p53 deficient breast cancer cells reprogram preadipocytes toward tumor-protective immunomodulatory cells.

The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and breast tumors, undergo transcriptional, metabolic, and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an inflammatory tumor microenvironment, including increased abundance of Ly6C+ and Ly6G+ myeloid cells and elevated expression of the immune checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 deregulation in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 dysfunction may promote cancer. Further elucidation of the interplay between p53 and adipocytes within the tumor microenvironment may suggest effective therapeutic targets for the treatment of breast cancer patients.

Symptoms of selective mutism beyond failure to speak in children and adolescents.

Understanding the symptoms of a mental disorder is essential for accurate diagnosis or selecting appropriate treatment targets. Despite this, there is a surprising lack of systematic research on the symptoms of selective mutism (SM). While the DSM-5 defines failure to speak as the only core symptom of SM, sparse research suggests that children with SM may experience additional symptoms. Previous studies have been limited in their identification of symptoms of SM, either by using a predefined set of symptoms or by only asking for anxiety-specific symptoms. This may have resulted in important symptoms being overlooked. In this study, we provided n = 86 parents of children and adolescents with SM (3-18 years) with a symptom definition appropriate for the target group. Additionally, parents were asked an open-ended question about any other symptoms they had observed in their children, beyond the failure to speak. The symptoms reported were categorized using qualitative content analysis (QCA) and examined for frequency and association with symptom severity. Ten different symptom categories were identified, with fear, freezing, and avoidance/security behaviors being the most prevalent. On average, parents reported M = 4.74 (SD = 2.37) symptoms from different symptom categories. Only fear was found to be related to symptom severity of SM. As the findings suggest that SM encompasses various symptoms beyond failure to speak, a more sophisticated understanding of SM as a mental disorder with multiple symptoms seems essential. The clinical implications of this are discussed in further detail.

Cognitive Variables in Social Anxiety Disorder in Children and Adolescents: A Network Analysis.

Clark and Wells' prominent model of social anxiety disorder (SAD) assumes that cognitive variables such as negative expectations or dysfunctional cognitions play a central role in the symptomatology of SAD. In contrast to adults, it is less clear how well the cognitive model can be applied to children and adolescents. A network analysis with seven nodes was conducted to explore the importance of cognitive variables and their interaction with symptoms of SAD based on N = 205 children and adolescents (8-18 years, M = 11.54 years). Cognitive variables had a high but differential impact within the positively connected network of SAD. Dysfunctional cognitions were most strongly connected within the network. Dysfunctional cognitions, as predicted by Clark and Wells' model, seem to act as a hub affecting several symptoms. The association between negative expectations and avoidance indicates that negative expectations may particularly contribute to the maintenance of SAD.

Differentiating and Mitigating Methane Emissions from Fugitive Leaks from Natural Gas Distribution, Historic Landfills, and Manholes in Montréal, Canada.

Rapidly reducing urban methane (CH4) emissions is a critical component of strategies aimed at limiting climate change. Individual source measurements provide the details necessary to develop actionable mitigation strategies and are highly complementary to mobile surveys and other top-down methods. Here, we perform 615 individual source measurements in Montréal, Canada, to quantify CH4 emissions from historic landfills, manholes, and fugitive emissions from natural gas (NG) distribution systems. We find that in 2020, historic landfills produced 901 (452 to 1541, 95% c.i.) tons of CH4, manholes emitted 786 (32 to 2602, 95% c.i.) tons of CH4, and NG distribution systems emitted 451 (176-843, 95% c.i.) tons of CH4, placing them all within the top four CH4 sources in Montréal. Methane emissions from both historic landfills and manholes are not accounted for in any greenhouse gas inventory. We find that geochemistry alone cannot positively identify source subcategories (e.g., type of manhole or NG infrastructure) in almost all cases, although C2/C1 ratios can distinguish NG distribution sources from biogenic sources (historic landfills and manholes). Using our individual source measurement data, we show that historic landfills have the greatest potential for CH4 reductions but the highest mitigation costs, unless we target the highest emitting landfills. In contrast, CH4 emissions from manholes can be reduced at low costs, but reduction methods are commercially unavailable. For NG distribution, methods such as increasing repair rates for high-emitting industrial meters can greatly reduce mitigation costs and emissions. Overall, our results highlight the role of individual source measurements in developing actionable CH4 mitigation strategies to meet municipal, regional, and national climate action plans.

Characteristics of person, place, and activity that trigger failure to speak in children with selective mutism.

Selective Mutism (SM) is an anxiety disorder with predictable and circumscribed situations in which children remain silent while they speak unaffectedly in others. However, core features of anxiety inducing stimuli have rarely been studied so far. Parents of children with elevated SM symptomatology participated in an online-based study and answered open ended questions about specific characteristics of a person, place, and activity that elicit failure to speak in their child. The final sample consisted of n = 91 parents with children aged between 3 and 17 years (M = 8.02 years, SD = 3.94). Answers were analyzed by qualitative content analysis. Characteristics of a person were assigned to five categories with lack of distance as the most frequently reported feature. With respect to a place, the majority of parents mentioned unknown places as a silence trigger. The most frequently mentioned feature of an activity that was designated to be associated to silence was new activity. There were only few associations between the designation of these features, age, and gender. For the first time, anxiety inducing triggers related to person, place, and activity were comprehensively assessed in children with SM. This allows a differentiated and deeper understanding of an understudied disorder. The majority of characteristics can be associated with proposed etiological factors such as increased behavioral inhibition, conditioning processes, social anxiety, and a strong need for control. Implications for effective treatments are discussed.

Zelkovamycin is an OXPHOS Inhibitory Member of the Argyrin Natural Product Family.

Natural products (NPs) are an important inspirational source for developing drugs and chemical probes. In 1999, the group of Omura reported the constitutional elucidation of zelkovamycin. Although largely unrecognized so far, this NP displays structural similarities as well as differences to the argyrin NP family, a class of peptidic NPs with promising anticancer activities and diverse mode-of-action at the molecular level. By a combination of structure elucidation experiments, the first total synthesis of zelkovamycin and bioassays, the zelkovamycin configuration was determined and its previously proposed molecular structure was revised. The full structure assignment proves zelkovamycin as an additional member of the argyrins with however unique OXPHOS inhibitory properties. Zelkovamycin may therefore not only serve as a new starting point for chemical inhibitors of the OXPHOS system, but also guide customized argyrin NP isolation and biosynthesis studies.

Eight-Year Estimates of Methane Emissions from Oil and Gas Operations in Western Canada Are Nearly Twice Those Reported in Inventories.

The provinces of Alberta and Saskatchewan account for 70% of Canada's methane emissions from the oil and gas sector. In 2018, the Government of Canada introduced methane regulations to reduce emissions from the sector by 40-45% from the 2012 levels by 2025. Complementary to inventory accounting methods, the effectiveness of regulatory practices to reduce emissions can be assessed using atmospheric measurements and inverse models. Total anthropogenic (oil and gas, agriculture, and waste) emission rates of methane from 2010 to 2017 in Alberta and Saskatchewan were derived using hourly atmospheric methane measurements over a six-month winter period from October to March. Scaling up the winter estimate to annual indicated an anthropogenic emission rate of 3.7 ± 0.7 MtCH4/year, about 60% greater than that reported in Canada's National Inventory Report (2.3 MtCH4). This discrepancy is tied primarily to the oil and gas sector emissions as the reported emissions from livestock operations (0.6 MtCH4) are well substantiated in both top-down and bottom-up estimates and waste management (0.1 MtCH4) emissions are small. The resulting estimate of 3.0 MtCH4 from the oil and gas sector is nearly twice that reported in Canada's National Inventory (1.6 MtCH4).

Investigation of the Spatial Distribution of Methane Sources in the Greater Toronto Area Using Mobile Gas Monitoring Systems.

For methane emission reduction strategies in urban areas to be effective, large emitters must be identified. Recent studies in U.S. cities have highlighted the contribution of methane emissions from natural gas distribution networks and end use. We present a methane emission source identification and quantification method for the Greater Toronto Area (GTA), the largest metropolitan area in Canada, using mobile gas monitoring systems. From May 2018 to August 2019, we collected 77 surveys of methane mixing ratios, covering a distance of about 6400 km, and sampled emission plumes from sources such as closed landfills, natural gas compressor stations, and waterways. Our results indicate that inactive landfills emit less than inventory estimates. Despite this discrepancy, we confirm that the waste sector is the largest methane emitter in the GTA. We also report that the frequency of methane leaks from the local distribution system ranges between 4 and 22 leaks per 100 km of roadway in downtown Toronto, which is comparable to the range observed in U.S. cities, which have invested in modern natural gas distribution infrastructure. Last, we find that engineered waterways, whose emissions are currently not reported in inventories, may be a significant source of methane.

Fears and fear-related cognitions in children with selective mutism.

Selective mutism (SM) is classified under the category of anxiety disorders in DSM-5 [1], although concrete fears that underlie the condition are not specified contrary to all other anxiety disorders. Given the lack of studies systematically investigating fears in SM, content and frequency of concrete fears as well as related cognitions have remained unclear so far. One hundred and twenty-four participants [M = 13.25 years (SD = 3.24), range 8-18 years] with SM (n = 65), social phobia (SP n = 18) or with typical development (TD n = 51) took part in an online survey. Participants with SM (n = 65) answered an open-ended question concerning fears that might cause the consistent failure to speak in select situations. Additionally, participants with SM, SP and TD completed a survey containing 34 fear-related cognitions that might occur in speech-demanding situations. Open text answers were systematically evaluated by extracting higher-order categories using a Qualitative Content Analysis. Single item scores of the survey were compared between the three groups. 59% of all spontaneously reported fears were assigned to the cluster of social fears. Other reported fears represented the categories fear of mistakes (28%), language-related fears (8%) and voice-related fears (5%). The SM- and SP group only differed regarding the cognition that one's own voice might sound funny (SM > SP). Social fears and the fear of mistakes account for the majority of fears in SM. Therefore, future interventions should consider specifically targeting these types of fears.

Ingeborg Levin (1953-2024).

Pioneer in radiocarbon and atmospheric research.

Lipids as mediators of cancer progression and metastasis.

Metastasis formation is a complex process, involving multiple crucial steps, which are controlled by different regulatory mechanisms. In this context, the contribution of cancer metabolism to the metastatic cascade is being increasingly recognized. This Review focuses on changes in lipid metabolism that contribute to metastasis formation in solid tumors. We discuss the molecular mechanisms by which lipids induce a pro-metastatic phenotype and explore the role of lipids in response to oxidative stress and as signaling molecules. Finally, we reflect on potential avenues to target lipid metabolism to improve the treatment of metastatic cancers.

Interactions of Fatty Acid and Cholesterol Metabolism with Cellular Stress Response Pathways in Cancer.

Lipids have essential functions as structural components of cellular membranes, as efficient energy storage molecules, and as precursors of signaling mediators. While deregulated glucose and amino acid metabolism in cancer have received substantial attention, the roles of lipids in the metabolic reprogramming of cancer cells are less well understood. However, since the first description of de novo fatty acid biosynthesis in cancer tissues almost 70 years ago, numerous studies have investigated the complex functions of altered lipid metabolism in cancer. Here, we will summarize the mechanisms by which oncogenic signaling pathways regulate fatty acid and cholesterol metabolism to drive rapid proliferation and protect cancer cells from environmental stress. The review also discusses the role of fatty acid metabolism in metabolic plasticity required for the adaptation to changing microenvironments during cancer progression and the connections between fatty acid and cholesterol metabolism and ferroptosis.

USP28 controls SREBP2 and the mevalonate pathway to drive tumour growth in squamous cancer.

SREBP2 is a master regulator of the mevalonate pathway (MVP), a biosynthetic process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol and also provides substrates for protein prenylation. Here, we identify SREBP2 as a novel substrate for USP28, a deubiquitinating enzyme that is frequently upregulated in squamous cancers. Our results show that silencing of USP28 reduces expression of MVP enzymes and lowers metabolic flux into this pathway. We also show that USP28 binds to mature SREBP2, leading to its deubiquitination and stabilisation. USP28 depletion rendered cancer cells highly sensitive to MVP inhibition by statins, which was rescued by the addition of geranyl-geranyl pyrophosphate. Analysis of human tissue microarrays revealed elevated expression of USP28, SREBP2 and MVP enzymes in lung squamous cell carcinoma (LSCC) compared to lung adenocarcinoma (LADC). Moreover, CRISPR/Cas-mediated deletion of SREBP2 selectively attenuated tumour growth in a KRas/p53/LKB1 mutant mouse model of lung cancer. Finally, we demonstrate that statins synergise with a dual USP28/25 inhibitor to reduce viability of SCC cells. Our findings suggest that combinatorial targeting of MVP and USP28 could be a therapeutic strategy for the treatment of squamous cell carcinomas.

LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma.

Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc- . The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet-unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high-risk neuroblastoma and potentially other MYCN-amplified entities.

Chasing after methane's ultra-emitters.

[Figure: see text].

Silence and related symptoms in children and adolescents: a network approach to selective mutism.

BACKGROUND: Silence in certain situations represents the core symptom of selective mutism (SM). However, it is unclear what additional symptoms are part of this disorder. Although knowledge of symptoms is essential for diagnostics and intervention, to date, only scarce research exists on circumscribed symptoms of SM. Given the large overlap between SM and social anxiety disorder (SAD), it remains also unclear which symptoms can differentiate both disorders. METHODS: A network analysis of potential symptoms of SM was performed based on a mixed sample of N = 899 children and adolescents with and without indication of SM (n = 629 with silence in certain situations). In a preliminary analysis, we demonstrated that children with and without silence in certain situations do not differ with respect to their network structure, justifying an analysis on the entire mixed sample. Possible communities (symptom clusters) within the network and thus potential latent variables were examined, and symptoms were analyzed in terms of their centrality (the extent to which they are associated with other symptoms in the network). To investigate the differentiability of symptoms of the SM network from symptoms of SAD, we computed a network that additionally contains symptoms of SAD. RESULTS: In the resulting network on symptoms of SM, silence was, as expected, the symptom with the highest centrality. We identified two communities (symptom cluster): (1) symptoms associated with the fear response of freezing, (2) symptoms associated with speech production and avoidance. SM network symptoms and SAD symptoms largely formed two separate symptom clusters, with only selectivity of speaking behavior (more talkative at home and taciturn or mute outside the home) falling into a common cluster with SAD symptoms. CONCLUSIONS: Silence appears to have been confirmed by analysis as a core symptom of SM. Additional anxiety-related symptoms, such as avoidance behavior or motor inhibition associated with freezing, seem to co-occur with silence. The two communities of SM potentially indicate different mechanisms of silence. The symptoms of SM appear to be distinguishable from those of SAD, although there seems to be overlap in terms of difficulty speaking in situations outside the home.

Persister state-directed transitioning and vulnerability in melanoma.

Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. Melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5Bhigh cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5Bhigh persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine 2-phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor plasticity and primes melanoma cells towards lineage-specific elimination.

A multi-city urban atmospheric greenhouse gas measurement data synthesis.

Urban regions emit a large fraction of anthropogenic emissions of greenhouse gases (GHG) such as carbon dioxide (CO2) and methane (CH4) that contribute to modern-day climate change. As such, a growing number of urban policymakers and stakeholders are adopting emission reduction targets and implementing policies to reach those targets. Over the past two decades research teams have established urban GHG monitoring networks to determine how much, where, and why a particular city emits GHGs, and to track changes in emissions over time. Coordination among these efforts has been limited, restricting the scope of analyses and insights. Here we present a harmonized data set synthesizing urban GHG observations from cities with monitoring networks across North America that will facilitate cross-city analyses and address scientific questions that are difficult to address in isolation.

Psychophysiological mechanisms underlying the failure to speak: a comparison between children with selective mutism and social anxiety disorder on autonomic arousal.

BACKGROUND: Selective mutism (SM) has been conceptualized as an extreme variant of social anxiety disorder (SAD), in which the failure to speak functions as an avoidance mechanism leading to a reduction of intense fear arousal. However, psychophysiological studies in children with SM are scarce and physiological mechanisms underlying the failure to speak are largely unknown. In contrast, children with SAD are characterized by a combination of a chronically elevated physiological arousal and a blunted physiological fear response to social stress. Due to the large overlap between SM and SAD, similar mechanisms might apply to both disorders, while differences might explain why children with SM fail to speak. The aim of our study is to investigate psychophysiological mechanisms of the failure to speak in children with SM. METHODS: We assessed in a total of N = 96 children [8-12 years, SM: n = 31, SAD: n = 32, typical development (TD): n = 33] resting baseline arousal in absence of social threat and the course of physiological fear response in two social stress paradigms, differing in terms of whether the children are expected to speak (verbal task) or not (nonverbal task). RESULTS: Children with SM were characterized by increased tonic arousal compared to the other two groups, and by a more inflexible stress response in the nonverbal but not in the verbal task compared to TD-children. Further analyses revealed that children with SM who did not speak during the verbal task already demonstrated reduced arousal in anticipation of the verbal task. CONCLUSION: The increased tonic arousal generalized to non-social situations in SM could indicate a long-term alteration of the autonomic nervous system. Furthermore, the differential physiological stress response may indicate that silence acts as a maladaptive compensatory mechanism reducing stress in verbal social situations, which does not function in nonverbal situations. Our findings support the idea that the failure to speak might function as an avoidance mechanism, which is already active in anticipation of a verbal situation. Treatment of SM should take into account that children with SM may suffer from chronically elevated stress levels and that different mechanisms might operate in verbal and nonverbal social situations.

Integrated urban services: Experience from four cities on different continents.

Rapid urbanization combined with climate change necessitates new types of urban services that make best use of science and technology. The Integrated Urban Hydro-Meteorological, Climate and Environmental Services and systems are a new initiative from the World Meteorological Organization (WMO) that seeks to provide science-based integrated urban services supporting safe, healthy and resilient cities. Various cities have already started development and implementation of such Integrated Urban Services and successfully test and use them following specific requirements of local stakeholders. This paper demonstrates the novel concept and approach of Integrated Urban Hydro-Meteorological, Climate and Environmental Services (IUS) from a set of four case study cities: Hong Kong, Toronto, Mexico City and Paris, that use different IUS configurations with good existing practice. These cities represent a range of countries, climates and geophysical settings. The aggregate main joint similarities of the IUS in these cities and synergy of the cities' experience, achievements and research findings are presented, as well as identification of existing gaps in knowledge and further research needs. A list of potential criteria for identifying and classifying IUS demonstration cities is proposed. It will aid future, more detailed analysis of the IUS experience, and selection of additional demonstration cities.