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The Swiss StudentLife Study (SSL Study) is a longitudinal social network data collection conducted in three undergraduate student cohorts (N1 = 226, N2 = 261, N3 = 660) in 2016−2019. The main goal of the study was to understand the emergence of informal student communities and their effects on different individual outcomes, such as well-being, motivation, and academic success. To this end, multiple dimensions of social ties were assessed, combining computer-based surveys, social sensors, social media data, and field experiments. The dynamics of these social networks were measured on various time scales. In this paper, we present the design and data collection strategy of the SSL Study. We discuss practical challenges and solutions related to the data collection in four areas that were key to the success of our project: study design, research ethics, communication, and population definition.

Altered RNA expression of repetitive sequences and retrotransposition are frequently seen in colorectal cancer, implicating a functional importance of repeat activity in cancer progression. We show the nucleoside reverse transcriptase inhibitor 3TC targets activities of these repeat elements in colorectal cancer preclinical models with a preferential effect in p53-mutant cell lines linked with direct binding of p53 to repeat elements. We translate these findings to a human phase II trial of single-agent 3TC treatment in metastatic colorectal cancer with demonstration of clinical benefit in 9 of 32 patients. Analysis of 3TC effects on colorectal cancer tumorspheres demonstrates accumulation of immunogenic RNA:DNA hybrids linked with induction of interferon response genes and DNA damage response. Epigenetic and DNA-damaging agents induce repeat RNAs and have enhanced cytotoxicity with 3TC. These findings identify a vulnerability in colorectal cancer by targeting the viral mimicry of repeat elements.Significance:Colorectal cancers express abundant repeat elements that have a viral-like life cycle that can be therapeutically targeted with nucleoside reverse transcriptase inhibitors (NRTI) commonly used for viral diseases. NRTIs induce DNA damage and interferon response that provide a new anticancer therapeutic strategy.This article is highlighted in the In This Issue feature, p. 1397

Background and Hypothesis Cognitive impairment is a hallmark of schizophrenia, but no effective treatment is available to date. The underlying pathophysiology includes disconnectivity between hippocampal and prefrontal brain regions. Supporting evidence comes from diffusion-weighted imaging studies that suggest abnormal organization of frontotemporal white matter pathways in schizophrenia. Study Design Here, we hypothesize that in schizophrenia, deficient maturation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes substantially contributes to abnormal frontotemporal macro- and micro-connectivity and subsequent cognitive deficits. Study Results Our postmortem studies indicate a reduced oligodendrocyte number in the cornu ammonis 4 (CA4) subregion of the hippocampus, and others have reported the same histopathological finding in the dorsolateral prefrontal cortex. Our series of studies on aerobic exercise training showed a volume increase in the hippocampus, specifically in the CA4 region, and improved cognition in individuals with schizophrenia. The cognitive effects were subsequently confirmed by meta-analyses. Cell-specific schizophrenia polygenic risk scores showed that exercise-induced CA4 volume increase significantly correlates with OPCs. From animal models, it is evident that early life stress and oligodendrocyte-related gene variants lead to schizophrenia-related behavior, cognitive deficits, impaired oligodendrocyte maturation, and reduced myelin thickness. Conclusions Based on these findings, we propose that pro-myelinating drugs (e.g., the histamine blocker clemastine) combined with aerobic exercise training may foster the regeneration of myelin plasticity as a basis for restoring frontotemporal connectivity and cognition in schizophrenia.

Significant evidence links obesity and schizophrenia (SZ), but the brain associations are still largely unclear. 48 people with SZ were divided into two subgroups: patients with lower waist circumference (SZ-LWC: n = 24) and patients with higher waist circumference (SZ-HWC: n = 24). Healthy controls (HC) were included for comparison (HC: n = 27). Using tract-based spatial statistics, we compared fractional anisotropy (FA) of the whole-brain white matter skeleton between these three groups (SZ-LWC, SZ-HWC, HC). Using Free Surfer, we compared whole-brain cortical thickness and the selected subcortical volumes between the three groups. FA of widespread white matter and the mean cortical thickness in the right temporal lobe and insular cortex were significantly lower in the SZ-HWC group than in the HC group. The FA of regional white matter was significantly lower in the SZ-LWC group than in the HC group. There were no significant differences in mean subcortical volumes between the groups. This study provides evidence for microstructural abnormalities of white matter and cortical thickness in patients with SZ, which are more pronounced in those with excessive abdominal obesity.

Supplementary Figure from Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer

Supplementary Data from Reverse Transcriptase Inhibition Disrupts Repeat Element Life Cycle in Colorectal Cancer

Altered RNA expression of repetitive sequences and retrotransposition are frequently seen in colorectal cancer, implicating a functional importance of repeat activity in cancer progression. We show the nucleoside reverse transcriptase inhibitor 3TC targets activities of these repeat elements in colorectal cancer preclinical models with a preferential effect in p53-mutant cell lines linked with direct binding of p53 to repeat elements. We translate these findings to a human phase II trial of single-agent 3TC treatment in metastatic colorectal cancer with demonstration of clinical benefit in 9 of 32 patients. Analysis of 3TC effects on colorectal cancer tumorspheres demonstrates accumulation of immunogenic RNA:DNA hybrids linked with induction of interferon response genes and DNA damage response. Epigenetic and DNA-damaging agents induce repeat RNAs and have enhanced cytotoxicity with 3TC. These findings identify a vulnerability in colorectal cancer by targeting the viral mimicry of repeat elements.Significance:Colorectal cancers express abundant repeat elements that have a viral-like life cycle that can be therapeutically targeted with nucleoside reverse transcriptase inhibitors (NRTI) commonly used for viral diseases. NRTIs induce DNA damage and interferon response that provide a new anticancer therapeutic strategy.This article is highlighted in the In This Issue feature, p. 1397

Background Significant evidence links white matter (WM) microstructural abnormalities to cognitive impairment in schizophrenia (SZ), but the relationship of these abnormalities with functional outcome remains unclear. Methods In two independent cohorts (C1, C2), patients with SZ were divided into two subgroups: patients with higher cognitive performance (SZ-HCP-C1, n = 25; SZ-HCP-C2, n = 24) and patients with lower cognitive performance (SZ-LCP-C1, n = 25; SZ-LCP-C2, n = 24). Healthy controls (HC) were included in both cohorts (HC-C1, n = 52; HC-C2, n = 27). We compared fractional anisotropy (FA) of the whole-brain WM skeleton between the three groups (SZ-LCP, SZ-HCP, HC) by a whole-brain exploratory approach and an atlas-defined WM regions-of-interest approach via tract-based spatial statistics. In addition, we explored whether FA values were associated with Global Assessment of Functioning (GAF) scores in the SZ groups. Results In both cohorts, mean FA values of whole-brain WM skeleton were significantly lower in the SCZ-LCP group than in the SCZ-HCP group. Whereas in C1 the FA of the frontal part of the left inferior fronto-occipital fasciculus (IFOF) was positively correlated with GAF score, in C2 the FA of the temporal part of the left IFOF was positively correlated with GAF score. Conclusions We provide robust evidence for WM microstructural abnormalities in SZ. These abnormalities are more prominent in patients with low cognitive performance and are associated with the level of functioning.

Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13–41%) and 20% for PDAC (five of 25; 95% CI, 7–41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19–58%) in CRC and 29% (five of 17; 95% CI, 10–56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers. Ting and colleagues report the safety and efficacy of combined radiation and immunotherapy in a phase II trial on patients with MSS colorectal or pancreatic cancer and observe that disease control correlates with higher repetitive RNA transcription.

Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we reported a reduction in oligodendrocyte number in CA4 in schizophrenia and of granular neurons in the dentate gyrus (DG). Here, we aimed to replicate these findings in an independent sample. We used a stereological approach to investigate the numbers and densities of neurons, oligodendrocytes, and astrocytes in CA4 and of granular neurons in the DG of left and right hemispheres in 11 brains from men with schizophrenia and 11 brains from age- and sex-matched healthy controls. In schizophrenia, a decreased number and density of oligodendrocytes was detected in the left and right CA4, whereas mean volumes of CA4 and the DG and the numbers and density of neurons, astrocytes, and granular neurons were not different in patients and controls, even after adjustment of variables because of positive correlations with postmortem interval and age. Our results replicate the previously described decrease in oligodendrocytes bilaterally in CA4 in schizophrenia and point to a deficit in oligodendrocyte maturation or a loss of mature oligodendrocytes. These changes result in impaired myelination and neuronal decoupling, both of which are linked to altered functional connectivity and subsequent cognitive dysfunction in schizophrenia.

Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that human satellite II (HSATII) satellite repeat expression was highly associated with epithelial-mesenchymal transition (EMT) and anticorrelated with IFN-response genes indicative of a more aggressive phenotype. SATII expression - and its correlation with EMT and anticorrelation with IFN-response genes - was also found in ovarian cancer RNA-Seq data and was associated with significantly shorter survival in a second independent cohort of patients with ovarian cancer. Repeat RNAs were enriched in tumor-derived extracellular vesicles capable of stimulating monocyte-derived macrophages, demonstrating a mechanism that alters the tumor microenvironment with these viral-like sequences. Targeting of HSATII with antisense locked nucleic acids stimulated IFN response and induced MHC I expression in ovarian cancer cell lines, highlighting a potential strategy of modulating the repeatome to reestablish antitumor cell immune surveillance.

Across all branches of science, medicine and engineering, high-resolution microscopy is required to understand functionality. Although optical methods have been developed to `defeat' the diffraction limit and produce 3D images, and electrons have proven ever more useful in creating pictures of small objects or thin sections, so far there is no substitute for X-ray microscopy in providing multiscale 3D images of objects with a single instrument and minimal labeling and preparation. A powerful technique proven to continuously access length scales from 10 nm to 10 µm is ptychographic X-ray computed tomography, which, on account of the orthogonality of the tomographic rotation axis to the illuminating beam, still has the limitation of necessitating pillar-shaped samples of small (ca 10 µm) diameter. Large-area planar samples are common in science and engineering, and it is therefore highly desirable to create an X-ray microscope that can examine such samples without the extraction of pillars. Computed laminography, where the axis of rotation is not perpendicular to the illumination direction, solves this problem. This entailed the development of a new instrument, LamNI, dedicated to high-resolution 3D scanning X-ray microscopy via hard X-ray ptychographic laminography. Scanning precision is achieved by a dedicated interferometry scheme and the instrument covers a scan range of 12 mm × 12 mm with a position stability of 2 nm and positioning errors below 5 nm. A new feature of LamNI is a pair of counter-rotating stages carrying the sample and interferometric mirrors, respectively., Journal of Synchrotron Radiation, 27 (3), ISSN:0909-0495, ISSN:1600-5775

Spin-based logic architectures provide nonvolatile data retention, near-zero leakage, and scalability, extending the technology roadmap beyond complementary metal-oxide-semiconductor logic1-13. Architectures based on magnetic domain walls take advantage of the fast motion, high density, non-volatility and flexible design of domain walls to process and store information1,3,14-16. Such schemes, however, rely on domain-wall manipulation and clocking using an external magnetic field, which limits their implementation in dense, large-scale chips. Here we demonstrate a method for performing all-electric logic operations and cascading using domain-wall racetracks. We exploit the chiral coupling between neighbouring magnetic domains induced by the interfacial Dzyaloshinskii-Moriya interaction17-20, which promotes non-collinear spin alignment, to realize a domain-wall inverter, the essential basic building block in all implementations of Boolean logic. We then fabricate reconfigurable NAND and NOR logic gates, and perform operations with current-induced domain-wall motion. Finally, we cascade several NAND gates to build XOR and full adder gates, demonstrating electrical control of magnetic data and device interconnection in logic circuits. Our work provides a viable platform for scalable all-electric magnetic logic, paving the way for memory-in-logic applications.

Objective: To evaluate infectious pathogen transmission data visualizations in outbreak publications. Design: Scoping review. Methods: Medline was searched for outbreak investigations of infectious diseases within healthcare facilities that included ≥1 data visualization of transmission using data observable by an infection preventionist showing temporal and/or spatial relationships. Abstracted data included the nature of the cluster(s) (pathogen, scope of transmission, and individuals involved) and data visualization characteristics including visualization type, transmission elements, and software. Results: From 1,957 articles retrieved, we analyzed 30 articles including 37 data visualizations. The median cluster size was 20.5 individuals (range, 7–1,963) and lasted a median of 214 days (range, 12–5,204). Among the data visualization types, 10 (27%) were floor-plan transmission maps, 6 (16%) were timelines, 11 (30%) were transmission networks, 3 (8%) were Gantt charts, 4 (11%) were cluster map, and 4 (11%) were other types. In addition, 26 data visualizations (70%) contained spatial elements, 26 (70%) included person type, and 19 (51%) contained time elements. None of the data visualizations contained contagious periods and only 2 (5%) contained symptom-onset date. Conclusions: The data visualizations of healthcare-associated infectious disease outbreaks in the systematic review were diverse in type and visualization elements, though no data visualization contained all elements important to deriving hypotheses about transmission pathways. These findings aid in understanding the visualizing transmission pathways by describing essential elements of the data visualization and will inform the creation of a standardized mapping tool to aid in earlier initiation of interventions to prevent transmission.

The Swiss Student Life study was conducted between 2016 and 2020 (Vörös et al. 2021; Stadtfeld et al. 2019). Its aim was to understand the emergence of a student community and its short-term and long-term effects on the academic outcomes and well-being of its members. While similar questions and settings are commonly examined using a single data collection technique (e.g. survey, observation), we employ multiple methods to map the social dynamics of the community at different time periods and on different time scales. The study follows three cohorts of students (Cohort I: N = 226, Cohort II: N = 244, Cohort III: N = 652), who started 3-year bachelor programs at a Swiss technical university in 2016 and 2017. Members of each cohort shared most of their classes and often did course work in groups. Students came from various regions and countries; at the beginning of their studies, most of them did not know each other. However, after a few months they developed densely-knit multidimensional social networks, which were likely to influence their university experience and outcomes. This codebook document describes the various kinds of data that have been collected in the context of the Swiss StudentLife Study.

Cognitive deficits are a hallmark of schizophrenia, for which no convincing pharmacological treatment option is currently available. Here, we tested spironolactone as a repurposed compound in Tcf4 transgenic mice subjected to psychosocial stress. In this ‘2-hit’ gene by environment mouse (GxE) model, the animals showed schizophrenia-related cognitive deficits. We had previously shown that spironolactone ameliorates working memory deficits and hyperactivity in a mouse model of cortical excitatory/inhibitory (E/I) dysbalance caused by an overactive NRG1-ERBB4 signaling pathway. In an add-on clinical study design, we used spironolactone as adjuvant medication to the standard antipsychotic drug aripiprazole. We characterized the compound effects using our previously established Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling (PsyCoP). PsyCoP is a widely applicable analysis pipeline based on the Research Domain Criteria (RDoC) framework aiming at facilitating translation into the clinic. In addition, we use dimensional reduction to analyze and visualize overall treatment effect profiles. We found that spironolactone and aripiprazole improve deficits of several cognitive domains in Tcf4tg x SD mice but partially interfere with each other’s effect in the combination therapy. A similar interaction was detected for the modulation of novelty-induced activity. In addition to its strong activity-dampening effects, we found an increase in negative valence measures as a side effect of aripiprazole treatment in mice. We suggest that repurposed drug candidates should first be tested in an adequate preclinical setting before initiating clinical trials. In addition, a more specific and effective NRG1-ERBB4 pathway inhibitor or more potent E/I balancing drug might enhance the ameliorating effect on cognition even further.

Oligodendrocytes (OLs) are critical for myelination and are implicated in several brain disorders. Directed differentiation of human-induced OLs (iOLs) from pluripotent stem cells can be achieved by forced expression of different combinations of the transcription factors SOX10 (S), OLIG2 (O), and NKX6.2 (N). Here, we applied quantitative image analysis and single-cell transcriptomics to compare different transcription factor (TF) combinations for their efficacy towards robust OL lineage conversion. Compared with S alone, the combination of SON increases the number of iOLs and generates iOLs with a more complex morphology and higher expression levels of myelin-marker genes. RNA velocity analysis of individual cells reveals that S generates a population of oligodendrocyte-precursor cells (OPCs) that appear to be more immature than those generated by SON and to display distinct molecular properties. Our work highlights that TFs for generating iOPCs or iOLs should be chosen depending on the intended application or research question, and that SON might be beneficial to study more mature iOLs while S might be better suited to investigate iOPC biology.

Background Schizophrenia spectrum disorders (SSDs) are presumed to be associated with retinal thinning. However, evidence is lacking as to whether these retinal alterations reflect a disease-specific process or are rather a consequence of comorbid diseases or concomitant microvascular impairment. Methods The study included 126 eyes of 65 patients with SSDs and 143 eyes of 72 healthy controls. We examined macula and optic disc measures by optical coherence tomography (OCT) and OCT angiography (OCT-A). Additive mixed models were used to assess the impact of SSDs on retinal thickness and perfusion and to explore the association of retinal and clinical disease-related parameters by controlling for several ocular and systemic covariates (age, sex, spherical equivalent, intraocular pressure, body mass index, diabetes, hypertension, smoking status, and OCT signal strength). Results OCT revealed significantly lower parafoveal macular, macular ganglion cell–inner plexiform layer (GCIPL), and macular retinal nerve fiber layer (RNFL) thickness and thinner mean and superior peripapillary RNFL in SSDs. In contrast, the applied OCT-A investigations, which included macular and peripapillary perfusion density, macular vessel density, and size of the foveal avascular zone, did not reveal any significant between-group differences. Finally, a longer duration of illness and higher chlorpromazine equivalent doses were associated with lower parafoveal macular and macular RNFL thickness. Conclusions This study strengthens the evidence for disease-related retinal thinning in SSDs.

Empirical evidence suggests that children's socio-emotional skills—an important determinant of school achievement—vary by socio-economic family background. In this study, we assessed the degree to which differences in socio-emotional skills contribute to the achievement gap between socioeconomically advantaged and disadvantaged children. We used data on 74 countries from the 2018 Programme for International Student Assessment (PISA), which contains an extensive set of psychological measures, including growth mindset, self-efficacy, and work mastery. We developed three conceptual scenarios to analyze the role of socio-emotional skills in learning inequality: simple accumulation, multiplicative accumulation, and compensatory accumulation. Our findings are in line with the simple accumulation scenario: socioeconomically advantaged children have somewhat higher levels of socio-emotional skills than their disadvantaged peers, but the effect of these skills on academic performance is largely similar for both groups. Using a counterfactual decomposition method, we show that the measured socio-emotional skills explain no more than 8.8% of the socioeconomic achievement gap. Based on these findings, we argue that initiatives to promote social and emotional learning (SEL) are unlikely to substantially reduce educational inequalities.

The design and development of a photoelectron spectromicroscope working in transmission mode are presented., The successful design, installation and operation of a high spatial resolution X-ray photoelectron spectrometer at the Swiss Light Source is presented. In this instrument, a Fresnel zone plate is used to focus an X-ray beam onto the sample and an electron analyzer positioned at 45° with respect to the incoming beam direction is used to collect photoelectrons from the backside of the sample. By raster scanning the sample, transmitted current, X-ray absorption and X-ray photoemission maps can be simultaneously acquired. This work demonstrates that chemical information can be extracted with micrometre resolution; the results suggest that a spatial resolution better than 100 nm can be achieved with this approach in future. This kind of photoelectron spectromicroscope will allow in situ measurements with high spatial resolution also under ambient pressure conditions (in the millibar range). Element-specific X-ray photoemission maps can be obtained before and while exposing the sample to gas/gas mixtures to show morphological and chemical changes of the surface.

Transcriptional profiling has defined PDAC into distinct classical epithelial (E) or quasi-mesenchymal (QM) subtypes, and these subtypes exist on a continuum of interconverting cell states. This epithelial to mesenchymal transition (EMT) plasticity is thought to be important for the metastatic dissemination and intrinsic resistance to chemotherapy. Our prior work identified TAK1 as an important driver of EMT in mouse circulating tumor cells, and we had identified a compound (5z)-7-oxozeaenol (Oxo) as a small molecule inhibitor of TAK1. Here, we have expanded upon this prior work by evaluating Oxo in 3 human patient derived PDAC cell lines as an EMT plasticity inhibitor. Treatment with Oxo induced a shift of all PDAC cell lines towards an E phenotype in both E and QM PDAC cell lines using RNA-seq and quantitative RNA in situ hybridization. This was associated with increased FFX sensitivity, loss of migratory abilities of all cell lines by Boyden chamber, and decreased invasion in matrigel. Interestingly, genetic TAK1 knockout via CRISPR/Cas9 in these PDAC cell lines showed different effects from Oxo. We found that TAK1 knockout decreased E PDAC cell line migratory behavior and increased FFX sensitivity, but QM PDAC cell lines were not affected by TAK1 knockout. This suggests that QM PDAC cell lines have additional signaling cascades that compensate for TAK1 loss and that Oxo effects across PDAC cell lines are not solely TAK1 dependent. Using phospho-proteomics, in FFX treated PDAC cell lines, we have identified potential candidate pathways in RNA splicing and viral processes that may be additional processes affected by Oxo that merits further investigation. Altogether, we have identified Oxo as a potential broad EMT plasticity inhibitor across PDAC subtypes, and there is a potential role of selective TAK1 inhibitors for E PDAC tumors. Citation Format: Eunae You, Ildiko Phillips E. Phillips, Richard Y. Ebright, Niyati Desai, Michael J. Raabe, Evan R. Lang, Linda T. Nieman, Soroush Hajizadeh, Johannes Kreuzer, Wilhelm Haas, David T. Ting. 5z-7-oxozeaenol as an epithelial mesenchymal transition plasticity inhibitor in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A066.

Pancreatic ductal adenocarcinoma lethality can be attributed to a combination of rapid metastatic dissemination and intrinsic resistance to conventional therapies. Our prior studies using single cell RNA-seq in pancreatic circulating tumor cells (CTCs) revealed that these “seeds of metastasis” had a biphenotypic state of both epithelial and mesenchymal features. This suggested that CTCs are highly plastic cells that exist in an intermediate state along epithelial (E) to mesenchymal (M) transition (EMT). Analysis of CTC markers in primary PDAC tumors revealed that this subpopulation of cancer cells was concentrated at the interface of tumor cells and stromal cancer associated fibroblasts (CAFs). To evaluate the contribution of CAFs in PDAC EMT plasticity, we utilized patient derived PDAC-CAF co-culture preclinical models demonstrating that PDAC EMT heterogeneity was modulated by the density of CAFs and partially driven by TGF-b secretion. Moreover, analysis of patient derived PDAC tumor spheres treated with FOLFIRINOX (FFX) demonstrated selection or induction of EMT changes that were also found in patient tumors that were resected after neoadjuvant FFX. Altogether, our collective work along with others demonstrates the importance of EMT plasticity in PDAC cell metastatic propensity and the ability to resist cytotoxic chemotherapy. A multi-institutional randomized Phase II trial supported by SU2C-Lustgarten Foundation evaluating the role of the TGF-b modulating activities of losartan on locally advanced PDAC response to chemotherapy and suppression of metastatic dissemination has neared completion. This 3 arm (n=40 per arm) trial of neoadjuvant FFX, FFX + losartan, or FFX+ losartan + nivolumab (anti-PD1). Here, we have performed EMT RNA in situ hybridization in all post-treatment resection specimens to determine if there is a difference in EMT proportions between the different arms of the study. As an orthogonal unbiased approach, we have utilized the NanoString GeoMx Digital Spatial Profiler whole transcriptome assay (18,000+ protein coding genes) on each of the resection specimens with analysis of the tumor cells, CAFs, and immune cell separately for multiple regions of interest in these specimens. This provides deeper molecular insight of the PDAC tumor cells that resisted neoadjuvant therapy, the changes in the surrounding CAFs, and the modulation of immune infiltrates that might differ between each arm of the study. We anticipate the results of the trial will be completed before the conference and initial correlative analysis of spatial transcriptomics and RNA-ISH will be presented. Citation Format: Amaya Pankaj, Michael J. Raabe, Bidish Patel, Evan R. Lang, Joshua Kocher, Katherine H. Xu, Linda T. Nieman, Alec C. Kimmelman, David P. Ryan, Theodore S. Hong, William L. Hwang, Martin Aryee, David T. Ting. Characterizing the effects of neoadjuvant therapy in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR004.

Aberrant transcription of the repeat RNAs is a common feature in epithelial cancers including PDAC, but the function of these non-coding RNAs in cancer development is relatively unexplored. We have found that these repeat RNAs are sensed and replicate like retroviruses, and now have identified the ability of these viral-like elements to be transmitted from cancer cells through extracellular vesicles (EVs). PDAC-derived EVs applied to cancer-associated fibroblasts (CAFs) activates interferon-stimulated genes (ISGs) and is able to drive CAFs towards an inflammatory CAF (iCAF) phenotype with concordant loss of myofibroblast CAF (myCAF) marker genes. Using in-vitro transcription, we demonstrate that individual repeat RNAs (HSATII, HERVK (env), LINE-1 5’UTR and LINE-1 3’UTR) are sufficient to induce ISG response in CAFs with HSATII and HERVK (env) having the most potent ISG response. In contrast, PDAC cells were found to induce epithelial-mesenchymal transition (EMT) with loss of epithelial gene expression. To determine the potential sensor of HSATII repeat RNAs, we utilized CRISPR/Cas9 knockout of the viral RNA sensors RIG-I, MDA5, and MAVS in PDAC and CAF cells. Notably, these sensors were important for PDAC repeat RNA sensing and response, but not in CAF cells. Evaluating the innate immune pathway further downstream, we used genetic knockout of IRF3 with CRISPR/Cas9 knockout and find significant downregulation of key EMT genes that are shared with myCAF markers (ACTA2, FN1, SERPINE1). Interestingly, HSATII RNA activated IRF3 dependent EMT genes in PDAC cells, but induced IRF3 degradation in CAF cells that results in loss of myCAF gene expression. Furthermore, we found that conditioned media from HSATII transfected CAF activates EMT-related gene expression (ACTA2, FN1, SERPINE1) in PDAC cell lines, which indicates an cell extrinsic mechanism to augment EMT induction in PDAC cells. We utilized next generation spatial transcriptomic platforms NanoString GeoMx and CosMx to understand the spatial distribution of repeat RNAs in human PDAC tumors. We find that repeat RNAs can be found as a gradient from PDAC cells to the surround tumor microenvironment consistent with delivery of these RNA species. Analysis of over 300,000 individual cells in 3 PDAC tumor specimens, we find that high repeat PDAC cells have lost epithelial gene expression and high repeat CAFs have lost myCAF gene expression. Altogether, these findings support the “infection” of repeat RNAs disrupts cellular identity in both tumor cells and the CAF microenvironment as a mechanism for tumor progression. Citation Format: Eunae You, Luli Zou, Patrick Danaher, Ildiko E. Phillips, Michael J. Raabe, Bidish Patel, Amaya Pankaj, Khrystyna North, Sean Kim, Youngmi Kim, Martin Aryee, David T. Ting. Repeat RNA dysregulation of cellular states in the pancreatic cancer microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C038.

BACKGROUND: The hepatocellular carcinoma (HCC) tumor microenvironment (TME) is composed of a complex ecosystem dominated by cancer cells and the endothelial cells that line tumor blood vessels. Although many genomic drivers have been identified and at least three transcriptional subsets have been proposed, these efforts have not yet led to novel therapies or otherwise significantly impacted management options. Single cell transcriptional profiling has generated deep insights into the multiple heterogeneous cell types within tissues, but the spatial context of these data is lost during single cell processing. Spatial transcriptomic approaches aim to bridge the gap between dissociative single cell technologies and in situ histopathological characterization.METHODS: To gain insight into potential in situ cancer-endothelial crosstalk interactions, we utilized the Nanostring GeoMx spatial transcriptomics platform with the Cancer Transcriptome Atlas ~1800 gene oligonucleotide probe panel to generate tumor (Arginase+) and blood vessel (CD31+) areas of interest (AOI) gene expression profiles from formalin-fixed, paraffin-embedded archival tissue specimens obtained from HCC resection specimens. Oligonucleotides released from each microscopic AOI were then captured, processed by DNA sequencing, and analyzed using custom computational pipelines.RESULTS: Using the 119 ROI containing data from both tumor and vessels that passed quality control filters, we performed unbiased hierarchical clustering of both the tumor and vessel areas of interest (AOI) within each ROI using the most highly variable genes for each AOI set and identified at least 3 clusters within each AOI type (tumor and vessel). Based on gene ontology analysis of the tumor AOIs, the two subsets were distinguished by unique immune and inflammatory-related genes. Analogous ontology-based characterization of the vessel AOIs demonstrated two groups: 1) an interferon-activated, inflamed progenitor, and immune checkpoint-associated cluster; and 2) a TGF-beta and oxidative stress-associated cluster. Notably, both vessel clusters also contained significant numbers of leukocyte genes, concordant with the intimate relationship of the vasculature and immune system. Canonical correlation analysis (CCA) utilizing both the most variable genes within each AOI set showed significant correlated gene sets within tumor AOIs and vessel AOIs, implying biologically significant interactions in multiple signaling pathways.CONCLUSIONS: Spatial transcriptomic profiling enables an understanding of cell-cell interactions in situ that can uncover biologically distinct tumor and blood vessel niches within the HCC microenvironment. Subsequent efforts will be focused on functionally assessing the spatially linked cancer and endothelial cell phenotypes with the goals of developing improved prognostic and predictive biomarkers and generating novel drug targets. Citation Format: Joseph W Franses, Michael J Raabe, Amaya Pankaj, Bidish Patel, Avril Coley, Irun Bhan, Martin Aryee, David T Ting. Spatial transcriptomic profiling to characterize the tumor-vascular interactome of hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO016.

A Correction to this paper has been published: https://doi.org/10.1057/s41599-020-00675-9

The ability to tune the competition between the in-plane and out-of-plane orientation of magnetization provides a means to construct thermal sensors with a sharp spin re-orientation transition at specific temperatures. We have observed such a tuneable, temperature driven spin re-orientation in structurally amorphous, ferrimagnetic rare earth-transition metal (RE-TM) alloy thin films using scanning transmission X-ray microscopy (STXM) and magnetic measurements. The nature of the spin re-orientation transition in FeGd can be fully explained by a non-equilibrium, nanoscale modulation of the chemical composition of the films. This modulation leads to a magnetic domain pattern of nanoscale speckles superimposed on a background of in-plane domains that form Laudau configurations in micron-scale patterned elements. It is this speckle magnetic structure that gives rise to a sharp two step-reversal mechanism that is temperature dependent. The possibility to balance competing anisotropies through the temperature opens opportunities to create and manipulate topological spin textures.

Spin waves offer intriguing novel perspectives for computing and signal processing, since their damping can be lower than the Ohmic losses in conventional CMOS circuits. For controlling the spatial extent and propagation of spin waves on the actual chip, magnetic domain walls show considerable potential as magnonic waveguides. However, low-loss guidance of spin waves with nanoscale wavelengths, in particular around angled tracks, remains to be shown. Here we experimentally demonstrate that such advanced control of propagating spin waves can be obtained using natural features of magnetic order in an interlayer exchange-coupled, anisotropic ferromagnetic bilayer. Using Scanning Transmission X-Ray Microscopy, we image generation of spin waves and their propagation across distances exceeding multiple times the wavelength, in extended planar geometries as well as along one-dimensional domain walls, which can be straight and curved. The observed range of wavelengths is between 1 {\mu}m and 150 nm, at corresponding excitation frequencies from 250 MHz to 3 GHz. Our results show routes towards practical implementation of magnonic waveguides employing domain walls in future spin wave logic and computational circuits.

Individuals’ favorite subjects in school can predetermine their educational and occupational careers. If girls develop weaker preferences for science, technology, engineering, and math (STEM), it can contribute to macrolevel gender inequalities in income and status. Relying on large-scale panel data on adolescents from Sweden (218 classrooms, 4,998 students), we observe a widening gender gap in preferring STEM subjects within a year (girls, 19 to 15 percent; boys, 21 to 20 percent). By applying newly developed random-coefficient multilevel stochastic actor-oriented models on social network data (27,428 friendships), we investigate how social context contributes to those changes. We find strong evidence that students adjust their preferences to those of their friends (friend influence). Moreover, girls tend to retain their STEM preferences when other girls in their classroom also like STEM (peer exposure). We conclude that these mechanisms amplify preexisting preferences and thereby contribute to the observed dramatic widening of the STEM gender gap.

Significance Understanding the factors that explain academic failure and success of university students is a core interest of educational researchers, teachers, and managers. We demonstrate how the dynamic social networks that informally evolve between students can affect their academic performance. We closely followed the emergence of multiple social networks within a cohort of 226 undergraduate university students. They were strangers to each other on their first day at university, but developed densely knit social networks through time. We show that functional studying relationships tended to evolve from informal friendship relations. In a critical examination period after one year, these networks proved to be crucial: Socially isolated students had significantly lower examination grades and were more likely to drop out of university., Academic success of students has been explained with a variety of individual and socioeconomic factors. Social networks that informally emerge within student communities can have an additional effect on their achievement. However, this effect of social ties is difficult to measure and quantify, because social networks are multidimensional and dynamically evolving within the educational context. We repeatedly surveyed a cohort of 226 engineering undergraduates between their first day at university and a crucial examination at the end of the academic year. We investigate how social networks emerge between previously unacquainted students and how integration in these networks explains academic success. Our study measures multiple important dimensions of social ties between students: their positive interactions, friendships, and studying relations. By using statistical models for dynamic network data, we are able to investigate the processes of social network formation in the cohort. We find that friendship ties informally evolve into studying relationships over the academic year. This process is crucial, as studying together with others, in turn, has a strong impact on students’ success at the examination. The results are robust to individual differences in socioeconomic background factors and to various indirect measures of cognitive abilities, such as prior academic achievement and being perceived as smart by other students. The findings underline the importance of understanding social network dynamics in educational settings. They call for the creation of university environments promoting the development of positive relationships in pursuit of academic success.

The discussion of the social, political and economic consequences of the lockdown during the COVID-19 pandemic mainly revolves around negative effects. This study exploits a unique opportunity and analyses data from a survey (N = 13,316) that happened to be in the field in the months of the development and eventual manifestation of the COVID-19 pandemic. It documents slightly higher levels of average general life satisfaction as well as of satisfaction with various specific aspects of life (health, work, work-life balance and leisure) during the lockdown among scientists in Austria, Germany and Switzerland. It is argued that the lockdown can be regarded as a large-scale social experiment of a very sudden and abrupt change of work and social life, which is unique in history. Daily survey data elicited before and after the lockdown allows the construction of a quasi-experimental design for analysing how this abrupt change of social reality has affected satisfaction. For scientists, the lockdown mainly entailed the transition to work from home, leading to a reduced speed of life and allowing for more flexibility in incorporating family and leisure into the work day. It is discussed how some of these mechanisms might apply to the general population., Humanities and Social Sciences Communications, 7 (1), ISSN:2662-9992

Time-resolved scanning transmission x-ray microscopy (TR-STXM) has been used for the direct imaging of spin wave dynamics in thin film yttrium iron garnet (YIG) with spatial resolution in the sub 100 nm range. Application of this x-ray transmission technique to single crystalline garnet films was achieved by extracting a lamella (13x5x0.185 $\mathrm{\mu m^3}$) of liquid phase epitaxy grown YIG thin film out of a gadolinium gallium garnet substrate. Spin waves in the sample were measured along the Damon-Eshbach and backward volume directions of propagation at gigahertz frequencies and with wavelengths in a range between 100~nm and 10~$\mathrm{\mu}$m. The results were compared to theoretical models. Here, the widely used approximate dispersion equation for dipole-exchange spin waves proved to be insufficient for describing the observed Damon-Eshbach type modes. For achieving an accurate description, we made use of the full analytical theory taking mode-hybridization effects into account.

Background:ALPS patients show impaired generation of humoral memory for T independent antigens whereas they generate memory for self-antigens due to impaired FAS-dependent removal of autoreactive germinal center B cells. It is known that FAS signaling via caspase activation results in cell apoptosis. However, FAS ligation may also initiate or modulate non-apoptotic signaling as shown for example by its ability to activate NF-κB. Recent data implicate a regulatory role of FAS in the modulation of mTOR signaling in ALPS double-negative T cells. Moreover, a recently described C194V FAS mutation disturbs its post-translational modification leading to impaired apoptosis induction while non-apoptotic signalling is still intact. Consequently, C194V FAS protects from the autoimmune phenotype in the murine ALPS system. This supports the view that FAS may prevent autoimmunity with other mechanisms than inducing apoptosis.Objectives:We hypothesize that FAS mutations impair this modulatory signaling, leading to hyper-activation of B cells. Therefore we aim to investigate non apoptotic FAS signaling in B cells derived from healthy individuals and ALPS patients.Methods:We studied resting and activated B cells in ALPS patients in presence or absence of FAS ligand by flow cytometry analysing relevant molecules to the CD40 signaling pathway. We used mass cytometry to perform functional phenotyping of B cells isolated from secondary lymphoid organs. Proteomic studies were performed to identify potential signaling circuits and RNA sequencing to study the consequences of FAS signaling on B cell fate.Results:In CD40L activated B cells, FAS signaling results in specific modulation of the mTOR signaling pathway. This modulation is absent in ALPS derived B cells. In line with these data germinal center B cells and plasmablast from secondary lymphoid organs of ALPS patients show hyperactive mTOR signaling pathway. Proteomic studies identify a circuit that links FAS to the phosphatase PTEN via DAXX and the deubiquitinase USP7.Conclusion:We describe a new role of FAS in the regulation of B cell activation. Defects in FAS signaling in ALPS contribute to dysregulation of the mTOR signaling pathway and disturbed B cell development.Disclosure of Interests:None declared

Peers have long been found to be of relevance for educational aspirations and hence educational success. While sociological and social psychological theories often assume concrete social mechanisms that focus on ‘significant’ peers, past research predominantly had to rely on classroom-level aggregates. This study examines how educational aspirations among adolescents cluster in friendship networks within school classes. Through the utilization of social network measures from the CILS4EU data on Germany, The Netherlands, and Sweden (15,203 individuals, 50 per cent girls, MAGE 14.9 years), we construct two measures of the most significant peers around individuals, i.e. of the peer milieu, and explore the salience of educational aspirations in these milieus. Applying longitudinal logistic regression models and first-difference models with individual-level fixed effects, we find evidence for clustering of individuals with the same educational aspirations within classrooms, underlining the relevance of peers for educational success.

In the field of magnetism, spin waves are a subject of great interest for fundamental and application-oriented research. Time-resolved scanning transmission x-ray microscopy, a technique that allows for direct spin-wave imaging below the optical resolution limit, is usually limited to thin layers deposited on x-ray transparent membranes. Here, the authors report on a preparation routine that makes single-crystalline materials accessible to this powerful technique. The latter is subsequently implemented on the ferrimagnetic insulator yttrium iron garnet, where spin waves down to 100-nm wavelength are observed.

Ethnic minorities in Europe show diverging patterns of educational success, but in most national contexts, migrants and children of immigrants have lower achievements in terms of grades than their majority peers. This study asks whether social exclusion in the classroom can contribute to explaining this pattern. While limited access to social resources is often assumed to be of significance for educational success, it has rarely been measured explicitly. In this study, social exclusion is measured accurately and on a large, cross-national scale, by using social network data from 731 classrooms in England, Germany, and Sweden (CILS4EU data). Results show that social exclusion is negatively associated with school grades, but this does not contribute much to understanding grade differences between children of immigrant and children of majority background., Child Indicators Research, 12 (3)