julilili42/papers huggingface dataset:
Secondary Metabolite Transcriptomic Pipeline (SeMa-Trap), an expression-based exploration tool for increased secondary metabolite production in bacteria
2022-04-29

Abstract For decades, natural products have been used as a primary resource in drug discovery pipelines to find new antibiotics, which are mainly produced as secondary metabolites by bacteria. The biosynthesis of these compounds is encoded in co-localized genes termed biosynthetic gene clusters (BGCs). However, BGCs are often not expressed under laboratory conditions. Several genetic manipulation strategies have been developed in order to activate or overexpress silent BGCs. Significant increases in production levels of secondary metabolites were indeed achieved by modifying the expression of genes encoding regulators and transporters, as well as genes involved in resistance or precursor biosynthesis. However, the abundance of genes encoding such functions within bacterial genomes requires prioritization of the most promising ones for genetic manipulation strategies. Here, we introduce the ‘Secondary Metabolite Transcriptomic Pipeline’ (SeMa-Trap), a user-friendly web-server, available at https://sema-trap.ziemertlab.com. SeMa-Trap facilitates RNA-Seq based transcriptome analyses, finds co-expression patterns between certain genes and BGCs of interest, and helps optimize the design of comparative transcriptomic analyses. Finally, SeMa-Trap provides interactive result pages for each BGC, allowing the easy exploration and comparison of expression patterns. In summary, SeMa-Trap allows a straightforward prioritization of genes that could be targeted via genetic engineering approaches to (over)express BGCs of interest.
Elevated Expression of the Immune Checkpoint Ligand CD276 (B7-H3) in Urothelial Carcinoma Cell Lines Correlates Negatively with the Cell Proliferation
2022-04-29

The cell surface molecule CD276 (B7-H3) is an immune checkpoint antigen. The elevated expression of CD276 on tumors contributes to the suppression of anti-tumor T-cell responses and correlates with poor prognosis. Methods: The expression of CD276 was explored in vitro on eight urothelial carcinoma cell lines (UM-UC) in comparison to eight normal urothelial cells (NUCs) by RT-qPCR, Western blotting, and flow cytometry. Cell proliferation was enumerated over consecutive passages. The expression of cancer stem cell markers CD24 and CD44, cytokeratins, and vimentin was investigated by immunofluorescence. The expression of CD276 in bladder tumor samples and metastases was explored by immunohistochemistry. Results: Expression of CD276 on cell surfaces was elevated on UM-UCs when compared to NUCs. In UM-UCs, CD276 transcripts correlated moderately positive with CD276 protein expression (ρ = 0.660) and strongly positive with CD276 surface-expression (ρ = 0.810). CD276 mRNA expression (ρ = −0.475) and CD276 protein expression (ρ = −0.417) had a significant negative correlation with proliferation, while a significant correlation between proliferation and cell surface expression was not observed in UM-UCs. Conclusion: The expression of CD276 on UM-UC bladder tumor cell surfaces is elevated. Slow proliferating UM-UC cells express more CD276 mRNA and protein than fast proliferating cells. In patients, slow proliferating CD276high tumor (stem) cells may evade immune surveillance. However, cancer therapy targeting CD276 may be effective in the treatment of slow proliferating tumor cells.
The GAPS programme at TNG
2022-04-29

Context. Active-region evolution plays an important role in the generation and variability of magnetic fields on the surface of lower main sequence stars. However, determining the lifetime of active-region growth and decay as well as their evolution is a complex task. Most previous studies of this phenomenon are based on optical light curves, while little is known about the chromosphere and the transition region. Aims. We aim to test whether or not the lifetime of active-region evolution shows any dependency on stellar parameters, particularly stellar age. Methods. We identified a sample of stars with well-defined ages via their kinematics and membership to young stellar associations and moving groups. We made use of high-resolution échelle spectra from HARPS at La Silla 3.6m-telescope and HARPS-N at TNG to compute rotational velocities, activity levels, and emission excesses. We used these data to revisit the activity-rotation-age relationship. The time-series of the main optical activity indicators, namely Ca II H and K, Balmer lines, Na I D1, D2, and He I D3, were analysed together with the available photometry using state-of-the-art Gaussian processes to model the stellar activity of these stars. Autocorrelation functions of the available photometry were also analysed. We used the derived lifetimes of active-region evolution to search for correlations with stellar age, spectral type, and activity level. We also used the pooled variance technique to characterise the activity behaviour of our targets. Results. Our analysis confirms the decline of activity and rotation as a star ages. We also confirm that the rotation rate decays with age more slowly for cooler stars and that, for a given age, cooler stars show higher levels of activity. We show that F- and G-type young stars also depart from the inactive stars in the flux–flux relationship. The Gaussian process analysis of the different activity indicators does not seem to provide any useful information on the lifetime and evolution of active regions. On the other hand, the lifetimes of active regions derived from the light-curve analysis might correlate with stellar age and temperature. Conclusions. Although we suggest caution because of small number statistics, our results suggest that active regions seem to live longer on younger, cooler, and more active stars.
Cost-utility analysis of increasing uptake of universal seasonal quadrivalent influenza vaccine (QIV) in children aged 6 months and older in Germany
2022-04-29

Seasonal influenza causes many cases and related deaths in Europe annually, despite ongoing vaccination programs for older adults and people at high-risk of complications. Children have the highest risk of infection and play a key role in disease transmission. Our cost-utility analysis, based on a dynamic transmission model, estimated the impact of increasing the current vaccination coverage with inactivated quadrivalent influenza vaccine in Germany to all (healthy and high-risk) children under 5 years of age (40% uptake), or under 18 years (40% uptake), or only high-risk children under 18 years (90% uptake). Eight influenza complications were modeled, hospitalization and death rates were based on age and risk status. All three vaccination strategies provided more health benefits than the existing vaccination situation, reducing influenza cases, complications, hospitalizations and deaths across the entire population. The strategy targeting all children under 5 years was highly cost-effective (€6/quality-adjusted life-year gained, payer perspective). The other strategies were cost saving from the payer and societal perspectives. The vaccination strategy targeting all children under 18 years was estimated to provide the most health benefits (preventing on average 1.66 million cases, 179,000 complications, 14,000 hospitalizations and 3,600 deaths due to influenza annually) and the most cost savings (annually €20.5 million and €731.3 million from payer and societal perspectives, respectively). Our analysis provides policy decision-makers with evidence supporting strategies to expand childhood influenza vaccination, to directly protect children, and indirectly all other unvaccinated age groups, in order to reduce the humanistic and economic burden on healthcare systems and society.
Regio‐ and Stereoselective Epoxidation and Acidic Epoxide Opening of Antibacterial and Antiplasmodial Chlorotonils Yield Highly Potent Derivatives
2022-04-29

Abstract The rise of antimicrobial resistance poses a severe threat to public health. The natural product chlorotonil was identified as a new antibiotic targeting multidrug resistant Gram‐positive pathogens and Plasmodium falciparum . Although chlorotonil shows promising activities, the scaffold is highly lipophilic and displays potential biological instabilities. Therefore, we strived towards improving its pharmaceutical properties by semisynthesis. We demonstrated stereoselective epoxidation of chlorotonils and epoxide ring opening in moderate to good yields providing derivatives with significantly enhanced solubility. Furthermore, in vivo stability of the derivatives was improved while retaining their nanomolar activity against critical human pathogens (e.g. methicillin‐resistant Staphylococcus aureus and P. falciparum ). Intriguingly, we showed further superb activity for the frontrunner molecule in a mouse model of S. aureus infection.
Influence on the patient’s oral hygiene depending on the treatment performed by either one or different pre-graduate practitioners — a randomized, controlled, clinical short-term trial
2022-04-29

Abstract Objectives Plaque control by improved domestic oral hygiene is essential in periodontal treatment. However, changing treatment providers may interfere with building a dentist-patient relationship and in turn affect treatment success. The aim of this randomized, controlled, prospective short-term study was to determine the influence of either one or four different pre-graduate practitioners on patients’ oral hygiene parameters during active periodontal therapy. Material and Methods A total of 55 patients with periodontitis were allocated to two groups. Within the group “continuous treatment” (CT, n = 27), each patient was treated by one individual practitioner over the treatment period. For patients of the group “discontinuous treatment” (DT, n = 28), treatment in each session was performed by a different practitioner. Periodontal parameters (BOP, PBI, and PCR) were assessed at two timepoints: T1 (baseline) and T2 (end of active therapy). Results With CT, the PBI improved in 93% of the patients, compared to 71% with DT ( p = 0.048). T1-T2 intragroup analysis showed a statistically significant improvement of all observed clinical parameters with no differences in ∆PBI, ∆BOP, and ∆PCR. Spearman’s correlation analysis revealed a weak correlation between PCR and BOP of CT only. Conclusions In the present study, improvement of all parameters was comparable between the groups. PBI, as a parameter displaying patient’s domestic plaque control compliance, improved in more patients from CT than DT. This is possibly indicating an advantage of continuous treatment by one single practitioner. Clinical relevance Treatment by either a single practitioner or by multiple, constantly changing practitioners might influence patients’ compliance to modify their behaviour when medically necessary.
IFN-γ and TNF Induce Senescence and a Distinct Senescence-Associated Secretory Phenotype in Melanoma
2022-04-30

Immune checkpoint blockade (ICB) therapy is a central pillar of melanoma treatment leading to durable response rates. Important mechanisms of action of ICB therapy include disinhibition of CD4+ and CD8+ T cells. Stimulated CD4+ T helper 1 cells secrete the effector cytokines interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF), which induce senescence in tumor cells. Besides being growth-arrested, senescent cells are metabolically active and secrete a large spectrum of factors, which are summarized as senescence-associated secretory phenotype (SASP). This secretome affects the tumor growth. Here, we compared the SASP of cytokine-induced senescent (CIS) cells with the SASP of therapy-induced senescent (TIS) cells. Therefore, we established in vitro models for CIS and TIS in melanoma. The human melanoma cell lines SK-MEL-28 and WM115 were treated with the cytokines IFN-γ and TNF as CIS, the chemotherapeutic agent doxorubicin, and the cell cycle inhibitor palbociclib as TIS. Then, we determined several senescence markers, i.e., growth arrest, p21 expression, and senescence-associated β-galactosidase (SA-β-gal) activity. For SASP analyses, we measured the regulation and secretion of several common SASP factors using qPCR arrays, protein arrays, and ELISA. Each treatment initiated a stable growth arrest, enhanced SA-β-gal activity, and—except palbociclib—increased the expression of p21. mRNA and protein analyses revealed that gene expression and secretion of SASP factors were severalfold stronger in CIS than in TIS. Finally, we showed that treatment with the conditioned media (CM) derived from cytokine- and palbociclib-treated cells induced senescence characteristics in melanoma cells. Thus, we conclude that senescence induction via cytokines may lead to self-sustaining senescence surveillance of melanoma.
Incidences and characteristics of primary lung malignancies in childhood in Germany: An analysis of population‐based data from German cancer registries
2022-04-30

Abstract Background : Primary lung malignancies are a heterogeneous group of cancers that occur very rarely in childhood. Due to limited knowledge of their epidemiologic and clinical features, these tumors present a challenge to the treating physicians. This study aimed to increase the knowledge about the occurrence of primary lung malignancies in childhood in Germany. Materials and methods : Pseudonymized data of cases recorded at the German Center for Cancer Registry Data (ZfKD) between 1990 and 2017 were retrieved. Primary lung malignancies were identified using the ICD‐ and ICD‐O classification. Numbers were compared to those reported to the German Childhood Cancer Registry (GCCR). Crude incidence rates were calculated using the ZfKD database. Results : A total of 168 patients diagnosed with primary lung malignancies in the age below 19 years were identified from the ZfKD. The median age at diagnosis was 13 years. The most common tumor entities were lung carcinoids ( n = 49), lung carcinoma ( n = 36), and pleuropulmonary blastoma ( n = 14). An unexpected accumulation of lung cancer cases was noted in the first year of life without a clearly specified histopathological diagnosis. A substantial discrepancy in the numbers of primary lung malignancies between ZfKD and GCCR was found. Conclusions : We present population‐based data on the occurrence of primary childhood lung malignancies in Germany, which were more frequent than previously anticipated but likely remained underreported. For better understanding and optimal treatment of these entities, cancer registration needs to be improved through mandatory reporting to the GCCR and regular data sharing between GCCR, population‐based and clinical cancer registries.
HLA-DR Presentation of the Tumor Antigen MSLN Associates with Clinical Outcome of Ovarian Cancer Patients
2022-04-30

T-cell recognition of HLA-presented antigens is central for the immunological surveillance of malignant disease and key for the development of novel T-cell-based immunotherapy approaches. In recent years, large-scale immunopeptidome studies identified naturally presented tumor-associated antigens for several malignancies. Regarding ovarian carcinoma (OvCa), Mucin-16 (MUC16) and Mesothelin (MSLN) were recently described as the top HLA class I- and HLA class II-presented tumor antigens, respectively. Here, we investigate the role and impact of immunopeptidome-presented tumor antigens on the clinical outcomes of 39 OvCa patients with a follow-up time of up to 50 months after surgery. Patients with a HLA-restricted presentation of high numbers of different MSLN-derived peptides on their tumors exhibited significantly prolonged progression-free (PFS) and overall survival (OS), whereas the presentation of MUC16-derived HLA class I-restricted peptides had no impact. Furthermore, a high HLA-DRB gene expression was associated with increased PFS and OS. In line, in silico prediction revealed that MSLN-derived HLA class II-presented peptides are predominantly presented on HLA-DR allotypes. In conclusion, the correlation of MSLN tumor antigen presentation and HLA-DRB gene expression with prolonged survival indicates a central role of CD4+ T-cell responses for tumor immune surveillance in OvCa, and highlights the importance of immunopeptidome-guided tumor antigen discovery.
Personality, Intelligence, and Academic Achievement: Charting their Developmental Interplay
2022-04-30

Although intelligence and personality traits have long been recognized as key predictors of students’ academic achievement, little is known about their longitudinal and reciprocal associations. Here, we charted the developmental interplay of intelligence, personality (Big Five) and academic achievement in 3,880 German secondary school students, who were assessed four times between the ages 11 and 14 years (i.e., in grade 5, 6, 7, and 8). We fitted random-intercept cross-lagged panel models (RI-CLPs) to investigate reciprocal within-person associations between (a) academic achievement and intelligence, (b) academic achievement and personality, as well as (c) intelligence and personality. The results revealed negative within-person associations between Conscientiousness and Extraversion assessed at the first wave of measurement and intelligence assessed at the second wave. None of the reciprocal personality-achievement associations attained statistical significance. Academic achievement and intelligence showed reciprocal within-person relations, with the strongest coefficients found for achievement longitudinally predicting intelligence. Our work contributes to developmental theorizing on interrelations between personality, intelligence, and academic achievement, as well as to within-person conceptualizations in personality research.
Self-Regulated and Externally Regulated Learning in Adolescence: Developmental Trajectories and Relations with Teacher Behavior, Parent Behavior, and Academic Achievement
2022-04-30

Both self-regulation and external regulation are key to understanding adolescents’ learning and positive development at school. However, evidence on the joint development of self-regulated learning and externally related learning during adolescence is largely lacking. The present multi-level longitudinal analysis (N = 1,542 German adolescents; annual assessments from grade 5 to 9; mean age at grade 5 = 11.79 years, SD = 0.71, 51.75 % female) examined this development and its relations with academic achievement in mathematics, and autonomy support and achievement pressure at school and in the family. Results from multi-level latent basic growth curve models showed that self- and externally regulated learning decreased over the five years at both the individual student and the class level. Changes in self- and externally regulated learning were linked: classes with higher levels of self-regulated learning at grade 5 showed a stronger decrease in externally regulated learning over time. Initial levels of and changes in teachers’ and parents’ autonomy support and achievement pressure were associated with self- and externally regulated learning at the individual student level; teacher autonomy support and self-regulated learning were also linked at the class level. Self-regulated learning related positively to standardized achievement test scores but not to adolescents’ school grades. This study adds to the scarce evidence base on different regulatory forms of adolescents’ learning and can inform future research focusing on students’ positive development at school as well as educational practice.
Obituary for Kálmán Vánky (1930–2021)
2022-04-30

Abstract Kálmán Vánky (15 th of June 1930–18 th of October 2021) was arguably the most prolific researcher of smut fungi so far. He published more than 1000 taxonomic novelties, and crowned his outstanding oeuvre with the most comprehensive monograph of the smut fungi ( Smut Fungi of the World ) written to date.
Rescue Revascularisation in Acute Internal Carotid Artery Occlusion with a Super Extended Time Window of More than 48 hours
2022-04-30

Background and Aim. Mechanical thrombectomy (MT) and intravenous thrombolysis are the gold standard treatment for large vessel occlusion (LVO) strokes. 10–20% of LVO patients present as “minor strokes” with a National Institutes of Health Stroke Scale (NIHSS) ≤5 points. Therefore, MT is often not primarily performed. These patients rely on collateral blood flow but are prone to clinical deterioration and unfavourable outcome. MT is performed after clinical deterioration, often in an extended time window within 24 hours. No scores identify patients at risk for clinical deterioration. Methods. We present the case of a 71-year-old Caucasian male “minor stroke” patient with LVO, good collateral flow via the ophthalmic artery, receiving rescue MT following clinical deterioration after &gt;48 hours. NIHSS and modified Rankin scale (mRS) were used for follow-up and modified treatment in cerebral infarction (mTICI) score for angiographic results. Results. Excellent angiographic result (mTICI 3) and clinical improvement were achieved (NIHSS preintervention 18, on discharge 2 points). 90-day follow-up showed excellent outcome (mRS 1). Conclusions. Late intervention MT should be encouraged when clinical deficit exceeds infarct demarcation. Standardized identification based on clinical and imaging data is required to target critical patients with LVO and low NIHSS, favouring a primary intervention.
NSF/αSNAP2-mediated cis-SNARE complex disassembly precedes membrane fusion generating the cell plate during Arabidopsis cytokinesis
2022-04-30

Summary Eukaryotic membrane fusion requires trans -SNARE complexes bridging the gap between adjacent membranes (Jahn and Scheller, 2006). Fusion between a transport vesicle and its target membrane transforms the trans -into a cis -SNARE complex. The latter interacts with the hexameric AAA + -ATPase NSF and its co-factor αSNAP, forming a 20S complex (Zhou et al., 2015; Zhao and Brunner, 2016). ATPase activity disassembles the SNARE complex into Qa-SNARE, which folds back onto itself, and its partners (Huang et al., 2019; Kim et al., 2021). Fusion of identical membranes has a different sequence of events (Baker and Hughson, 2016). The fusion partners each have cis -SNARE complexes to be broken up by NSF and αSNAP. The Qa-SNARE monomers are then stabilized by interaction with Sec1-type regulators (SM proteins) to form trans -SNARE complexes, as shown for the yeast vacuole (Baker et al., 2015). Membrane fusion in Arabidopsis cytokinesis is formally akin to vacuolar fusion (Müller and Jürgens, 2016). Membrane vesicles fuse with one another to form the partitioning membrane known as cell plate. C is -SNARE complexes of cytokinesis-specific Qa-SNARE KNOLLE and its SNARE partners are assembled at the ER and delivered by traffic via Golgi/TGN to the cell division plane (Karnahl and Park et al., 2017). SM protein KEULE is required for the formation of trans -SNARE complexes between adjacent membrane vesicles (Park et al., 2012). Here, we identify the missing NSF-type AAA + -ATPase and its adaptor αSNAP2 required for disassembly of KNOLLE cis -SNARE complexes. In addition, we show that NSF is also required for other trafficking pathways and interacts with the respective Q-SNAREs. In conclusion, the SNARE complex disassembly machinery is conserved in plants and plays a unique essential role in cytokinesis.