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Abstract Background Hypoxia-induced glycogen turnover is implicated in cancer proliferation and therapy resistance. Triple-negative breast cancers (TNBCs), characterized by a hypoxic tumor microenvironment, respond poorly to therapy. We studied the expression of glycogen synthase 1 (GYS1), the key regulator of glycogenesis, and other glycogen-related enzymes in primary tumors of patients with breast cancer and evaluated the impact of GYS1 downregulation in preclinical models. Methods mRNA expression of GYS1 and other glycogen-related enzymes in primary breast tumors and the correlation with patient survival were studied in the METABRIC dataset (n = 1904). Immunohistochemical staining of GYS1 and glycogen was performed on a tissue microarray of primary breast cancers (n = 337). In four breast cancer cell lines and a mouse xenograft model of triple-negative breast cancer, GYS1 was downregulated using small-interfering or stably expressed short-hairpin RNAs to study the effect of downregulation on breast cancer cell proliferation, glycogen content and sensitivity to various metabolically targeted drugs. Results High GYS1 mRNA expression was associated with poor patient overall survival (HR 1.20, P = 0.009), especially in the TNBC subgroup (HR 1.52, P = 0.014). Immunohistochemical GYS1 expression in primary breast tumors was highest in TNBCs (median H-score 80, IQR 53–121) and other Ki67-high tumors (median H-score 85, IQR 57–124) (P

In the last decade, we have been able to probe further down the galaxy luminosity function than ever before and expand into the regime of ultra-faint dwarfs (UFDs), which are some of the best probes we have of small-scale cosmology and galaxy formation. Digital sky surveys have enabled the discovery and study of these incredibly low-mass, highly dark-matter-dominated systems around the Local Group, but it is critical that we expand the satellite census further out to understand if Milky Way and M31 satellites are representative of dwarf populations in the local Universe. Using data from the Hubble Space Telescope (HST) Advanced Camera for Surveys (ACS), we present updated characterization of four satellite systems in the M81 group. These systems—D1005+68, D1006+69, DWJ0954+6821, and D1009+68—were previously discovered using ground-based Subaru Hyper Suprime-Cam data as overdensities in M81's halo, and are now confirmed with HST/ACS by this work. These are all faint ( M _V ≥ −7.9) and consistent with old (∼13 Gyr), metal-poor ([M/H] < −1.5) populations. Each system possesses relatively unusual features—including one of the most concentrated satellite galaxies with a Sérsic index of n ∼ 5, one of the most elliptical galaxies outside the Local Group with an ϵ ∼ 0.6, and one of the most compact galaxies for its magnitude. Two of the satellites have very low surface brightness, lower than most known galaxies in this absolute magnitude range. This work previews the scientific promise of the upcoming Rubin Observatory and Roman Telescope for illuminating the diversity of UFDs in the Local Volume and beyond.

Mergers of and interactions between galaxies imprint a wide diversity of morphological, dynamical, and chemical characteristics in stellar halos and tidal streams. Measuring these characteristics elucidates aspects of the progenitors of the galaxies we observe today. The M81 group is the perfect galaxy group to understand the past, present, and future of a group of galaxies in the process of merging. Here, we measure the end of star formation ( t _90 ) and metallicity ([M/H]) of the stellar halo of M82 and the eastern tidal stream of NGC 3077 to: (1) test the idea that M82 possesses a genuine stellar halo, formed before any interaction with M81; (2) determine if NGC 3077's tidal disruption is related to the star formation history in its tails; and (3) create a timeline of the assembly history of the central trio in the M81 group. We argue that M82 possesses a genuine, metal-poor ([M/H] ∼ −1.62 dex) stellar halo, formed from the merger of a small satellite galaxy roughly 6.6 Gyr ago. We also find that the stars present in NGC 3077's tails formed before tidal disruption with M81, and possess a roughly uniform metallicity as shown in S. Okamoto et al., implying that NGC 3077's progenitor had significant population gradients. Finally, we present a timeline of the central trio’s merger/interaction history.

Introduction Worldwide, annually more than 800,000 suicides occur. In the Netherlands, suicide rates rose from 8.6 per 100,000 in 2007 to 11.4 per 100,000 in 2016. Rates in the province of Noord-Brabant were consistently higher than the national average. Noord-Brabant is a province in the south of the Netherlands covering an area of over 4700 km2 with 2.5 million inhabitants. Although Noord-Brabant has five specialised mental healthcare institutions (SMHIs), and 90% of suicides are deemed related to mental disorders, 60% of those who died by suicide did not receive mental health treatment. However, with good access to treatment, suicide could be preventable. Objectives To evaluate whether the systems intervention compared to the regular care approach led to a reduction in suicides in Noord-Brabant. We aimed to attain a reduction in suicides of at least 20%. Methods Co-design and development of a digital monitoring system and decision aid. Stepwise implementation per subregion of the systems intervention by the five specialized mental healthcare institutions (SMHIs) and their chain partners. Pre-post analysis for the whole province (Exact Rate Ratio Test, Poisson count). Results The SUPREMOCOL systems intervention consisted of four pillars, which were all supported by a digital decision aid and monitoring system. This was provided via a desktop computer with a secured login. The data were kept on a secured encrypted server. The number of professionals accessing the system was limited to two per SMHI or other chain partner. They could only see patients in their subregion, not in the whole of the province. The pillars of our systems intervention for suicide prevention are: 1. Swift identication of people at risk for suicide by triage on the spot after a non-fatal suicide attempt. 2. Provision of swift access to specialised mental health care for those at risk 3. Accommodating transitions in care following a collaborative care approach 4. Prevention of suicidal attempts after discharge or treatment dropout by 12 months telephone follow-up. Suicide rates dropped 17.8% (p=.013) from baseline (2017) to implementation in 2018 and 2019. This is a significant reduction (p=0.043) compared to the non-significant drop in the rest of the Netherlands. Suicide rates dropped further by 21.5% (p = 0.002) in 2021. Noord-Brabant also dropped in the relative rank of the number of suicides, from second place in 2015 to third in 2018. Conclusions During the SUPREMOCOL systems intervention, over a period of 4 years, there was a sustained and significant reduction of suicides in Noord-Brabant. We attained a reduction of 21,5% in total. Noord-Brabant dropped in the relative rank of the number of suicides, from second place in 2015 to third in 2018. This is a result that warrants further research and implementation into system interventions for suicide prevention with digital support such as SUPREMOCOL. Disclosure of Interest C. Van Der Feltz-Cornelis Grant / Research support from: The Netherlands Organisation for Health Research and Development, I. Elfeddali: None Declared, M. Metz: None Declared, S. de Jong: None Declared, M. Bakker: None Declared, C. van Nieuwenhuizen: None Declared

Compositional traits in potato [Solanum tuberosum L.] are economically important but genetically complex, often controlled by many loci of small effect; new methods need to be developed to accelerate analysis and improvement of such traits, like chip quality. In this study, we used network analysis to organize hundreds of metabolic features detected by mass spectrometry into groups, as a precursor to genetic analysis. 981 features were condensed into 44 modules; module eigenvalues were used for genetic mapping and correlation analysis with phenotype data collected by the Solanaceae Coordinated Agricultural Project. Half of the modules were associated with at least one SNP according to GWAS; 11 of those modules were also significantly correlated with chip color. Within those modules features associated with chipping provide potential targets for selection in addition to selection for reduced glucose. Loci associated with module eigenvalues were not evenly distributed throughout the genome but were instead clustered on chromosomes 3, 7, and 8. Comparison of GWAS on single features and modules of clustered features often identified the same SNPs. However, features with related chemistries (for example, glycoalkaloids with precursor/product relationships) were not found to be near neighbors in the network analysis and did not share common SNPs from GWAS. Instead, the features within modules were often structurally disparate, suggesting that linkage disequilibrium complicates network analyses in potato. This result is consistent with recent genomic studies of potato showing that chromosomal rearrangements that create barriers to recombination are common in cultivated germplasm.

M64, often called the “Evil Eye” galaxy, is unique among local galaxies. Beyond its dramatic, dusty nucleus, it also hosts an outer gas disk that counter-rotates relative to its stars. The mass of this outer disk is comparable to the gas content of the Small Magellanic Cloud (SMC), prompting the idea that it was likely accreted in a recent minor merger. Yet, detailed follow-up studies of M64's outer disk have shown no evidence of such an event, leading to other interpretations, such as a “flyby” interaction with the distant diffuse satellite Coma P. We present Subaru Hyper Suprime-Cam observations of M64's stellar halo, which resolve its stellar populations and reveal a spectacular radial shell feature, oriented ∼30° relative to the major axis and along the rotation axis of the outer gas disk. The shell is ∼45 kpc southeast of M64, while a similar but more diffuse plume to the northwest extends to >100 kpc. We estimate a stellar mass and metallicity for the southern shell of M _⋆ = 1.80 ± 0.54 × 10 ^8 M _⊙ and [M/H] = −1.0, respectively, and a similar mass of 1.42 ± 0.71 × 10 ^8 M _⊙ for the northern plume. Taking into account the accreted material in M64's inner disk, we estimate a total stellar mass for the progenitor satellite of M _⋆,prog ≃ 5 × 10 ^8 M _⊙ . These results suggest that M64 is in the final stages of a minor merger with a gas-rich satellite strikingly similar to the SMC, in which M64's accreted counter-rotating gas originated, and which is responsible for the formation of its dusty inner star-forming disk.

Abstract Background In this study, we aimed to identify and define the fundamental components of the working alliance in multidisciplinary (Flexible) Assertive Community Treatment teams with shared caseloads, in order to support their daily practice and further research. Methods After reviewing the literature, concept mapping with professionals and clients was used to define the working alliance in (F) ACT teams. The resulting concept maps formed the basis for the working alliance assessment instrument, which was pilot tested with professionals and clients through cognitive interviews with a think-aloud procedure. Results The study led to the development of a twenty five-item assessment instrument to evaluate working alliances in multidisciplinary teams (WAM) that was comprised of three subscales: bond, task/goal and team. Two different versions were developed for clients and professionals. Conclusions The WAM instrument was developed to determine the quality of the working alliance in (F) ACT teams. Future research will focus on testing its psychometric properties and predictive value.

Abstract Background Patient-derived bulk expression profiles of cancers can provide insight into the transcriptional changes that underlie reprogrammed metabolism in cancer. These profiles represent the average expression pattern of all heterogeneous tumor and non-tumor cells present in biopsies of tumor lesions. Hence, subtle transcriptional footprints of metabolic processes can be concealed by other biological processes and experimental artifacts. However, consensus independent component analyses (c-ICA) can capture statistically independent transcriptional footprints of both subtle and more pronounced metabolic processes. Methods We performed c-ICA with 34,494 bulk expression profiles of patient-derived tumor biopsies, non-cancer tissues, and cell lines. Gene set enrichment analysis with 608 gene sets that describe metabolic processes was performed to identify the transcriptional components enriched for metabolic processes (mTCs). The activity of these mTCs was determined in all samples to create a metabolic transcriptional landscape. Results A set of 555 mTCs was identified of which many were robust across different datasets, platforms, and patient-derived tissues and cell lines. We demonstrate how the metabolic transcriptional landscape defined by the activity of these mTCs in samples can be used to explore the associations between the metabolic transcriptome and drug sensitivities, patient outcomes, and the composition of the immune tumor microenvironment. Conclusions To facilitate the use of our transcriptional metabolic landscape, we have provided access to all data via a web portal ( www.themetaboliclandscapeofcancer.com ). We believe this resource will contribute to the formulation of new hypotheses on how to metabolically engage the tumor or its (immune) microenvironment.

Abstract Sea level rise (SLR) will affect water levels and increase flood risk in river deltas. To adapt river deltas to SLR, various strategies can be followed. Many urbanised river deltas already have flood protection in place. Continuing a protection strategy under an increasing SLR, would mean higher embankments along the coast and rivers and possibly closing off the river mouths from the sea. However, closing of rivers will hamper the river flow. How to adapt river deltas and enabling rivers to discharge into the sea is a challenging question. This paper assesses impacts of SLR on flood risks in the Rhine‐Meuse Delta in the Netherlands in case the current protection strategy is continued and explores two alternative protection strategies: (1) a closed system with pumps and discharge sluices and (2) an open system in which rivers are diverted to less densely populated areas. The second alternative results in a more flexible river delta, which can accommodate larger SLR. The paper shows that a systems approach and using quantitative assessments of the implications of strategies is possible. This is needed to further assess the adaptation options, so we can anticipate and adapt when needed and avoid regret of decisions.

Introduction Social connectedness might positively influence the course of clinical symptoms in people with psychotic disorders. Objectives This study examines satisfaction with social connectedness (SSC) as predictor of positive and negative symptoms in people with a psychotic disorder. Methods Data from the Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS, 2014-2019) was used from patients diagnosed with a psychotic disorder (N=2109). Items about social connectedness of the Manchester short assessment of Quality of Life (ManSA) were used to measure SSC. Linear mixed models were used to estimate the association of SSC with the Positive and Negative Syndrome Scale (PANSS) after one and two years against α=0.01. Analyses were adjusted for symptoms, time since onset, gender and age. Additionally, fluctuation of positive and negative symptom scores over time was estimated. Results Mean duration of illness of the sample was 18.8 years (SD 10.7) with >65% showing only small variation in positive and negative symptoms over a two to five-year time period. After adjustment for covariates, SSC showed to be negatively associated with positive symptoms after one year (β=-0.47, p

It is not yet settled how the combination of secular processes and merging gives rise to the bulges and pseudobulges of galaxies. The nearby ( D ∼ 4.2 Mpc) disk galaxy M94 (NGC 4736) has the largest pseudobulge in the local universe, and offers a unique opportunity for investigating the role of merging in the formation of its pseudobulge. We present a first ever look at M94's stellar halo, which we expect to contain a fossil record of M94's past mergers. Using Subaru's Hyper Suprime-Cam, we resolve and identify red giant branch (RGB) stars in M94's halo, finding two distinct populations. After correcting for completeness through artificial star tests, we can measure the radial profile of each RGB population. The metal-rich RGB stars show an unbroken exponential profile to a radius of 30 kpc that is a clear continuation of M94's outer disk. M94's metal-poor stellar halo is detectable over a wider area and clearly separates from its metal-rich disk. By integrating the halo density profile, we infer a total accreted stellar mass of ∼2.8 × 10 ^8 M _⊙ , with a median metallicity of [M/H] = −1.4. This indicates that M94's most-massive past merger was with a galaxy similar to, or less massive than, the Small Magellanic Cloud. Few nearby galaxies have had such a low-mass dominant merger; therefore we suggest that M94's pseudobulge was not significantly impacted by merging.

Knowledge of optimal technical performance is used to determine match strategy and the design of training programs. Previous studies in men's soccer have identified certain technical characteristics that are related to success. These studies however, have relative limited sample sizes or limited ranges of performance indicators, which may have limited the analytical approaches that were used. Research in women's soccer and our understanding of optimal technical performance, is even more limited (n = 3). Therefore, the aim of this study was to identify technical determinants of match outcome in the women's game and to compare analytical approaches using a large sample size (n = 1390 team performances) and range of variables (n = 450). Three different analytical approaches (i.e. combinations of technical performance variables) were used, a data-driven approach, a rational approach and an approach based on the literature in men's soccer. Match outcome was modelled using variables from each analytical approach, using generalised linear modelling and decision trees. It was found that the rational and data-driven approaches outperformed the literature-driven approach in predicting match outcome. The strongest determinants of match outcome were; scoring first, intentional assists relative to the opponent, the percentage of shots on goal saved by the goalkeeper relative to the opponent, shots on goal relative to the opponent and the percentage of duels that are successful. Moreover the rational and data-driven approach achieved higher prediction accuracies than comparable studies about men's soccer.