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1.
Euro Surveill ; 28(41)2023 10.
Article En | MEDLINE | ID: mdl-37824248

BackgroundUnprecedented non-pharmaceutical interventions to control the COVID-19 pandemic also had an effect on other infectious diseases.AimWe aimed to determine their impact on transmission and diagnosis of notifiable diseases other than COVID-19 in Bavaria, Germany, in 2020 and 2021.MethodsWe compared weekly cases of 15 notifiable infectious diseases recorded in Bavaria between 1 January 2016 and 31 December 2021 in time series analyses, median age and time-to-diagnosis using Wilcoxon rank sum test and hospitalisation rates using univariable logistic regression during three time periods: pre-pandemic (weeks 1 2016-9 2020), pandemic years 1 (weeks 10-52 2020) and 2 (2021).ResultsWeekly case numbers decreased in pandemic year 1 for all diseases assessed except influenza, Lyme disease and tick-borne encephalitis; markedly for norovirus gastroenteritis (IRR = 0.15; 95% CI: 0.12-0.20) and pertussis (IRR = 0.22; 95% CI: 0.18-0.26). In pandemic year 2, influenza (IRR = 0.04; 95% CI: 0.02-0.09) and pertussis (IRR = 0.11; 95% CI: 0.09-0.14) decreased markedly, but also chickenpox, dengue fever, Haemophilus influenzae invasive infection, hepatitis C, legionellosis, noro- and rotavirus gastroenteritis and salmonellosis. For enterohaemorrhagic Escherichia coli infections, median age decreased in pandemic years 1 and 2 (4 years, interquartile range (IQR): 1-32 and 3 years, IQR: 1-18 vs 11 years, IQR: 2-42); hospitalisation proportions increased in pandemic year 1 (OR = 1.60; 95% CI: 1.08-2.34).ConclusionReductions for various infectious diseases and changes in case characteristics in 2020 and 2021 indicate reduced transmission of notifiable diseases other than COVID-19 due to interventions and under-detection.


COVID-19 , Communicable Diseases , Gastroenteritis , Influenza, Human , Whooping Cough , Humans , Pandemics , Whooping Cough/epidemiology , Influenza, Human/epidemiology , COVID-19/epidemiology , Communicable Diseases/epidemiology , Gastroenteritis/epidemiology
2.
Euro Surveill ; 28(34)2023 08.
Article En | MEDLINE | ID: mdl-37616114

BackgroundLyme borreliosis (LB), caused by Borrelia burgdorferi (Bb), is the most common tick-borne infection in Germany. Antibodies against Bb are prevalent in the general population but information on temporal changes of prevalence and estimates of seroconversion (seroincidence) and seroreversion are lacking, especially for children and adolescents.AimWe aimed at assessing antibodies against Bb and factors associated with seropositivity in children and adolescents in Germany.MethodsWe estimated seroprevalence via two consecutive cross-sectional surveys (2003-2006 and 2014-2017). Based on a longitudinal survey component, we estimated annual seroconversion/seroreversion rates.ResultsSeroprevalence was 4.4% (95% confidence interval (CI): 3.9-4.9%) from 2003 to 2006 and 4.1% (95% CI: 3.2-5.1%) from 2014 to 2017. Seroprevalence increased with age, was higher in male children, the south-eastern regions of Germany and among those with a high socioeconomic status. The annual seroconversion rate was 0.3% and the annual seroreversion rate 3.9%. Males were more likely to seroconvert compared with females. Low antibody levels were the main predictor of seroreversion.ConclusionWe did not detect a change in seroprevalence in children and adolescents in Germany over a period of 11 years. Potential long-term changes, for example due to climatic changes, need to be assessed in consecutive serosurveys. Seroconversion was more likely among children and adolescents than among adults, representing a target group for preventive measures. Seroreversion rates are over twice as high in children and adolescents compared with previous studies among adults. Thus, seroprevalence estimates and seroconversion rates in children are likely underestimated.


Borrelia burgdorferi , Lyme Disease , Adolescent , Adult , Child , Female , Humans , Male , Antibodies, Bacterial , Cross-Sectional Studies , Germany/epidemiology , Immunoglobulin G , Seroconversion , Seroepidemiologic Studies , Lyme Disease/epidemiology
3.
Microorganisms ; 11(4)2023 Apr 07.
Article En | MEDLINE | ID: mdl-37110384

In 2020, a record number of tick-borne encephalitis (TBE) cases was reported in major endemic areas in Germany, i.e., the southern federal states of Baden-Wuerttemberg and Bavaria. Most cases were unvaccinated. Other tick-borne diseases (TBDs), including Lyme borreliosis and tularemia, are rising, too. Thus, strategies are needed to increase TBE vaccination uptake in risk areas and promote education on TBD prevention. Primary care physicians are key providers of both vaccinations and TBD education. The TBD-Prevention (TBD-Prev) study aimed to investigate the knowledge, attitudes and behaviors of primary care physicians in Baden-Wuerttemberg and Bavaria with regard to TBE vaccination and prevention of TBDs and to derive strategies for increasing vaccination rates and improving knowledge about TBE and other TBDs in the population and among primary care physicians. We invited all primary care physicians (N = 14,046) in both states to participate by mail. Using standardized, self-administered questionnaires, available both on paper and online, we asked physicians anonymously about their knowledge, attitudes and behaviors with respect to TBE vaccination and TBD prevention and their need for further information/educational materials. A total of 2321 physicians participated between May and September 2022 (response rate 17%), of whom 1222 (53%) worked in Baden-Wuerttemberg and 1067 (46%) in Bavaria. Among the participating physicians, 56% were male, 71% were >50 years and 51% worked in an individual practice. Furthermore, 91% were aware of the German national vaccination guidelines, and 98% perceived their knowledge of the risks and benefits of vaccination as adequate. A total of 97% offer TBE vaccinations, 67% provide vaccination counselling during initial consultations with new patients and 64% actively remind patients about due vaccinations. In addition, 24% expressed a need for further information materials, mainly traditional, analogue media such as flyers (82%) and posters (50%), and named timeliness, quality assurance, easy comprehensibility and independence from the pharmaceutical industry as the most important characteristics of such materials. Almost all participating physicians reported offering TBE vaccinations and feeling well-informed about TBE vaccination and TBDs. However, active offering of vaccinations and education could be further improved, and additional, low-threshold information materials are needed. Based on these results, we will develop and provide various materials on TBE vaccination and TBDs, in particular flyers and posters, for use by physicians during consultations.

4.
EMBO J ; 42(7): e113865, 2023 Apr 03.
Article En | MEDLINE | ID: mdl-36883570

The EMBO Journal discusses the current state of RNA research and presents a series of review articles throughout 2023 that will cover various aspects of RNA biology.

5.
PLoS Genet ; 18(9): e1010122, 2022 09.
Article En | MEDLINE | ID: mdl-36126066

Human RECQL4 is a member of the RecQ family of DNA helicases and functions during DNA replication and repair. RECQL4 mutations are associated with developmental defects and cancer. Although RECQL4 mutations lead to disease, RECQL4 overexpression is also observed in cancer, including breast and prostate. Thus, tight regulation of RECQL4 protein levels is crucial for genome stability. Because mammalian RECQL4 is essential, how cells regulate RECQL4 protein levels is largely unknown. Utilizing budding yeast, we investigated the RECQL4 homolog, HRQ1, during DNA crosslink repair. We find that Hrq1 functions in the error-free template switching pathway to mediate DNA intrastrand crosslink repair. Although Hrq1 mediates repair of cisplatin-induced lesions, it is paradoxically degraded by the proteasome following cisplatin treatment. By identifying the targeted lysine residues, we show that preventing Hrq1 degradation results in increased recombination and mutagenesis. Like yeast, human RECQL4 is similarly degraded upon exposure to crosslinking agents. Furthermore, over-expression of RECQL4 results in increased RAD51 foci, which is dependent on its helicase activity. Using bioinformatic analysis, we observe that RECQL4 overexpression correlates with increased recombination and mutations. Overall, our study uncovers a role for Hrq1/RECQL4 in DNA intrastrand crosslink repair and provides further insight how misregulation of RECQL4 can promote genomic instability, a cancer hallmark.


Breast Neoplasms , Saccharomyces cerevisiae Proteins , Breast Neoplasms/genetics , Cisplatin/pharmacology , DNA , Female , Genomic Instability/genetics , Humans , Lysine/genetics , Proteasome Endopeptidase Complex/genetics , RecQ Helicases/metabolism , Recombination, Genetic , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism
7.
EMBO J ; 41(1): e110330, 2022 01 04.
Article En | MEDLINE | ID: mdl-34981519

Looking back at the journal's first issue in January 1982 provides an opportunity to reflect on its historical development and to introduce upcoming initiatives.

8.
Zoonoses Public Health ; 69(2): 106-116, 2022 03.
Article En | MEDLINE | ID: mdl-34780120

In November 2018, a tularaemia outbreak occurred in Bavaria, Germany, among participants of a hare hunt and butchery employees handling the hares. We conducted an epidemiological outbreak investigation, including a retrospective cohort study among hunting participants, to identify likely transmission routes and activities associated with infection. Twelve of 41 participants were antibody-positive for Francisella (F.) tularensis (attack rate: 29%). Cases reported influenza-like symptoms (n = 11), lymphadenopathy (n = 1) and conjunctivitis (n = 1). Infection only occurred in those hunting participants present while hares were processed, while risk of infection was highest when directly involved (RR = 10.0; 95%CI: 2.6-392). F. tularensis was isolated from 1/4 hares. Only two individuals reported using some of the recommended personal protective equipment (PPE). Occurrence of mainly non-specific symptoms, likely due to early treatment, was not indicative of a specific transmission route. Transmissions via direct (skin/mucosa) contact and by inhalation of contaminated aerosols seem plausible. Promoting and increasing appropriate use of PPE among people processing hares is crucial to prevent future outbreaks.


Francisella tularensis , Hares , Tularemia , Animals , Disease Outbreaks , Germany/epidemiology , Humans , Retrospective Studies , Tularemia/epidemiology , Tularemia/veterinary
9.
Microorganisms ; 9(9)2021 Sep 03.
Article En | MEDLINE | ID: mdl-34576768

Lyme borreliosis (LB) is the most common tick-borne disease in Germany. Mandatory notification of acute LB manifestations (erythema migrans (EM), neuroborreliosis (NB), and Lyme arthritis (LA)) was implemented in Bavaria on 1 March 2013. We aimed to describe the epidemiological situation and to identify LB risk areas and populations. Therefore, we analyzed LB cases notified from March 2013 to December 2020 and calculated incidence (cases/100,000 inhabitants) by time, place, and person. Overall, 35,458 cases were reported during the study period (EM: 96.7%; NB: 1.7%; LA: 1.8%). The average incidence was 34.3/100,000, but annual incidence varied substantially (2015: 23.2; 2020: 47.4). Marked regional differences at the district level were observed (annual average incidence range: 4-154/100,000). The Bavarian Forest and parts of Franconia were identified as high-risk regions. Additionally, high risk for LB was found in 5-9-year-old males and in 60-69-year-old females. The first group also had the highest risk of a severe disease course. We were able to identify areas and populations in Bavaria with an increased LB risk, thereby providing a basis for targeted measures to prevent LB. Since LB vaccination is currently not available, such measures should comprise (i) avoiding tick bites, (ii) removing ticks rapidly after a bite, and (iii) treating LB early/adequately.

10.
Microorganisms ; 8(12)2020 Nov 25.
Article En | MEDLINE | ID: mdl-33255673

Lyme borreliosis (LB) caused by Borrelia burgdorferi spp. is the most common human tick-borne disease in Europe. Although seroprevalence studies are conducted in several countries, rates of seroconversion and seroreversion are lacking, and they are essential to determine the risk of infection. Seropositivity was determined using a two-step approach-first, a serological screening assay, and in the event of a positive or equivocal result, a confirmatory immunoblot assay. Seroconversion and seroreversion rates were assessed from blood samples taken from participants included in two nation-wide population-based surveys. Moreover, the impact of antigen reactivity on seroreversion rates was assessed. The seroprevalence of antibodies reacting against B. burgdorferi spp. in the German population was 8.5% (95% CI 7.5-9.6) in 1997-99 and 9.3% (95% CI 8.3-10.4) in 2008-2011. Seroprevalence increased with age, up to 20% among 70-79 year-olds. The age-standardized seroprevalence remained the same. The yearly seroconversion rate was 0.45% (95% CI: 0.37-0.54), and the yearly seroreversion rate was 1.47% (95% CI: 1.24-2.17). Lower levels of antibodies were associated with seroreversion. Participants with a strong response against antigen p83 had the lowest odds on seroreversion. Given the yearly seroreversion rate of 1.47% and a seroprevalence up to 20% in the oldest age groups, at least 20% of the German population becomes infected with B. burgdorferi in their lifetime. The slight increase in seroprevalence between the two serosurveys was caused by an aging population.

11.
Microorganisms ; 8(11)2020 Oct 23.
Article En | MEDLINE | ID: mdl-33114188

In November 2018, an outbreak of tularemia occurred among hare hunters in Bavaria, Germany. At least one infected hare was confirmed as the source of infection. A number of hunting dogs showed elevated antibody titers to Francisella tularensis, but the absence of titer increases in subsequent samples did not point to acute infections in dogs. Altogether, 12 persons associated with this hare hunt could be diagnosed with acute tularemia by detection of specific antibodies. In nine patients, the antibody and cytokine responses could be monitored over time. Eight out of these nine patients had developed detectable antibodies three weeks after exposure; in one individual the antibody response was delayed. All patients showed an increase in various cytokines and chemokines with a peak for most mediators in the first week after exposure. Cytokine levels showed individual variations, with high and low responders. The kinetics of seroconversion has implications on serological diagnoses of tularemia.

12.
Lancet Infect Dis ; 20(8): 920-928, 2020 08.
Article En | MEDLINE | ID: mdl-32422201

BACKGROUND: In December, 2019, the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, causing COVID-19, a respiratory disease presenting with fever, cough, and often pneumonia. WHO has set the strategic objective to interrupt spread of SARS-CoV-2 worldwide. An outbreak in Bavaria, Germany, starting at the end of January, 2020, provided the opportunity to study transmission events, incubation period, and secondary attack rates. METHODS: A case was defined as a person with SARS-CoV-2 infection confirmed by RT-PCR. Case interviews were done to describe timing of onset and nature of symptoms and to identify and classify contacts as high risk (had cumulative face-to-face contact with a confirmed case for ≥15 min, direct contact with secretions or body fluids of a patient with confirmed COVID-19, or, in the case of health-care workers, had worked within 2 m of a patient with confirmed COVID-19 without personal protective equipment) or low risk (all other contacts). High-risk contacts were ordered to stay at home in quarantine for 14 days and were actively followed up and monitored for symptoms, and low-risk contacts were tested upon self-reporting of symptoms. We defined fever and cough as specific symptoms, and defined a prodromal phase as the presence of non-specific symptoms for at least 1 day before the onset of specific symptoms. Whole genome sequencing was used to confirm epidemiological links and clarify transmission events where contact histories were ambiguous; integration with epidemiological data enabled precise reconstruction of exposure events and incubation periods. Secondary attack rates were calculated as the number of cases divided by the number of contacts, using Fisher's exact test for the 95% CIs. FINDINGS: Patient 0 was a Chinese resident who visited Germany for professional reasons. 16 subsequent cases, often with mild and non-specific symptoms, emerged in four transmission generations. Signature mutations in the viral genome occurred upon foundation of generation 2, as well as in one case pertaining to generation 4. The median incubation period was 4·0 days (IQR 2·3-4·3) and the median serial interval was 4·0 days (3·0-5·0). Transmission events were likely to have occurred presymptomatically for one case (possibly five more), at the day of symptom onset for four cases (possibly five more), and the remainder after the day of symptom onset or unknown. One or two cases resulted from contact with a case during the prodromal phase. Secondary attack rates were 75·0% (95% CI 19·0-99·0; three of four people) among members of a household cluster in common isolation, 10·0% (1·2-32·0; two of 20) among household contacts only together until isolation of the patient, and 5·1% (2·6-8·9; 11 of 217) among non-household, high-risk contacts. INTERPRETATION: Although patients in our study presented with predominately mild, non-specific symptoms, infectiousness before or on the day of symptom onset was substantial. Additionally, the incubation period was often very short and false-negative tests occurred. These results suggest that although the outbreak was controlled, successful long-term and global containment of COVID-19 could be difficult to achieve. FUNDING: All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.


Betacoronavirus/isolation & purification , Communicable Diseases, Imported/transmission , Coronavirus Infections/transmission , Disease Outbreaks , Disease Transmission, Infectious , Pneumonia, Viral/transmission , Travel-Related Illness , Adolescent , Adult , Betacoronavirus/classification , Betacoronavirus/genetics , COVID-19 , Child , Child, Preschool , China , Communicable Diseases, Imported/epidemiology , Communicable Diseases, Imported/pathology , Communicable Diseases, Imported/virology , Coronavirus Infections/epidemiology , Germany/epidemiology , Humans , Interviews as Topic , Middle Aged , Mutation , Pandemics , Pneumonia, Viral/epidemiology , RNA, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction , Risk Assessment , SARS-CoV-2 , Travel , Young Adult
13.
Cell Death Dis ; 11(4): 238, 2020 04 17.
Article En | MEDLINE | ID: mdl-32303682

Approximately half of all cases of Hoyeraal-Hreidarsson syndrome (HHS), a multisystem disorder characterized by bone marrow failure, developmental defects and very short telomeres, are caused by germline mutations in genes related to telomere biology. However, the varying symptoms and severity of the disease indicate that additional mechanisms are involved. Here, a 3-year-old boy with HHS was found to carry biallelic germline mutations in WRAP53 (WD40 encoding RNA antisense to p53), that altered two highly conserved amino acids (L283F and R398W) in the WD40 scaffold domain of the protein encoded. WRAP53ß (also known as TCAB1 or WDR79) is involved in intracellular trafficking of telomerase, Cajal body functions and DNA repair. We found that both mutations cause destabilization, mislocalization and faulty interactions of WRAP53ß, defects linked to misfolding by the TRiC chaperonin complex. Consequently, WRAP53ß HHS mutants cannot elongate telomeres, maintain Cajal bodies or repair DNA double-strand breaks. These findings provide a molecular explanation for the pathogenesis underlying WRAP53ß-associated HHS and highlight the potential contribution of DNA damage and/or defects in Cajal bodies to the early onset and/or severity of this disease.


Coiled Bodies/metabolism , DNA Repair/genetics , Dyskeratosis Congenita/genetics , Fetal Growth Retardation/genetics , Intellectual Disability/genetics , Microcephaly/genetics , Molecular Chaperones/metabolism , Telomerase/metabolism , Telomere/metabolism , Child, Preschool , Humans , Male , Mutation
14.
BMC Health Serv Res ; 19(1): 616, 2019 Sep 02.
Article En | MEDLINE | ID: mdl-31477095

BACKGROUND: In Germany, antenatal influenza vaccination is recommended since 2010, but uptake remains low. Several countries recently introduced antenatal pertussis vaccination, which is currently under consideration in Germany. We conducted a survey among gynaecologists on attitudes, practices and barriers regarding influenza and pertussis vaccination during pregnancy. METHODS: Gynaecologists were invited to complete a pre-tested, 24-item questionnaire published in the German Professional Association of Gynaecologists' journal in September 2017 within 2 months. Associations between variables were examined using Chi-Squared, Fischer's Exact or t-tests. Variables associated with gynaecologists' self-reported implementation of vaccination in pregnant women were identified using univariate and multivariate logistic regression analyses. RESULTS: Of 867 participants (response 11%), 91.4 and 59.4% reported currently vaccinating pregnant women against influenza and pertussis, respectively. Gynaecologists who reported obtaining annual influenza vaccination and actively informing their patients about these vaccinations were significantly more likely to vaccinate pregnant women against influenza (96.5% vs. 65.7 and 95.1% vs. 62.2%) and pertussis (63.1% vs. 44.3 and 82.4% vs. 12.9%). Performing influenza vaccination was least likely among gynaecologists who perceived logistical difficulties as a vaccination barrier (35.9%), while pertussis vaccination was least likely if the lacking official recommendation (32.0%), logistical difficulties (27.1%), safety concerns (17.5%) and limited vaccine effectiveness (11.1%) were perceived as barriers. Of participants not yet vaccinating pregnant women against pertussis, 86.5% reported they would follow an official recommendation. Including vaccination recommendations in the maternity record (95.2%) and informing the public (88.7%) and health care professionals (86.6%) were considered the most suitable measures to achieve high pertussis vaccination coverage. CONCLUSIONS: The large proportion reporting performance of influenza vaccination during pregnancy and high acceptance of a potential recommendation for pertussis vaccination reflected positive attitudes towards vaccination among participants. However, factors associated with failure to vaccinate may be more prevalent among non-participants. Results suggest that gynaecologists' confidence in vaccination is crucial for implementing vaccination in pregnancy. Thus, doubts on vaccine effectiveness and safety should be allayed among gynaecologists and pregnant women via various communication channels, and solutions for logistical barriers sought. Including antenatal vaccination recommendations in the maternity record would serve as an important reminder for both groups.


Attitude of Health Personnel , Health Knowledge, Attitudes, Practice , Influenza Vaccines/administration & dosage , Influenza, Human/prevention & control , Patient Acceptance of Health Care , Whooping Cough/prevention & control , Female , Germany , Humans , Male , Middle Aged , Patient Acceptance of Health Care/statistics & numerical data , Pregnancy , Surveys and Questionnaires
15.
Nat Commun ; 10(1): 3485, 2019 08 02.
Article En | MEDLINE | ID: mdl-31375684

MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.


Apoptosis/genetics , Gene Expression Regulation, Neoplastic/genetics , Lung Neoplasms/genetics , Proto-Oncogene Proteins c-myc/metabolism , Small Cell Lung Carcinoma/genetics , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , CRISPR-Cas Systems/genetics , Cell Line, Tumor , DNA Damage/drug effects , DNA Damage/genetics , Disease Models, Animal , Gene Expression Regulation, Neoplastic/drug effects , HEK293 Cells , Humans , Lung Neoplasms/drug therapy , Mice , Molecular Targeted Therapy/methods , Proto-Oncogene Proteins c-myc/genetics , RNA, Small Interfering/metabolism , Small Cell Lung Carcinoma/drug therapy
16.
Clin Genet ; 96(3): 216-225, 2019 09.
Article En | MEDLINE | ID: mdl-31081129

Pathogenic germline TP53 variants predispose to a wide range of early onset cancers, often recognized as the Li-Fraumeni syndrome (LFS). They are also identified in 1% of families with hereditary breast cancer (HrBC) that do not fulfill the criteria for LFS. In this study, we present a total of 24 different TP53 variants identified in 31 Swedish families with LFS or HrBC. Ten of these variants, nine exonic and one splice, have previously not been described as germline pathogenic variants. The nine exonic variants were functionally characterized and demonstrated partial transactivation activity compared to wild-type p53. Some show nuclear localization similar to wild-type p53 while others possess cytoplasmic or perinuclear localization. The four frameshift variants (W91Gfs*32, L111 Wfs*12, S227 Lfs*20 and S240Kfs*25) had negligible, while F134 L and T231del had low level of p53 activity. The L111 Wfs*12 and T231del variants are also deficient for induction of apoptosis. The missense variant R110C retain p53 effects and the nonsense E349* shows at least partial transcription factor activity but has reduced ability to trigger apoptosis. This is the first functional characterization of novel germline TP53 pathogenic or likely pathogenic variants in the Swedish cohort as an attempt to understand its association with LFS and HrBC, respectively.


Genetic Variation , Germ-Line Mutation , Tumor Suppressor Protein p53/genetics , Alleles , Amino Acid Substitution , Apoptosis , Cell Line, Tumor , Gene Expression Regulation , Genetic Association Studies , Genetic Loci , Genetic Predisposition to Disease , Genotype , Humans , Li-Fraumeni Syndrome/genetics , Protein Transport , Sequence Analysis, DNA , Sweden
17.
J Atten Disord ; 23(7): 692-701, 2019 May.
Article En | MEDLINE | ID: mdl-28162026

OBJECTIVE: Evidence suggests that perinatal factors may contribute to the development of ADHD. Our objective was to examine the association between hypertensive disorders of pregnancy (HDP) and ADHD, and behavioral difficulties among 7-year-old children. METHOD: The study cohort consisted of 13,192 children (weighted = 13,500) who participated in the Millennium Cohort Study (MCS) at age 7. HDP (raised blood pressure, preeclampsia, eclampsia, and toxemia) were reported by mothers 9 months postdelivery. ADHD was reported by parents at age 7 years. Weighted logistic regression models were used to assess the association. RESULTS: In all, 1,069 (7.9%) women reported HDP and 166 (1.2%) children had an ADHD diagnosis. There was a significant association between HDP and ADHD (adjusted odds ratio [OR] = 1.78, 95% confidence interval [CI] = [1.03, 3.07]). CONCLUSION: These findings suggest that HDP is associated with an increased risk of ADHD. It is important to confirm this in larger cohorts and to understand the biological basis of this association.


Attention Deficit Disorder with Hyperactivity/epidemiology , Hypertension, Pregnancy-Induced , Adolescent , Adult , Child , Cohort Studies , Female , Humans , Logistic Models , Male , Odds Ratio , Pregnancy , Risk Factors , Young Adult
18.
Mol Cell ; 70(5): 906-919.e7, 2018 06 07.
Article En | MEDLINE | ID: mdl-29804830

Stress granules (SGs) are cytoplasmic assemblies of mRNPs stalled in translation initiation. They are induced by various stress conditions, including exposure to the environmental toxin and carcinogen arsenic. While perturbed SG turnover is linked to the pathogenesis of neurodegenerative diseases, the molecular mechanisms underlying SG formation and turnover are still poorly understood. Here, we show that ZFAND1 is an evolutionarily conserved regulator of SG clearance. ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs. In the absence of ZFAND1, SGs lack the 26S proteasome and p97, accumulate defective ribosomal products, and persist after arsenite removal, indicating their transformation into aberrant, disease-linked SGs. Accordingly, ZFAND1 depletion is epistatic to the expression of pathogenic mutant p97 with respect to SG clearance, suggesting that ZFAND1 function is relevant to the multisystem degenerative disorder IBMPFD/ALS.


Arsenites/toxicity , Cytoplasmic Granules/drug effects , Intracellular Signaling Peptides and Proteins/metabolism , Proteasome Endopeptidase Complex/metabolism , Sodium Compounds/toxicity , Stress, Physiological , TNF Receptor-Associated Factor 2/metabolism , Autophagy/drug effects , Cytoplasmic Granules/enzymology , Cytoplasmic Granules/pathology , HEK293 Cells , HeLa Cells , Humans , Intracellular Signaling Peptides and Proteins/genetics , Proteasome Endopeptidase Complex/genetics , Protein Transport , Proteolysis , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Signal Transduction/drug effects , TNF Receptor-Associated Factor 2/genetics
19.
Cell Rep ; 20(12): 2833-2845, 2017 Sep 19.
Article En | MEDLINE | ID: mdl-28930680

Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients.


Molecular Targeted Therapy , Neoplasms/enzymology , Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Cell Cycle Proteins , Cell Line, Tumor , Cyclin T/metabolism , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Cyclin-Dependent Kinase 9/metabolism , HEK293 Cells , High-Throughput Screening Assays , Humans , Neoplasms/genetics , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/metabolism , Protein Kinase Inhibitors/chemistry , RNA Polymerase II/metabolism , Transcription Elongation, Genetic/drug effects , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Transcription, Genetic/drug effects
20.
Materials (Basel) ; 10(9)2017 Sep 15.
Article En | MEDLINE | ID: mdl-28914792

Collagen is a main component of the extracellular matrix. It is often used in medical applications to support tissue regeneration, hemostasis, or wound healing. Due to different sources of collagen, the properties and performance of available products can vary significantly. In this in vitro study, a comparison of seven different collagen matrices derived from bovine, equine, and porcine sources was performed. As performance indicators, the scaffold function for fibroblasts and platelet aggregation were used. We found strong variation in platelet aggregation and fibroblast growth on the different collagen materials. The observed variations could not be attributed to species differences alone, but were highly dependent on differences in the manufacturing process.

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