DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of lamin A/C.

The integrity of the nuclear envelope (NE) is essential for maintaining the structural stability of the nucleus. Rupture of the NE has been frequently observed in cancer cells, especially in the context of mechanical challenges, such as physical confinement and migration. However, spontaneous NE rupture events, without any obvious physical challenges to the cell, have also been described. The molecular mechanism(s) of these spontaneous NE rupture events remain to be explored. Here, we show that DNA damage and subsequent ATR activation leads to NE rupture. Upon DNA damage, lamin A/C is phosphorylated in an ATR-dependent manner, leading to changes in lamina assembly and, ultimately, NE rupture. In addition, we show that cancer cells with intrinsic DNA repair defects undergo frequent events of DNA-damage-induced NE rupture, which renders them extremely sensitive to further NE perturbations. Exploiting this NE vulnerability could provide a new angle to complement traditional, DNA-damage-based chemotherapy.

Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis.

DNA double-strand breaks (DSBs) are deleterious lesions that challenge genome integrity. To mitigate this threat, human cells rely on the activity of multiple DNA repair machineries that are tightly regulated throughout the cell cycle1. In interphase, DSBs are mainly repaired by non-homologous end joining and homologous recombination2. However, these pathways are completely inhibited in mitosis3-5, leaving the fate of mitotic DSBs unknown. Here we show that DNA polymerase theta6 (Polθ) repairs mitotic DSBs and thereby maintains genome integrity. In contrast to other DSB repair factors, Polθ function is activated in mitosis upon phosphorylation by Polo-like kinase 1 (PLK1). Phosphorylated Polθ is recruited by a direct interaction with the BRCA1 C-terminal domains of TOPBP1 to mitotic DSBs, where it mediates joining of broken DNA ends. Loss of Polθ leads to defective repair of mitotic DSBs, resulting in a loss of genome integrity. This is further exacerbated in cells that are deficient in homologous recombination, where loss of mitotic DSB repair by Polθ results in cell death. Our results identify mitotic DSB repair as the underlying cause of synthetic lethality between Polθ and homologous recombination. Together, our findings reveal the critical importance of mitotic DSB repair in the maintenance of genome integrity.

Quality-of-life outcomes with endoscopic and microscopic type I tympanoplasty-a prospective cohort study.

PURPOSE: Endoscopic type I tympanoplasty was originally introduced in the 1990s and the extensive spread of this practice can be easily observed. The conventional technique performed involves the repair of a tympanic membrane perforation and is defined as microscopic type I tympanoplasty. The aim of this study is the comparison of quality-of-life (QoL) outcomes with endoscopic to that with microscopic type I tympanoplasty. METHODS: All patients, or in the case of children with the aid of a parent, were asked to complete a novel QoL questionnaire drafted by our study group. The analysis was performed with descriptive statistics-mean, SD and relative frequency-and with a mixed model (generalized least squares fit). A two-sided p value of < 0.05 was regarded as statistically significant. RESULTS: A total of 83 patients completed the questionnaire, 38 in the endoscopic group and 45 in the microscopic group. Every question represented a different. A statistically significant result was found in favor of the endoscopic approach regarding average hospitalization rate (p = 0.003) and cosmetic outcomes (p = 0.015). No statistically significant difference was otherwise observed between the groups. CONCLUSIONS: Based on our prospective cohort study, the QoL outcomes of endoscopic type I tympanoplasty in terms of postoperative pain, headache, nausea, vomiting, dizziness, taste disorder and hearing were comparable to the microscopic type I tympanoplasty. In regard to cosmetics, an increase in desirable results was achieved in the endoscopic group, particularly the average hospitalization rate proved to be statistically significantly lower than in the microscopic group.

Functional Connectivity Lateralisation Shift of Resting State Networks is Linked to Visuospatial Memory and White Matter Microstructure in Relapsing-Remitting Multiple Sclerosis.

Laterality patterns of resting state networks (RSN) change in various neuropsychiatric conditions. Multiple sclerosis (MS) causes neuro-cognitive symptoms involving dysfunctional large-scale brain networks. Yet, whether healthy laterality patterns of RSNs are maintained in MS and whether altered laterality patterns explain disease symptoms has not been explicitly investigated. We analysed functional MRI and diffusion tensor imaging data from 24 relapsing-remitting MS patients and 25 healthy participants. We performed group-level independent component analysis and used dual regression to estimate individual versions of well-established RSNs. Voxelwise laterality indices were calculated for each RSN. Group differences were assessed via a general linear model-based approach. The relationship between functional laterality and white matter microstructural asymmetry was assessed using Tract-Based Spatial Statistics. Spearman's correlation was calculated between laterality indices and Brief International Cognitive Assessment for Multiple Sclerosis scores. Functional laterality of the dorsal attention network showed a significant leftward shift in the MS group in the posterior intraparietal sulcus (p < 0.033). Default-mode network laterality showed a significant leftward shift in the MS group in the angular gyrus (p < 0.005). Diminished dorsal attention network laterality was associated with increased fractional anisotropy asymmetry in the superior longitudinal fasciculus (p < 0.02). In the default-mode network, leftward laterality of the angular gyrus was associated with higher BVMT-R scores (R = - 0.52, p < 0.023). Our results confirm previous descriptions of RSN dysfunction in relapsing-remitting MS and show that altered functional connectivity lateralisation patterns of RSNs might contibute to cognitive performance and structural remodellation even in patients with mild clinical symptoms.

PhaSePro: the database of proteins driving liquid-liquid phase separation.

Membraneless organelles (MOs) are dynamic liquid condensates that host a variety of specific cellular processes, such as ribosome biogenesis or RNA degradation. MOs form through liquid-liquid phase separation (LLPS), a process that relies on multivalent weak interactions of the constituent proteins and other macromolecules. Since the first discoveries of certain proteins being able to drive LLPS, it emerged as a general mechanism for the effective organization of cellular space that is exploited in all kingdoms of life. While numerous experimental studies report novel cases, the computational identification of LLPS drivers is lagging behind, and many open questions remain about the sequence determinants, composition, regulation and biological relevance of the resulting condensates. Our limited ability to overcome these issues is largely due to the lack of a dedicated LLPS database. Therefore, here we introduce PhaSePro (https://phasepro.elte.hu), an openly accessible, comprehensive, manually curated database of experimentally validated LLPS driver proteins/protein regions. It not only provides a wealth of information on such systems, but improves the standardization of data by introducing novel LLPS-specific controlled vocabularies. PhaSePro can be accessed through an appealing, user-friendly interface and thus has definite potential to become the central resource in this dynamically developing field.

["Praecox-Gefühl". A brief look].

No abstract available.

[The immunological background of particular neurodevelopmental disorders].

No abstract avalilable.

[Diogenes Syndrome - case reports].

No abstract avalilable.

Are the MDS-UPDRS-Based Composite Scores Clinically Applicable?

BACKGROUND: The International Parkinson and Movement Disorder Society-sponsored UPDRS (MDS-UPDRS) is a powerful clinical outcome measure. OBJECTIVES: To evaluate the feasibility of various MDS-UPDRS-based composite scores and determine their minimal clinically important difference threshold values. METHODS: Overall, 1,113 paired investigations of 452 patients were reviewed implementing three different techniques simultaneously. RESULTS: Based on the ordinal regression modeling, the MDS-UPDRS II+III, MDS-UPDRS I+II+III, and the total score of MDS-UPDRS are clinically applicable outcome measures. Any improvement greater than 4.9 points or any worsening more than 4.2 points on MDS-UPDRS II+III represent a minimal, yet clinically meaningful, change. In reference to MDS-UPDRS I+II+III, the smallest changes considered clinically relevant were 6.7 and 5.2 points for improvement and deterioration, respectively. The thresholds for the total score of MDS-UPDRS were 7.1 points for improvement and 6.3 points for worsening. CONCLUSIONS: Our findings support the application of various MDS-UPDRS-based composite scores. © 2018 International Parkinson and Movement Disorder Society.

Minimal clinically important differences for the experiences of daily living parts of movement disorder society-sponsored unified Parkinson's disease rating scale.

BACKGROUND: The minimal clinically important difference is the smallest change of scores clinically meaningful to patients. OBJECTIVES: We aimed to calculate these threshold values in association with the International Parkinson and Movement Disorder Society UPDRS (MDS-UPDRS) Parts I and II and to evaluate the feasibility of the composite score of Part I and II (MDS-UPDRS I+II) as an outcome. METHODS: Nine hundred eighty-five paired investigations of 365 patients were reviewed, implementing three different techniques simultaneously. RESULTS: Based on the ordinal regression modeling, the MDS-UPDRS I+II score is an applicable outcome measure. Any improvement greater than 2.64 points or any worsening more than 2.45 points on MDS-UPDRS Part I represent a minimal, yet clinically meaningful change. In reference to Part II, the smallest changes considered clinically relevant were 3.05 and 2.51 points for improvement and deterioration, respectively. The thresholds for MDS-UPDRS I+II were 5.73 points for improvement and 4.70 points for worsening. CONCLUSIONS: Our minimal clinically important difference thresholds can be utilized in clinical practice in judging clinical relevance. © 2016 International Parkinson and Movement Disorder Society.

Changes in Quality of Life in Parkinson's Disease: How Large Must They Be to Be Relevant?

BACKGROUND: Minimal clinically important difference (MCID) is the smallest change in an outcome, which a patient identifies as meaningful. Although the 2 most frequently applied Parkinson's disease (PD) "quality of life" questionnaires (the PDQ-39 and PDQ-8) provide encouragingly similar results, their MCID thresholds appear to be vastly different. Our aim was to calculate the MCID estimates for both PDQ-39 and PDQ-8 Summary Indices (PDQ-39-SI and PDQ-8-SI) by the utilization of both anchor- and distribution-based techniques. METHODS: Nine hundred eighty-five paired investigations of 365 patients were included. Three different techniques were used simultaneously to calculate the MCID values. RESULTS: First, we replicated the previously published results demonstrating how both PDQ-39-SI and PDQ-8-SI provide similar values and respond in a similar way to changes. Subsequently, we calculated the MCID thresholds. The most optimal estimates for MCID thresholds for PDQ-39-SI were -4.72 and +4.22 for detecting minimal clinically important improvement and worsening. For PDQ-8-SI, these estimates were -5.94 and +4.91 points for detecting minimal clinically important improvement and worsening respectively. CONCLUSIONS: Our study is the first one that directly compared the MCID estimates for both PDQ-39-SI and PDQ-8-SI on a large pool of patients including all disease severity stages. These MICD estimates varied across PD severity.

How Efficient Is Subthalamic Deep Brain Stimulation in Reducing Dyskinesia in Parkinson's Disease?

BACKGROUND: Dyskinesia is among the most troublesome symptoms of advanced Parkinson's disease (PD). The recently developed Unified Dyskinesia Rating Scale (UDysRS) can simultaneously measure several subjective and objective aspects of dyskinesia, irrespective of the other motor symptoms of PD. Despite the advantages of deep brain stimulation (DBS), previous studies on DBS have not used the UDysRS yet. METHODS: In this prospective study, 71 consecutive patients undergoing DBS implantation were enrolled. Patients were examined twice: 1 week prior to the DBS implantation (baseline) and 12 months postoperatively. The severity of PD-related symptoms was assessed by the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS). The presence and severity of dyskinesia were specifically measured by the UDysRS and patient diaries. RESULTS: At baseline, all 71 patients had dyskinesia, but 1 year after DBS implantation, 25 patients were dyskinesia-free, and an additional 19 had only mild dyskinesia. The total score on the UDysRS decreased from 38.0 ± 17.8 to 10.8 ± 13.0 (p < 0.001). Besides this, all parts of the UDysRS showed significant improvement after STN DBS treatment, and the magnitude of these changes had a large effect size. The total score of MDS-UPDRS improved from 76.5 ± 24.3 to 60.4 ± 21.4 points (p < 0.001). CONCLUSIONS: Based on our results, UDysRS can reliably detect improvements in dyskinesia after DBS implantation.

Independent validation of the Quality of Life in Essential Tremor Questionnaire (QUEST).

BACKGROUND AND PURPOSE: Quality of Life in Essential Tremor Questionnaire (QUEST) was specially developed for essential tremor population to measure the health-related quality of life. Besides the development of the Hungarian version, we performed an independent testing of the scale adding further information on its clinimetric properties. METHODS: In this study 133 ET patients treated at University of Pécs, Hungary, were enrolled. Besides QUEST, we assessed Patient's Global Impression-Severity (PGI-S) and Fahn-Tolosa-Marin Tremor Rating Scales. After the independent validation in accordance to the Classic Theory of Tests, we evaluated cut-off values for detecting clinically meaningful ET-related disabilities based on receiver operating characteristics analysis. RESULTS: Cronbach's a was 0.897. QUEST demonstrated high convergent validity with PGI and divergent validity with disease-duration, positive family history, need for deep brain stimulation surgery, and the presence of depression and anxiety. Presence of moderate ET-related disabilities was identified by scores > 11.25 points on QUEST-SI (sensitivity: 77.4%, specificity: 83.3%); whereas scores > 20.35 points indicated severe ET-related disabilities (sensitivity: 83.3%, specificity: 59.1%). CONCLUSION: We demonstrated that the fundamental clinimetric properties of the QUEST are satisfactory.

[The immunological background of the pathogenesis of schizophrenia. A review of the literature].

No abstract available.

[Diagnosis and therapy for neurocognitive disorders in Parkinson's disease]. / Neurokognitív zavarok diagnosztizálási és kezelési lehetoségei Parkinson-kórban.

In the present review the recent developments in the definitions of neurocognitive disorders associated with Parkinson's disease are summarized including the possibilities for screening and treating. For a long time, the recognition of neurocognitive disorders associated in patients with Parkinson's disease was unsatisfactory due to the heterogeneity of definitions. The recently developed Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) introduced the definitions of mild and major neurocognitive disorders instead of mild cognitive impairment and dementia. The new DSM-5 definitions are clinically well applicable; therefore, the validation of the most frequent screening tests (Mini-Mental State Examination; Addenbrooke's Cognitive Examination; Montreal Cognitive Assessment; Mattis Dementia Rating Scale) is warranted. Based on a Hungarian sample of 295 patients with Parkinson's disease, the cut-off scores having the best discriminative values are highly dependent on education years (Addenbrooke's Cognitive Examination: 0-8 years of education: 82.5 points, 9-12 years of education: 83.5 points, and ≥13 years of education: 84.5 points; Mini-Mental State Examination: 26.5-27.5-28.5 points, Montreal Cognitive Assessment: 23.5-24.5-24.5 points, Mattis Dementia Rating Scale: 138.5-139.5-139.5 points, respectively).

Group authorship, an excellent opportunity laced with ethical, legal and technical challenges.

Group authorship (also known as corporate authorship, team authorship, consortium authorship) refers to attribution practices that use the name of a collective (be it team, group, project, corporation, or consortium) in the authorship byline. Data shows that group authorships are on the rise but thus far, in scholarly discussions about authorship, they have not gained much specific attention. Group authorship can minimize tensions within the group about authorship order and the criteria used for inclusion/exclusion of individual authors. However, current use of group authorships has drawbacks, such as ethical challenges associated with the attribution of credit and responsibilities, legal challenges regarding how copyrights are handled, and technical challenges related to the lack of persistent identifiers (PIDs), such as ORCID, for groups. We offer two recommendations: 1) Journals should develop and share context-specific and unambiguous guidelines for group authorship, for which they can use the four baseline requirements offered in this paper; 2) Using persistent identifiers for groups and consistent reporting of members' contributions should be facilitated through devising PIDs for groups and linking these to the ORCIDs of their individual contributors and the Digital Object Identifier (DOI) of the published item.

Age-dependent heat shock hormesis to HSF-1 deficiency suggests a compensatory mechanism mediated by the unfolded protein response and innate immunity in young Caenorhabditis elegans.

The transcription factor HSF-1 (heat shock factor 1) acts as a master regulator of heat shock response in eukaryotic cells to maintain cellular proteostasis. The protein has a protective role in preventing cells from undergoing ageing, and neurodegeneration, and also mediates tumorigenesis. Thus, modulating HSF-1 activity in humans has a promising therapeutic potential for treating these pathologies. Loss of HSF-1 function is usually associated with impaired stress tolerance. Contrary to this conventional knowledge, we show here that inactivation of HSF-1 in the nematode Caenorhabditis elegans results in increased thermotolerance at young adult stages, whereas HSF-1 deficiency in animals passing early adult stages indeed leads to decreased thermotolerance, as compared to wild-type. Furthermore, a gene expression analysis supports that in young adults, distinct cellular stress response and immunity-related signaling pathways become induced upon HSF-1 deficiency. We also demonstrate that increased tolerance to proteotoxic stress in HSF-1-depleted young worms requires the activity of the unfolded protein response of the endoplasmic reticulum and the SKN-1/Nrf2-mediated oxidative stress response pathway, as well as an innate immunity-related pathway, suggesting a mutual compensatory interaction between HSF-1 and these conserved stress response systems. A similar compensatory molecular network is likely to also operate in higher animal taxa, raising the possibility of an unexpected outcome when HSF-1 activity is manipulated in humans.

Investigation of peripheral inflammatory biomarkers in association with suicide risk in major depressive disorder.

Suicide is the most severe complication of major depressive disorder (MDD). Novel research assumes the role of immunological dysregulation in the background - several studies have reported alterations in the number of inflammatory cells related to both MDD and suicidality. There are currently no objective, routinely measured parameters to indicate suicidal vulnerability. However, altered inflammatory cell numbers and ratios have been proposed as potential biomarkers of suicide risk (SR). The present research aims to examine changes of these values related to increased SR in MDD as an assumed inflammatory state. We investigated laboratory parameters of psychiatric in-patients diagnosed with MDD (n = 101) retrospectively. Individuals with recent suicide attempt (SA) (n = 22) and with past SA (n = 19) represented the high SR group. MDD patients with no history of SA (n = 60) composed the intermediate SR group. We compared the number of neutrophil granulocytes, monocytes, lymphocytes, platelets, white blood cell count (WBC), neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), red blood cell distribution width (RDW) and erythrocyte sedimentation rate (ESR). Furthermore, we evaluated alterations of these parameters related to antidepressant (AD) and antipsychotic (AP) treatment, which have been proved to have anti-inflammatory effects. We found a significant increase in neutrophil granulocyte count, NLR, monocyte count, MLR, WBC and ESR in patients with recent SA compared to patients with no history of SA. Moreover, there was a significant elevation in monocyte count, MLR, ESR and RDW in patients with high SR compared to patients with intermediate SR. AD treatment resulted in a significant decrease in neutrophil granulocyte count and NLR, however, it did not affect monocyte count and MLR. Assuming immunological mechanisms in the background of MDD and suicidality, our findings support the role of NLR as a biomarker of acute SR, though its alterations may be masked by possible anti-inflammatory effects of AD treatment in the long term. However, MLR, a marker exhibiting changes which are not attenuated by pharmacotherapy, may be a possible indicator of both acute and long-term suicidal vulnerability.