a global health problem associated with a significant public health burden and costs. Although studies on costs of diseases are being considered as an increasingly important factor for health policies, information concerning costs of inpatient care of depression is still insufficient. Thus, the main aim of this study was to evaluate costs of hospitalization of patients treated in 2016 in psychiatric clinics in Poznan (Poland) and in Kiel (Germany) and to analyze treatment used in these centers. The study was conducted from September 2017 to February 2018. 545 hospital records were considered (187 in Poznan and 358 in Kiel). Eventually, 490 hospital records were included, 168 in Poland and 322 in Germany. In general, the costs were calculated based on the patients' sex and diagnosis (F32 and F33) separately and, subsequently, the outcomes were added and multiplied by the length of hospital stay, giving the cost of hospitalization. The annual cost of inpatient care of depression in 2016 was EUR 491,067.19 ([Formula: see text]) in Poznan and EUR 2,847,991.00 [Formula: see text] in Kiel. In Poznan, hospitalization was underfunded reaching EUR 183,042.55 (37.27% of total costs in Poznan). In Poznan, the most frequently prescribed medicine was quetiapine, followed by olanzapine and venlafaxine, whereas in Kiel it was venlafaxine, followed by mirtazapine and promethazine. Although non-pharmacological therapies were commonly used in both centers, in Kiel this type of treatment was better structured. The study confirms the degree of the economic burden of inpatient care of depression. The underfunding of mental health revealed, emphasizes the need for urgent amendment of organization and funding of mental health care in Poland. Patients in Poznan were hospitalized on average 10 days longer than in Kiel, thus a reduction of length of hospitalization in Poznan seems possible. Although pharmacotherapy seemed to be comprehensive in both centers, there were some differences between Poznan and Kiel. Access to non-pharmacological therapies during outpatient care was limited in Poznan, however, compared to Kiel.

Lipoic acid (LA) is a redox-active disulphide compound, which functions as a pivotal co-factor for mitochondrial oxidative decarboxylation. LA and chemical derivatives were shown to target mitochondria in cancer cells with altered energy metabolism, thereby inducing cell death. In this study, the impact of LA on the tumor suppressor protein p53 was analyzed in various colorectal cancer (CRC) cell lines, with a focus on the mechanisms driving p53 degradation. First, LA was demonstrated to trigger the depletion of both wildtype and mutant p53 protein in all CRC cells tested without influencing its gene expression and preceded LA-triggered cytotoxicity. Depletion of p53 coincided with a moderate, LA-dependent ROS production, but was not rescued by antioxidant treatment. LA induced the autophagy receptor p62 and differentially modulated autophagosome formation in CRC cells. However, p53 degradation was not mediated via autophagy as shown by chemical inhibition and genetic abrogation of autophagy. LA treatment also stabilized and activated the transcription factor Nrf2 in CRC cells, which was however dispensable for p53 degradation. Mechanistically, p53 was found to be readily ubiquitinylated and degraded by the proteasomal machinery following LA treatment, which did not involve the E3 ubiquitin ligase MDM2. Intriguingly, the combination of LA and anticancer drugs (doxorubicin, 5-fluorouracil) attenuated p53-mediated stabilization of p21 and resulted in synergistic killing in CRC cells in a p53-dependant manner.