Derivation of functional thymic epithelial organoid lines from adult murine thymus

Thymic epithelial cells (TECs) orchestrate T cell development by imposing positive and negative selection on thymocytes. Current studies on TEC biology are hampered by the absence of long-term ex vivo culture platforms, while the cells driving TEC self-renewal remain to be identified. Here, we generate long-term (>2 years) expandable 3D TEC organoids from the adult mouse thymus. For further analysis, we generated single and double FoxN1-P2A-Clover, Aire-P2A-tdTomato, and Cldn4-P2A-tdTomato reporter lines by CRISPR knockin. Single-cell analyses of expanding clonal organoids reveal cells with bipotent stem/progenitor phenotypes. These clonal organoids can be induced to express Foxn1 and to generate functional cortical- and Aire-expressing medullary-like TECs upon RANK ligand + retinoic acid treatment. TEC organoids support T cell development from immature thymocytes in vitro as well as in vivo upon transplantation into athymic nude mice. This organoid-based platform allows in vitro study of TEC biology and offers a potential strategy for ex vivo T cell development

Spin injection and spin accumulation in all-metal mesoscopic spin valves

We study the electrical injection and detection of spin accumulation in lateral ferromagnetic metal-nonmagnetic metal-ferromagnetic metal (F/N/F) spin valve devices with transparent interfaces. Different ferromagnetic metals, permalloy (Py), cobalt (Co) and nickel (Ni), are used as electrical spin injectors and detectors. For the nonmagnetic metal both aluminium (Al) and copper (Cu) are used. Our multi-terminal geometry allows us to experimentally separate the spin valve effect from other magneto resistance signals such as the anomalous magneto resistance (AMR) and Hall effects. We find that the AMR contribution of the ferromagnetic contacts can dominate the amplitude of the spin valve effect, making it impossible to observe the spin valve effect in a 'conventional' measurement geometry. In a 'non local' spin valve measurement we are able to completely isolate the spin valve signal and observe clear spin accumulation signals at T=4.2 K as well as at room temperature (RT). For aluminum we obtain spin relaxation lengths (lambda_{sf}) of 1.2 mu m and 600 nm at T=4.2 K and RT respectively, whereas for copper we obtain 1.0 mu m and 350 nm. The spin relaxation times tau_{sf} in Al and Cu are compared with theory and results obtained from giant magneto resistance (GMR), conduction electron spin resonance (CESR), anti-weak localization and superconducting tunneling experiments. The spin valve signals generated by the Py electrodes (alpha_F lambda_F=0.5 [1.2] nm at RT [T=4.2 K]) are larger than the Co electrodes (alpha_F lambda_F=0.3 [0.7] nm at RT [T=4.2 K]), whereas for Ni (alpha_F lambda_F<0.3 nm at RT and T=4.2 K) no spin signal is observed. These values are compared to the results obtained from GMR experiments.Comment: 16 pages, 12 figures, submitted to PR

Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification

Background: Organoids are in vitro three-dimensional structures that can be grown from patient tissue. Head and neck cancer (HNC) is a collective term used for multiple tumor types including squamous cell carcinomas and salivary gland adenocarcinomas. Methods: Organoids were established from HNC patient tumor tissue and characterized using immunohistochemistry and DNA sequencing. Organoids were exposed to chemo- and radiotherapy and a panel of targeted agents. Organoid response was correlated with patient clinical response. CRISPR-Cas9-based gene editing of organoids was applied for biomarker validation. Findings: A HNC biobank consisting of 110 models, including 65 tumor models, was generated. Organoids retained DNA alterations found in HNC. Comparison of organoid and patient response to radiotherapy (primary [n = 6] and adjuvant [n = 15]) indicated potential for guiding treatment options in the adjuvant setting. In organoids, the radio-sensitizing potential of cisplatin and carboplatin could be validated. However, cetuximab conveyed radioprotection in most models. HNC-targeted treatments were tested on 31 models, indicating possible novel treatment options with the potential for treatment stratification in the future. Activating PIK3CA mutations did not predict alpelisib response in organoids. Protein arginine methyltransferase 5 (PRMT5) inhibitors were identified as a potential treatment option for cyclin-dependent kinase inhibitor 2A (CDKN2A) null HNC. Conclusions: Organoids hold potential as a diagnostic tool in personalized medicine for HNC. In vitro organoid response to radiotherapy (RT) showed a trend that mimics clinical response, indicating the predictive potential of patient-derived organoids. Moreover, organoids could be used for biomarker discovery and validation

Spintronics: Fundamentals and applications

Spintronics, or spin electronics, involves the study of active control and manipulation of spin degrees of freedom in solid-state systems. This article reviews the current status of this subject, including both recent advances and well-established results. The primary focus is on the basic physical principles underlying the generation of carrier spin polarization, spin dynamics, and spin-polarized transport in semiconductors and metals. Spin transport differs from charge transport in that spin is a nonconserved quantity in solids due to spin-orbit and hyperfine coupling. The authors discuss in detail spin decoherence mechanisms in metals and semiconductors. Various theories of spin injection and spin-polarized transport are applied to hybrid structures relevant to spin-based devices and fundamental studies of materials properties. Experimental work is reviewed with the emphasis on projected applications, in which external electric and magnetic fields and illumination by light will be used to control spin and charge dynamics to create new functionalities not feasible or ineffective with conventional electronics.Comment: invited review, 36 figures, 900+ references; minor stylistic changes from the published versio

Derivation of functional thymic epithelial organoid lines from adult murine thymus

Summary: Thymic epithelial cells (TECs) orchestrate T cell development by imposing positive and negative selection on thymocytes. Current studies on TEC biology are hampered by the absence of long-term ex vivo culture platforms, while the cells driving TEC self-renewal remain to be identified. Here, we generate long-term (>2 years) expandable 3D TEC organoids from the adult mouse thymus. For further analysis, we generated single and double FoxN1-P2A-Clover, Aire-P2A-tdTomato, and Cldn4-P2A-tdTomato reporter lines by CRISPR knockin. Single-cell analyses of expanding clonal organoids reveal cells with bipotent stem/progenitor phenotypes. These clonal organoids can be induced to express Foxn1 and to generate functional cortical- and Aire-expressing medullary-like TECs upon RANK ligand + retinoic acid treatment. TEC organoids support T cell development from immature thymocytes in vitro as well as in vivo upon transplantation into athymic nude mice. This organoid-based platform allows in vitro study of TEC biology and offers a potential strategy for ex vivo T cell development

Multimessenger search for sources of gravitational waves and high-energy neutrinos: Initial results for LIGO-Virgo and IceCube

We report the results of a multimessenger search for coincident signals from the LIGO and Virgo gravitational-wave observatories and the partially completed IceCube high-energy neutrino detector, including periods of joint operation between 2007-2010. These include parts of the 2005-2007 run and the 2009-2010 run for LIGO-Virgo, and IceCube's observation periods with 22, 59 and 79 strings. We find no significant coincident events, and use the search results to derive upper limits on the rate of joint sources for a range of source emission parameters. For the optimistic assumption of gravitational-wave emission energy of 10-2 M⊙c2 at ˜150 Hz with ˜60 ms duration, and high-energy neutrino emission of 1 051 erg comparable to the isotropic gamma-ray energy of gamma-ray bursts, we limit the source rate below 1.6 ×1 0-2 Mpc-3 yr-1 . We also examine how combining information from gravitational waves and neutrinos will aid discovery in the advanced gravitational-wave detector era.status: publishe