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Copy number variation (CNV) of samples in TCGA

Supplementary Table S7 - XLSX file 61K, List of shRNAs used in this study

DEDD and MCL1 overexpression are not necessary for initiation of tumorigenesis.

Supplementary Figure 2 - PDF file 17K, SKIL induces Matrigel invasion

PDF file 146K, This file contains the legends to Supplementary Figures 1-7 and Supplementary methods

S1 XLSX file 63K, This Supplementary Table contains the results of ORF screen to identify genes that can rescue the suppression of TBK1 in a KRAS-dependent cell line

Focal amplification of chromosome 1q23.3 in patients with advanced primary or relapsed urothelial carcinomas is associated with poor survival. We interrogated chromosome 1q23.3 and the nearby focal amplicon 1q21.3, as both are associated with increased lymph node disease in patients with urothelial carcinoma. Specifically, we assessed whether the oncogene MCL1 that resides in 1q21.3 and the genes that reside in the 1q23.3 amplicon were required for the proliferation or survival of urothelial carcinoma. We observed that suppressing MCL1 or the death effector domain–containing protein (DEDD) in the cells that harbor amplifications of 1q21.3 or 1q23.3, respectively, inhibited cell proliferation. We also found that overexpression of MCL1 or DEDD increased anchorage independence growth in vitro and increased experimental metastasis in vivo in the nonamplified urothelial carcinoma cell line, RT112. The expression of MCL1 confers resistance to a range of apoptosis inducers, while the expression of DEDD led to resistance to TNFα-induced apoptosis. These observations identify MCL1 and DEDD as genes that contribute to aggressive urothelial carcinoma.Implications:These studies identify MCL1 and DEDD as genes that contribute to aggressive urothelial carcinomas.

PDF file 1227K, This file contains Supplemental Figures 1-7, which provide additional supporting information for each of the main figures

Supplementary Legends - PDF file 122K, Legends for all Supplementary information

Supplementary Figure 3 - PDF file 20K, 3q26 copy number in cancer cell lines

Supplementary Figure 1 - PDF file 25K, Correlation between TLOC1 suppression and cell proliferation

GO terms for NEK6 upregulated genes Day 5 after castration (filtered for >10 GeneHits).

LISA analysis of master regulators of differentially expressed genes

Supplementary Data including supplementary methods, supplementary figures, and supplementary figure legends.

GSEA Hallmarks analysis of RNA-seq of bulk lung tumors

RNA-seq data of bulk lung tumors from sgControl RPP, sgNotch1 RPP, sgNotch2 RPP, and sgAscl1 RPP CRISPR-based SCLC GEMMs

Therapeutic anticancer vaccination has been adapted as an immunotherapy in several solid tumors. However, the selection of promising candidates from the total quantity of possible epitopes poses a challenge to clinicians and bioinformaticians alike, and very few epitopes have been tested in experimental or clinical settings to validate their efficacy. Here, we present a comprehensive database of predicted nonmutated peptide epitopes derived from genes that are overly expressed in a group of 32 melanoma biopsies compared with healthy tissues and that were filtered against expression in a curated list of survival-critical tissues. We hypothesize that these "self-tolerant" epitopes have two desirable properties: they do not depend on mutations, being immediately applicable to a large patient collective, and they potentially cause fewer autoimmune reactions. To support epitope selection, we provide an aggregated score of expected therapeutic efficiency as a shortlist mechanism. The database has applications in facilitating epitope selection and trial design and is freely accessible at https://www.curatopes.com.Significance:A database is presented that predicts and scores antitumor T-cell epitopes, with a focus on tolerability and avoidance of severe autoimmunity, offering a supplementary epitope set for further investigation in immunotherapy.

In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions. In addition to the identification of known mediators of castration resistance, which served to validate the screen, we identified a mitotic-related serine/threonine kinase, NEK6, as a mediator of androgen-independent tumor growth. NEK6 was overexpressed in a subset of human prostate cancers. Silencing NEK6 in castration-resistant cancer cells was sufficient to restore sensitivity to castration in a mouse xenograft model system. Tumors in which castration resistance was conferred by NEK6 were predominantly squamous in histology with no evidence of AR signaling. Gene expression profiling suggested that NEK6 overexpression stimulated cytoskeletal, differentiation, and immune signaling pathways and maintained gene expression patterns normally decreased by castration. Phosphoproteome profiling revealed the transcription factor FOXJ2 as a novel NEK6 substrate, with FOXJ2 phosphorylation associated with increased expression of newly identified NEK6 transcriptional targets. Overall, our studies establish NEK6 signaling as a central mechanism mediating castration-resistant prostate cancer. Cancer Res; 77(3); 753–65. ©2016 AACR.

Description of additional methods and procedures used in the study.

RNA-seq data of the SCLC adherent cells that are either Notch-WT or Notch-Mutant

Neuroendocrine to nonneuroendocrine plasticity supports small cell lung cancer (SCLC) tumorigenesis and promotes immunogenicity. Approximately 20% to 25% of SCLCs harbor loss-of-function (LOF) NOTCH mutations. Previous studies demonstrated that NOTCH functions as a SCLC tumor suppressor, but can also drive nonneuroendocrine plasticity to support SCLC growth. Given the dual functionality of NOTCH, it is not understood why SCLCs select for LOF NOTCH mutations and how these mutations affect SCLC tumorigenesis. In a CRISPR-based genetically engineered mouse model of SCLC, genetic loss of Notch1 or Notch2 modestly accelerated SCLC tumorigenesis. Interestingly, Notch-mutant SCLCs still formed nonneuroendocrine subpopulations, and these Notch-independent, nonneuroendocrine subpopulations were driven by Runx2-mediated regulation of Rest. Notch2-mutant nonneuroendocrine cells highly express innate immune signaling genes including stimulator of interferon genes (STING) and were sensitive to STING agonists. This work identifies a Notch-independent mechanism to promote nonneuroendocrine plasticity and suggests that therapeutic approaches to activate STING could be selectively beneficial for SCLCs with NOTCH2 mutations.Significance:A genetically engineered mouse model of NOTCH-mutant SCLC reveals that nonneuroendocrine plasticity persists in the absence of NOTCH, driven by a RUNX2-REST–dependent pathway and innate immune signaling.

Legend for Supplemental Figures S1-S6.

Contains further information on raw data, its sources and processing (NGS pipeline, tissue lists and selection). We also provide supporting information on the selected genes and their expression patterns in the relevant tissues.

Neuroendocrine to nonneuroendocrine plasticity supports small cell lung cancer (SCLC) tumorigenesis and promotes immunogenicity. Approximately 20% to 25% of SCLCs harbor loss-of-function (LOF) NOTCH mutations. Previous studies demonstrated that NOTCH functions as a SCLC tumor suppressor, but can also drive nonneuroendocrine plasticity to support SCLC growth. Given the dual functionality of NOTCH, it is not understood why SCLCs select for LOF NOTCH mutations and how these mutations affect SCLC tumorigenesis. In a CRISPR-based genetically engineered mouse model of SCLC, genetic loss of Notch1 or Notch2 modestly accelerated SCLC tumorigenesis. Interestingly, Notch-mutant SCLCs still formed nonneuroendocrine subpopulations, and these Notch-independent, nonneuroendocrine subpopulations were driven by Runx2-mediated regulation of Rest. Notch2-mutant nonneuroendocrine cells highly express innate immune signaling genes including stimulator of interferon genes (STING) and were sensitive to STING agonists. This work identifies a Notch-independent mechanism to promote nonneuroendocrine plasticity and suggests that therapeutic approaches to activate STING could be selectively beneficial for SCLCs with NOTCH2 mutations. Significance: A genetically engineered mouse model of NOTCH-mutant SCLC reveals that nonneuroendocrine plasticity persists in the absence of NOTCH, driven by a RUNX2-REST–dependent pathway and innate immune signaling.

Rationale: In the INSTAGE trial in patients with idiopathic pulmonary fibrosis (IPF) and severely impaired gas exchange, nintedanib plus sildenafil was associated with numerical benefits on St. George’s Respiratory Questionnaire (SGRQ) total score, brain natriuretic peptide (BNP), and FVC decline versus nintedanib alone. Exploratory analyses of the STEP-IPF (Sildenafil Trial of Exercise Performance in IPF) trial suggested that sildenafil may have a greater effect on SGRQ score in patients with IPF who have right heart dysfunction (RHD). Objectives: Assess whether RHD influenced the effects of nintedanib plus sildenafil versus nintedanib alone in the INSTAGE trial. Methods: Subgroup analyses of patients with (n = 117) versus those without (n = 156) echocardiographic signs of RHD at baseline. Measurements and Main Results: There was no heterogeneity between subgroups by presence of RHD in the effect of nintedanib plus sildenafil versus nintedanib alone on change in SGRQ total score at Week 12 (P = 0.74) or Week 24 (P = 0.90), or change in FVC at Week 12 (P = 0.58) or Week 24 (P = 0.55). In both subgroups, nintedanib plus sildenafil had a numerically greater effect on reducing FVC decline versus nintedanib alone. Between-group differences in change in BNP at Week 24 were −119.9 ng/L (95% confidence interval = −171.3 to −68.5) and −3.6 ng/L (95% confidence interval = −47.2 to 40.0) in patients with and without signs of RHD at baseline, respectively (P

PurposeThe purpose of this study is to refine theory of negotiation by empirically investigating the extent to which national-, societal- and individual-level cultures relate to negotiators' tendency to endorse questionable negotiation tactics.Design/methodology/approachTo assess the hypothesized relationships between culture and ethically questionable negotiation tactics at three cultural levels of analysis, the authors collected data from Turks who reside in Turkey and in Germany and from Greeks who reside in Greece and in Cyprus. Respondents' national-level cultural values were inferred from their nationality, respondents' societal-level cultural values were inferred from their country of residency, and respondents' individual-level cultural values were inferred from their discrete and unique individuality.FindingsAt the national level, the authors found that Turks in Turkey and Germany scored significantly higher than Greeks in Greece and Cyprus on the endorsement of pretending negotiation tactics. At the societal level, the authors found that Turkish negotiators in Germany displayed higher levels of lying negotiation tactics and lower levels of pretending negotiation tactics than Turkish negotiators in Turkey. Greek negotiators in Greece endorsed deceiving and lying tactics more than Greek negotiators in Cyprus. At the individual level, the authors found that negotiators who score high on vertical individualism and collectivism endorse questionable negotiation tactics significantly more than negotiators who score high on horizontal individualism and collectivism.Originality/valueThe authors empirically demonstrate how national-, societal- and individual-level cultures differentially influence negotiators' tendency to endorse questionable negotiation tactics. The study's trilevel analysis allows for integrating the societal-level theories of negotiators' acculturation and cultural adjustment to a host culture, highlighting the importance of bicultural identity.

With the Expanded Long Wavelength Array and pulsar binning techniques, we searched for off-pulse emission from PSR B0950 + 08 at 76 MHz. Previous studies suggest that off-pulse emission can be due to pulsar wind nebulae (PWNe) in younger pulsars. Other studies, such as that done by Basu et al., propose that in older pulsars this emission extends to some radius that is on the order of the light cylinder radius, and is magnetospheric in origin. Through imaging analysis, we conclude that this older pulsar with a spin-down age of 17 Myr has a surrounding PWN, which is unexpected since as a pulsar ages its PWN spectrum is thought to shift from being synchrotron to inverse Compton scattering dominated. At 76 MHz, the average flux density of the off-pulse emission is 0.59 ± 0.16 Jy. The off-pulse emission from B0950+08 is ∼ 110 ± 17 arcsec (0.14 ± 0.02 pc) in size, extending well beyond the light cylinder diameter and ruling out a magnetospheric origin. Using data from our observation and the surveys VLSSr, TGSS, NVSS, FIRST, and VLASS, we have found that the spectral index for B0950 + 08 is about −1.36 ± 0.20, while the PWN’s spectral index is steeper than −1.85 ± 0.45.

Approximately one-third of existing $\gamma$-ray sources identified by the $\textit{Fermi Gamma-Ray Space Telescope}$ are considered to be unassociated, with no known counterpart at other frequencies/wavelengths. These sources have been the subject of intense scrutiny and observational effort during the observatory's mission lifetime, and here we present a method of leveraging existing radio catalogs to examine these sources without the need for specific dedicated observations, which can be costly and complex. Via the inclusion of many sensitive low-frequency catalogs we specifically target steep spectrum sources such as pulsars. This work has found steep-spectrum radio sources contained inside 591 $\textit{Fermi}$ unassociated fields, with at least 21 of them being notable for having pulsar-like $\gamma$-ray properties as well. We also identify a number of other fields of interest based on various radio and $\gamma$-ray selections., Comment: 13 pages, 5 figures, 3 tables, accepted for publication in ApJ

Autonomous mobile robots with manipulators are becoming increasingly important in industry because they are the most flexible type of mobile robots. Therefore, these mobile robots are employed in dynamic, heterogeneous and partly structured environments. However, as depicted in ANSI/RIA R15.08-1-2020, new safety requirements focusing the fitness of the mobile robots to its operational scenarios arise. In contrast to fenced industrial robots, mobile robots need to reason about their environment, specifically the monitored space and adapt accordingly. However, since the monitored space is often limited, today’s autonomous industrial mobile robots type C (IMR-C) as R15.08-1-2020 names this kind of robots waste much potential reducing their pace of work due to limited monitored space. To counteract this issue, we first analyze the effects of limited monitored space using system theoretic process analysis (STPA) and then come up with a novel monitoring tool closing the blind spots of the IMR-Cs. The comparison of the STPAs with and without external monitoring tools show risk reduction in the original loss scenarios but new loss scenarios and consuming effort in order to assemble them. We present a methodology to weight the gains and losses of assembling an additional monitoring tool using the Digital Twin. The evaluation of our prototype in a goods receipt scenario shows promising results.

Description, Cross-species genetic screens for mitochondrial regulators revealed EPS-8 as a link between actin stability and mitochondria., The dysfunction of mitochondria is associated with the physiological consequences of aging and many age-related diseases. Therefore, critical quality control mechanisms exist to protect mitochondrial functions, including the unfolded protein response of the mitochondria (UPRMT). However, it is still unclear how UPRMT is regulated in mammals with mechanistic discrepancies between previous studies. Here, we reasoned that a study of conserved mechanisms could provide a uniquely powerful way to reveal previously uncharacterized components of the mammalian UPRMT. We performed cross-species comparison of genetic requirements for survival under—and in response to—mitochondrial stress between karyotypically normal human stem cells and the nematode Caenorhabditis elegans. We identified a role for EPS-8/EPS8 (epidermal growth factor receptor pathway substrate 8), a signaling protein adaptor, in general mitochondrial homeostasis and UPRMT regulation through integrin-mediated remodeling of the actin cytoskeleton. This study also highlights the use of cross-species comparisons in genetic screens to interrogate cellular pathways.

Due to the increasing connectivity of modern vehicles, collected data is no longer only stored in the vehicle itself but also transmitted to car manufacturers and vehicle assistant apps. This development opens up new possibilities for digital forensics in criminal investigations involving modern vehicles. This paper deals with the digital forensic analysis of vehicle assistant apps of eight car manufacturers. We reconstruct the driver's activities based on the data stored on the smartphones and in the manufacturer's backend. For this purpose, data of the Android and iOS apps of the car manufacturers Audi, BMW, Ford, Mercedes, Opel, Seat, Tesla, and Volkswagen were extracted from the smartphone and examined using digital forensic methods in accordance with lawful government-approved forensics guidelines. Additionally, manufacturer data was retrieved using Subject Access Requests. Using the extensive data gathered, we successfully reconstruct trips and refueling processes, determine parking positions and duration, and track the locking and unlocking of the vehicle. These findings show that the digital forensic investigation of smartphone applications is a useful addition to vehicle forensics and should therefore be taken into account in the strategic preparation of future digital forensic investigations., This is the extended version of the Short Paper Grand Theft App: Digital Forensics of Vehicle Assistant Apps published at the 16th International Conference on Availability, Reliability and Security (ARES 2021)

The Committee on Radio Frequencies (CORF) is an independent committee of experts convened by the U.S. National Academies of Sciences, Engineering, and Medicine to consider the use of radio frequency spectrum for scientific applications and how such use may be protected amidst rising needs for the use of spectrum for numerous other purposes. This talk will provide an overview of a range of CORF activities with focus on the work of the committee in the past year.

Therapeutic anticancer vaccination has been adapted as an immunotherapy in several solid tumors. However, the selection of promising candidates from the total quantity of possible epitopes poses a challenge to clinicians and bioinformaticians alike, and very few epitopes have been tested in experimental or clinical settings to validate their efficacy. Here, we present a comprehensive database of predicted nonmutated peptide epitopes derived from genes that are overly expressed in a group of 32 melanoma biopsies compared with healthy tissues and that were filtered against expression in a curated list of survival-critical tissues. We hypothesize that these "self-tolerant" epitopes have two desirable properties: they do not depend on mutations, being immediately applicable to a large patient collective, and they potentially cause fewer autoimmune reactions. To support epitope selection, we provide an aggregated score of expected therapeutic efficiency as a shortlist mechanism. The database has applications in facilitating epitope selection and trial design and is freely accessible at https://www.curatopes.com. Significance: A database is presented that predicts and scores antitumor T-cell epitopes, with a focus on tolerability and avoidance of severe autoimmunity, offering a supplementary epitope set for further investigation in immunotherapy.

This article examines the links between responsible leadership and corporate social responsibility (CSR) in one country, the Grand Duchy of Luxembourg, a linguistically and culturally specific country, and how they are perceived to be enacted or not. The purpose of this study is to combine Hofstede’s cross-cultural research with a research on responsible leadership and CSR in Luxembourg, in order to determine if there are any particularities that apply only in the country. In this qualitative study from Spring/Summer 2017, 64 semi-structured interviews were conducted mainly in four culturally different categories. This study is combined with the results of a 2016 study “What is responsible leadership in Luxembourg.” Findings indicate that language is used as a key identifier, affecting CSR outcomes, and point to high uncertainty avoidance levels in Luxembourg as a possible reason for lack of change and innovation. Finally, the article discusses the various implications of the findings.

AIMS: Reduced nitric oxide (NO) availability may adversely affect renal perfusion and glomerular filtration. The aim of the present study was to characterize in detail the pharmacological effects of VAS203, an inhibitor of NO synthase, on renal haemodynamics in humans. METHODS: This double‐blind, randomized, placebo‐controlled, cross‐over phase‐I‐study comprised 18 healthy men. Renal haemodynamics were assessed with constant‐infusion input‐clearance technique with p‐aminohippurate and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR), respectively. After baseline measurement, a constant infusion of the tetrahydrobiopterin analogue ronopterin (VAS203, total 10 mg/kg body weight) or placebo was administered at random order for 6 hours additionally. After a wash‐out phase of 28 days, the second course was applied. In parallel, markers of early kidney injury and renal function were assessed repeatedly up to 48 hours after starting VAS203/placebo‐infusion. RESULTS: VAS203‐infusion resulted in a significant decrease of RPF (P < .0001) and GFR (P < .001) compared to placebo, but magnitude was within the physiological range. RPF and GFR recovered partly 2 hours after end of VAS203‐infusion and was normal at beginning of the second infusion period. Compared to placebo, preglomerular resistance (P < .0001), and to lesser extent postglomerular resistance (P < .0001) increased, resulting in a decrease of intraglomerular pressure (P < .01). No treatment related effect on markers of early kidney injury, and on renal function (P for all >.20) have been observed. CONCLUSIONS: Our phase‐I‐study in healthy humans indicates that VAS203 (10 mg/kg body weight) reduces renal perfusion and glomerular function within the physiological range mainly due to vasoconstriction at the preglomerular site.

Die Zahl der Patienten mit Vorhofflimmern (VHF) steigt mit zunehmender Alterung der Bevolkerung. Auch die Zahl der Patienten mit VHF und Indikation fur eine orale Antikoagulation (OAK) zur Schlaganfallpravention, die aufgrund eines akuten Koronarsyndroms (ACS) oder einer perkutanen Koronarintervention (PCI) eine duale antithrombozytare Therapie (DAPT) mit Acetylsalicylsaure (ASS) und einem P2Y12-Inhibitor benotigen, steigt. Diese Patienten erhielten dann fur 3 bis 12 Monate eine Triple-Therapie (TT). Diese TT ist nie hinsichtlich ihrer Wirksamkeit uberpruft worden, allerdings ist die Blutungskomplikationsrate gegenuber einer einfachen OAK bzw. einer DAPT signifikant erhoht. Register und kleinere Studien zeigen, dass eine Zweifachtherapie mit OAK und einem Thrombozyteninhibitor ausreichend sein kann, um Schlaganfalle und Stentthrombosen/Myokardinfarkte zu verhindern. Diese Fragestellung wurde in verschiedenen prospektiven und randomisierten Studien mit den 4 fur die Schlaganfallpravention bei VHF zugelassenen NOAK (Nicht-Vitamin-K-abhangige orale Antikoagulanzien) untersucht. Dabei wurden die NOAK gegenuber einer Therapie mit Vitamin-K-Antagonisten (VKA) verglichen, wobei auf eine DAPT verzichtet und eine singulare Thrombozytenhemmertherapie getestet wurde. Die Untersuchungen mit Rivaroxaban (PIONEER-AF-PCI) und Dabigatran (RE-DUAL-PCI) sind publiziert, die Ergebnisse mit Apixaban (AUGUSTUS) und Edoxaban (ENTRUST-AF-PCI) werden demnachst erwartet. Bisher konnte nachgewiesen werden, dass NOAK plus ein Thrombozytenhemmer, meistens Clopidogrel, einer TT mit VKA hinsichtlich der Blutungen uberlegen war, ohne beobachtete Zunahme der Schlaganfalle und/oder kardialen Ischamien. Die internationalen Leitlinien erlauben, bereits auf eine TT zu verzichten, wenn das Blutungsrisiko im Vordergrund steht. Dafur sollten ein NOAK und eine singulare Thrombozytenhemmertherapie eingesetzt werden. Daher scheint die TT fur die allermeisten Patienten mit VHF und nach ACS/perkutaner Koronarintervention (PCI) nicht mehr indiziert zu sein.

Este trabalho aborda tópicos relacionados ao ensino de física atômica para alunos do ensino médio, considerando que o conhecimento da estrutura da matéria é de fundamental importância para o estudo da ciência. O objetivo geral é promover a aquisição de novos conceitos relacionados à estrutura da matéria por meio de uma sequência didática na forma de uma Unidade de Ensino Potencialmente Significativa (UEPS). As atividades propostas foram norteadas pela teoria de aprendizagem significativa de Ausubel e seus colaboradores Novak e Moreira. As análises dos resultados obtidos, após a aplicação da sequência didática e suas sondagens, apresentaram indicações de aprendizagem significativa.

Background Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF). A subgroup analysis of a previously published trial suggested that sildenafil may provide benefits regarding oxygenation, gas exchange as measured by the diffusion capacity of the lungs for carbon monoxide (DlCO), symptoms, and quality of life in patients with IPF and severely decreased DlCO. That idea was tested in this trial. Methods We randomly assigned, in a 1:1 ratio, patients with IPF and a DlCO of 35% or less of the predicted value to receive nintedanib at a dose of 150 mg twice daily plus sildenafil at a dose of 20 mg three times daily (nintedanib-plus-sildenafil group) or nintedanib at a dose of 150 mg twice daily plus placebo three times daily (nintedanib group) for 24 weeks. The primary end point was the change from baseline in the total score on the St. George’s Respiratory Questionnaire (SGRQ) at week 12 (the total score ranges from 0 to 100, with higher scores indicating worse health-related qual...

During embryogenesis, optic vesicles develop from the diencephalon via a complex process of organogenesis. Using iPSC-derived human brain organoids, we attempted to simplify the complexities and demonstrate the formation of forebrain-associated bilateral optic vesicles, cellular diversity, and functionality. Around day thirty, brain organoids could assemble optic vesicles, which progressively develop as visible structures within sixty days. These optic vesicle-containing brain organoids (OVB-Organoids) constitute a developing optic vesicle’s cellular components, including the primitive cornea and lens-like cells, developing photoreceptors, retinal pigment epithelia, axon-like projections, and electrically active neuronal networks. Besides, OVB-Organoids also display synapsin-1, CTIP-positive, myelinated cortical neurons, and microglia. Interestingly, various light intensities could trigger photoreceptor activity of OVB-Organoids, and light sensitivities could be reset after a transient photo bleach blinding. Thus, brain organoids have the intrinsic ability to self-organize forebrain-associated primitive sensory structures in a topographically restricted manner and can allow conducting interorgan interaction studies within a single organoid.

The dorsal cochlear nucleus (DCN) is a mammalian-specific nucleus of the auditory system. Anatomically, it is classified as a cerebellum-like structure. These structures are proposed to share genetic programs with the cerebellum. Previous analyses demonstrated that inhibitory serial sister cell types (SCTs) of the DCN and cerebellum are derived from the pancreatic transcription factor 1a (Ptf1a) lineage. Postmitotic neurons of the Ptf1a lineage often express the transcription factor Ladybird homeobox protein homolog 1 (Lbx1) which is involved in neuronal cell fate determination. Lbx1 is therefore an attractive candidate for a further component of the genetic program shared between the DCN and cerebellum. Here, we used cell-type specific marker analysis in combination with an Lbx1 reporter mouse line to analyze in both tissues which cell types of the Ptf1a lineage express Lbx1. In the DCN, stellate cells and Purkinje-like cartwheel cells were part of the Lbx1 lineage and Golgi cells were not, as determined by cell counts. In contrast, in the cerebellum, stellate cells and Golgi cells were part of the Lbx1 lineage and Purkinje cells were not. Hence, two out of three phenotypically similar cell types differed with respect to their Lbx1 expression. Our study demonstrates that Lbx1 is differentially recruited to the developmental genetic program of inhibitory neurons both within a given tissue and between the DCN and cerebellum. The differential expression of Lbx1 within the DCN and the cerebellum might contribute to the genetic individuation of the inhibitory SCTs to adapt to circuit specific tasks.