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In order to reproduce previous results in Bi-2212 single crystals, the effects associated with the addition of Ti to the precursors of Laser Floating Zone textured Bi-2212 thin rods have been analyzed. It has been found that Ti induces a great number of nucleation centers in the molten zone and, in consequence, it reduces the grain size one order of magnitude. In addition, using the same growth conditions, the texture of the sample is strongly degraded. These microstructural changes strongly affect the superconducting properties showing that Ti addition destroys the network of low angle grain boundaries that are responsible for the high critical currents in these materials.Se ha analizado el efecto de la introducción de Ti en precursores de Bi-2212 para ser texturados mediante láser a través del método de zona flotante, todo ello debido a los resultados esperanzadores obtenidos en monocristales. Se ha encontrado que el Ti introduce un gran número de centros de nucleación en la zona fundida, por lo que se reducen las dimensiones de los granos en un orden de magnitud aproximadamente. Por otra parte, y utilizando las mismas condiciones de crecimiento, se observa que la textura de la muestra se degrada severamente, Estos cambios microestructurales afectan en gran medida a las propiedades superconductoras, demostrándose que la introducción de Ti destruye la red de fronteras de grano de bajo ángulo, que son las responsables en estos materiales de las altas corrientes criticas.

Germ-line mutations in PALB2 lead to a familial predisposition to breast and pancreatic cancer or to Fanconi Anemia subtype N. PALB2 performs its tumor suppressor role, at least in part, by supporting homologous recombination-type double strand break repair (HRDSBR) through physical interactions with BRCA1, BRCA2, and RAD51. To further understand the mechanisms underlying PALB2mediated DNA repair and tumor suppression functions, we targeted Palb2 in the mouse. Palb2-deficient murine ES cells recapitulated DNA damage defects caused by PALB2 depletion in human cells, and germline deletion of Palb2 led to early embryonic lethality. Somatic deletion of Palb2 driven by K14-Cre led to mammary tumor formation with long latency. Codeletion of both Palb2 and Tumor protein 53 (Trp53) accelerated mammary tumor formation. Like BRCA1 and BRCA2 mutant breast cancers, these tumors were defective in RAD51 focus formation, reflecting a defect in Palb2 HR-DSBR function, a strongly suspected contributor to Brca1, Brca2, and Palb2 mammary tumor development. However, unlike the case of Brca1mutant cells, Trp53bp1 deletion failed to rescue the genomic instability of Palb2- or Brca2-mutant primary lymphocytes. Therefore, Palb2-driven DNA damage control is, in part, distinct from that executed by Brca1 and more similar to that of Brca2. The mechanisms underlying Palb2 mammary tumor suppression functions can now be explored genetically in vivo.

Magnetic impurities on superconductors lead to bound states within the superconducting gap, so called Yu-Shiba-Rusinov (YSR) states. They are parity protected, which enhances their lifetime, but makes it more difficult to excite them. Here, we realize the excitation of YSR states by microwaves facilitated by the tunnel coupling to another superconducting electrode in a scanning tunneling microscope (STM). We identify the excitation process through a family of anomalous microwave-assisted tunneling peaks originating from a second-order resonant Andreev process, in which the microwave excites the YSR state triggering a tunneling event transferring a total of two charges. We vary the amplitude and the frequency of the microwave to identify the energy threshold and the evolution of this excitation process. Our work sets an experimental basis and proof-of-principle for the manipulation of YSR states using microwaves with an outlook towards YSR qubits., (© 2023. Springer Nature Limited.)

Electric control of spins has been a longstanding goal in the field of solid state physics due to the potential for increased efficiency in information processing. This efficiency can be optimized by transferring spintronics to the atomic scale. We present electric control of spin resonance transitions in single TiH molecules by employing electron spin resonance scanning tunneling microscopy (ESR-STM). We find strong bias voltage dependent shifts in the ESR signal of about ten times its line width. We attribute this to the electric field in the tunnel junction, which induces a displacement of the spin system changing the g-factor and the effective magnetic field of the tip. We demonstrate direct electric control of the spin transitions in coupled TiH dimers. Our findings open up new avenues for fast coherent control of coupled spin systems and expands on the understanding of spin electric coupling., (© 2023. Springer Nature Limited.)

In 2016, the Dutch government declared its commitment to phasing out animal experiments by 2025. Although a high number of animal experiments are still performed and the 2025 target will not be met, the commitment remains. Efforts are being made to identify levers that might foster the transition to animal-free science. Education has been found to play a key role in the future of animal-free science and young generations are increasingly seen as key stakeholders. However, their attitudes toward the transition to animal-free innovations have not been investigated. The present article focuses on the values and beliefs held by students, who in 2022, participated in the course 'Replacing Animal Testing' (RAT) Challenge, organized by a consortium of Dutch universities. Contextually, students' motivations to follow the course were investigated. The research was based on a qualitative study, including semi-structured interviews and a literature review. Our analysis of the findings revealed that students feel aligned with the social, ethical, and scientific reasons that support the transition to animal-free innovations. Moreover, the participants identified a series of regulatory, educational, cultural, and political obstacles to the transition that align with those identified in recent literature. From the discussion of these findings, we extrapolated six fundamental challenges that need to be addressed to foster the transition to animal-free science in an acceptable and responsible way., Competing Interests: The authors declare no conflict of interest.

Recently, imaging biomarkers have gained importance for the characterization of patients with Alzheimer's disease; however, the relationship between regional biomarker expression and cognitive function remains unclear. In our study, we investigated associations between scores on CERAD neuropsychological assessment battery (CERAD-NAB) subtests with regional glucose metabolism, cortical thickness and amyloid deposition in patients with early Alzheimer's disease (AD) using [18F]-fluorodeoxyglucose (FDG), structural MRI, and 11C-Pittsburgh Compound B (PiB) positron emission tomography (PET), respectively. A total of 76 patients (mean age 68.4 ± 8.5 years, 57.9% male) with early AD (median global clinical dementia rating (CDR) score = 0.5, range: 0.5-2.0) were studied. Associations were investigated by correlation and multiple regression analyses. Scores on cognitive subtests were most closely predicted by regional glucose metabolism with explained variance up to a corrected R² of 0.518, followed by cortical thickness and amyloid deposition. Prediction of cognitive subtest performance was increased up to a corrected R² of 0.622 for Word List-Delayed Recall, when biomarker information from multiple regions and multiple modalities were included. For verbal, visuoconstructive and mnestic domains the closest associations with FDG-PET imaging were found in the left lateral temporal lobe, right parietal lobe, and posterior cingulate cortex, respectively. Decreased cortical thickness in parietal regions was most predictive of impaired subtest performance. Remarkably, cerebral amyloid deposition significantly predicted cognitive function in about half of the subtests but with smaller extent of variance explained (corrected R² ≤ 0.220). We conclude that brain metabolism and atrophy affect cognitive performance in a regionally distinct way. Significant predictions of cognitive function by PiB-PET in half of CERAD-NAB subtests suggest functional relevance even in symptomatic patients with AD, challenging the concept of plateauing cortical amyloid deposition early in the disease course. Our results underscore the complex spatial relationship between different imaging biomarkers., (Copyright © 2020 Hedderich, Drost, Goldhardt, Ortner, Müller-Sarnowski, Diehl-Schmid, Zimmer, Förstl, Yakushev, Jahn and Grimmer.)

Following publication of the original article [1], the authors ask to correct the surname of co-author Dennis Hedderich from from Heddderich to Hedderich.

Background: As investigations of disease modifying drugs aim to slow down progression of Alzheimer' disease (AD) biomarkers to reliably track disease progression gain more importance. This is especially important as clinical symptoms, including psychometric measures, are only modestly associated with the underlying disease pathology, in particular at the pre-dementia stages. The decision which biomarkers to choose in clinical trials is crucial and depends on effect size. However, longitudinal studies of multiple biomarkers in parallel that allow direct comparison on effect size are scarce., Methods: We calculated effect size and minimal sample size for three common imaging biomarkers of AD, namely amyloid deposition measured with PiB-PET, neuronal dysfunction measured with FDG-PET and cortical thickness measured with MRI in a prospective 24-month follow-up study in a monocentric cohort of early AD., Results: Post hoc power calculation revealed large effect sizes of Cohen's d for PiB-PET and cortical thickness and a small effect size for FDG-PET (1.315, 0.914, and 0.341, respectively). Accordingly, sample sizes for PiB-PET and cortical thickness required significantly smaller sample sizes than FDG-PET to reliably detect statistically significant changes after 24 months in early AD (n = 7, n = 12, and n = 70, respectively)., Conclusion: Amyloid imaging with PET and measuring cortical thickness with MRI are suitable biomarkers to detect disease progression in early AD within a small sample.

Purpose: We aimed to characterize and target drug-tolerant BRCA1-deficient tumor cells that cause residual disease and subsequent tumor relapse. Experimental Design: We studied responses to various mono- and bifunctional alkylating agents in a genetically engineered mouse model for BRCA1/p53 -mutant breast cancer. Because of the large intragenic deletion of the Brca1 gene, no restoration of BRCA1 function is possible, and therefore, no BRCA1-dependent acquired resistance occurs. To characterize the cell-cycle stage from which Brca1 -/- ;p53 -/- mammary tumors arise after cisplatin treatment, we introduced the fluorescent ubiquitination-based cell-cycle indicator (FUCCI) construct into the tumor cells. Results: Despite repeated sensitivity to the MTD of platinum drugs, the Brca1 -mutated mammary tumors are not eradicated, not even by a frequent dosing schedule. We show that relapse comes from single-nucleated cells delaying entry into the S-phase. Such slowly cycling cells, which are present within the drug-naïve tumors, are enriched in tumor remnants. Using the FUCCI construct, we identified nonfluorescent G 0 -like cells as the population most tolerant to platinum drugs. Intriguingly, these cells are more sensitive to the DNA-crosslinking agent nimustine, resulting in an increased number of multinucleated cells that lack clonogenicity. This is consistent with our in vivo finding that the nimustine MTD, among several alkylating agents, is the most effective in eradicating Brca1 -mutated mouse mammary tumors. Conclusions: Our data show that targeting G 0 -like cells is crucial for the eradication of BRCA1/p53-deficient tumor cells. This can be achieved with selected alkylating agents such as nimustine. Clin Cancer Res; 23(22); 7020-33. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to breast cancer. BRCA1 plays an important role in DNA double-strand break (DSB) repair via homologous recombination (HR), which is important for tumor suppression. Although BRCA1-deficient cells are highly sensitive to treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses to platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors in clinical trials. It is unclear whether all pathogenic BRCA1 mutations have similar effects on the response to therapy. Here, we have investigated mammary tumorigenesis and therapy sensitivity in mice carrying the Brca1185stop and Brca15382stop alleles, which respectively mimic the 2 most common BRCA1 founder mutations, BRCA1185delAG and BRCA15382insC. Both the Brca1185stop and Brca15382stop mutations predisposed animals to mammary tumors, but Brca1185stop tumors responded markedly worse to HRD-targeted therapy than did Brca15382stop tumors. Mice expressing Brca1185stop mutations also developed therapy resistance more rapidly than did mice expressing Brca15382stop. We determined that both murine Brca1185stop tumors and human BRCA1185delAG breast cancer cells expressed a really interesting new gene domain-less (RING-less) BRCA1 protein that mediated resistance to HRD-targeted therapies. Together, these results suggest that expression of RING-less BRCA1 may serve as a marker to predict poor response to DSB-inducing therapy in human cancer patients.

Background: Mental health disorders may bring costs and benefits to areas and sectors lying outside the health care system. However, little is known about these inter-sectoral costs and benefits (ICBs) in spite of the increasing interest in societal cost-benefit analyses (SCBA) that attempt to quantify all costs and benefits involved.
AIM: To present a first inventory of ICBs relating to mental health care and to describe the relation between ICBs and SCBA.
METHOD: We reviewed the literature and conducted a secondary analysis of the results of a previous study.
RESULTS: We found that at least eight mental health disorders were reported to have a (financial) impact on at least three sectors outside the health care system.
CONCLUSION: Further research into ICBs is needed so that future inter-sectoral policy can be better directed and targeted more efficiently.