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A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125–0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1–4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated. Opis vira z dne 7. 3. 2023. Nasl. z nasl. zaslona. Bibliografija: str. 3992-3994. Abstract.

The effects of severe plastic deformation (SPD) by means of high-pressure torsion (HPT) on the structural properties of the two iron-based metallic glasses Fe73.9Cu1Nb3Si15.5B6.6 and Fe81.2Co4Si0.5B9.5P4Cu0.8 have been investigated and compared. While for Fe73.9Cu1Nb3Si15.5B6.6, HPT processing allows us to extend the known consolidation and deformation ranges, HPT processing of Fe81.2Co4Si0.5B9.5P4Cu0.8 for the first time ever achieves consolidation and deformation with a minimum number of cracks. Using numerous analyses such as X-ray diffraction, dynamic mechanical analyses, and differential scanning calorimetry, as well as optical and transmission electron microscopy, clearly reveals that Fe81.2Co4Si0.5B9.5P4Cu0.8 exhibits HPT-induced crystallization phenomena, while Fe73.9Cu1Nb3Si15.5B6.6 does not crystallize even at the highest HPT-deformation degrees applied. The reasons for these findings are discussed in terms of differences in the deformation energies expended, and the number and composition of the individual crystalline phases formed. The results appear promising for obtaining improved magnetic properties of glassy alloys without additional thermal treatment.

Background: The present study compared adult usage patterns of online activities, the frequency rate of problematic internet use (PIU), and risk factors (including the psychopathology associated with PIU, i.e., distress and impulsivity) among adults in 15 countries from Europe, America, and Asia. Methods: A total of 5130 adults from Belgium, Finland, Germany, Italy, Spain, France, Switzerland, Hungary, Poland, UK, Norway, Peru, Canada, US, and Indonesia completed an online survey assessing PIU and a number of psychological variables (i.e., depression, anxiety, stress, and impulsivity). The sample included more females, with a mean age of 24.71 years (SD = 8.70). Results: PIU was slightly lower in European countries (rates ranged from 1.1% in Finland to 10.1% in the UK, compared to 2.9% in Canada and 10.4% in the US). There were differences in specific PIU rates (e.g., problematic gaming ranged from 0.4% in Poland to 4.7% in Indonesia). Regression analyses showed that PIU was predicted by problematic social networking and gaming, lack of perseverance, positive urgency, and depression. Conclusions: The differences in PIU between countries were significant for those between continental regions (Europe versus non-European countries). One of the most interesting findings is that the specific PIU risks were generally low compared to contemporary literature. However, higher levels of PIU were present in countries outside of Europe, although intra-European differences existed.

PURPOSE Heart failure (HF) is a potentially life-threatening complication of treatment for childhood cancer. We evaluated the risk and risk factors for HF in a large European study of long-term survivors. Little is known of the effects of low doses of treatment, which is needed to improve current treatment protocols and surveillance guidelines. METHODS This study includes the PanCareSurFup and ProCardio cohort of ≥ 5-year childhood cancer survivors diagnosed between 1940 and 2009 in seven European countries (N = 42,361). We calculated the cumulative incidence of HF and conducted a nested case-control study to evaluate detailed treatment-related risk factors. RESULTS The cumulative incidence of HF was 2% (95% CI, 1.7 to 2.2) by age 50 years. The case-control study (n = 1,000) showed that survivors who received a mean heart radiation therapy (RT) dose of 5 to < 15 Gy have an increased risk of HF (odds ratio, 5.5; 95% CI, 2.5 to 12.3), when compared with no heart RT. The risk associated with doses 5 to < 15 Gy increased with exposure of a larger heart volume. In addition, the HF risk increased in a linear fashion with higher mean heart RT doses. Regarding total cumulative anthracycline dose, survivors who received ≥ 100 mg/m2 had a substantially increased risk of HF and survivors treated with a lower dose showed no significantly increased risk of HF. The dose-response relationship appeared quadratic with higher anthracycline doses. CONCLUSION Survivors who received a mean heart RT dose of ≥ 5 Gy have an increased risk of HF. The risk associated with RT increases with larger volumes exposed. Survivors treated with < 100 mg/m2 total cumulative anthracycline dose have no significantly increased risk of HF. These new findings might have consequences for new treatment protocols for children with cancer and for cardiomyopathy surveillance guidelines.

AbstractExperts modulate their performance of actions for teaching purposes, performing slower and exaggerated movements when demonstrating novel actions to novices. The present study asked whether such modulations also occur during teaching performance of a music instrument, where subtle movement modulations are crucial for achieving artistic expression. While exaggerating performances of goal-directed actions outside of artistic contexts may be straightforward, it is an open question whether and how exaggeration for the purpose of teaching operates for actions that are expressive even when performed outside of a teaching context. Pianists were asked to demonstrate to students the techniques required for implementing notated expressions, compared to performing the piece without didactic intentions. Expressions in the piece concerned either articulation (i.e., legato and staccato) or dynamics (i.e., forte and piano). The pianists played either with the goal to perform the piece to an audience or with the goal to teach the respective techniques to novices. When intending to teach articulation, skilled pianists produced more exaggerated staccato. When intending to teach dynamics, they created a larger contrast between forte and piano. We found consistent results across a simple musical scale (Experiment 1) and a more naturalistic piece of music (Experiment 2). These findings show that teaching-specific action modulations generalise to expressive actions and suggest that action modulations serve to highlight the most relevant aspects of the actions to be learnt.

AbstractIt is often claimed that humanity has stopped evolving because modern medicine erased all selection on survival. Even if that would be true, and it is not, there would be other mechanisms of evolution which could still led to changes in allelic frequencies. Here I show, by applying basic evolutionary genetics knowledge, that we expect humanity to evolve. The results from genome sequencing projects have repeatedly affirmed that there are still recent signs of selection in our genomes. I give some examples of such adaptation. Then I briefly discuss what our evolutionary future has in store for us.

Background: Survivors of Hodgkin lymphoma (HL) are at risk of developing non-Hodgkin lymphoma (NHL) after treatment; however, the risks of developing subsequent primary lymphomas (SPLs), including HL and NHL, after different types of childhood cancer are unknown. The authors quantified the risk of SPLs using the largest cohort of childhood cancer survivors worldwide. Methods: The Pan-European Network for Care of Survivors After Childhood and Adolescent Cancer (PanCare) Survivor Care and Follow-Up Studies (PanCareSurFup) cohort includes 69,460 five-year survivors of childhood cancer, diagnosed during 1940 through 2008, from 12 European countries. Risks of SPLs were quantified by standardized incidence ratios (SIRs) and relative risks (RRs) using multivariable Poisson regression. Results: Overall, 140 SPLs, including 104 NHLs and 36 HLs, were identified. Survivors were at 60% increased risk of an SPL compared with the general population (SIR, 1.6; 95% confidence interval [CI], 1.4?1.9). Survivors were twice as likely to develop NHL (SIR, 2.3; 95% CI, 1.9?2.8), with the greatest risks among survivors of HL (SIR, 7.1; 95% CI, 5.1?10.0), Wilms tumor (SIR, 3.1; 95% CI, 1.7?5.7), leukemia (SIR, 2.8; 95% CI, 1.8?4.4), and bone sarcoma (SIR, 2.7; 95% CI, 1.4?5.4). Treatment with chemotherapy for any cancer doubled the RR of NHL (RR, 2.1; 95% CI, 1.2?3.9), but treatment with radiotherapy did not (RR, 1.2; 95% CI, 0.7?2.0). Survivors were at similar risk of developing a subsequent HL as the general population (SIR, 1.1; 95% CI, 0.8?1.5). Conclusions: In addition to HL, the authors show here for the first time that survivors of Wilms tumor, leukemia, and bone sarcoma are at risk of NHL. Survivors and health care professionals should be aware of the risk of NHL in these survivors and in any survivors treated with chemotherapy. + ID der Publikation: unilu_62115 + Sprache: Englisch + Bemerkungen: https://doi.org/10.1002/cncr.34561 + Letzte Aktualisierung: 2022-12-07 16:03:24