Weisfeiler--Lehman goes Dynamic: An Analysis of the Expressive Power of Graph Neural Networks for Attributed and Dynamic Graphs

Graph Neural Networks (GNNs) are a large class of relational models for graph processing. Recent theoretical studies on the expressive power of GNNs have focused on two issues. On the one hand, it has been proven that GNNs are as powerful as the Weisfeiler-Lehman test (1-WL) in their ability to distinguish graphs. Moreover, it has been shown that the equivalence enforced by 1-WL equals unfolding equivalence. On the other hand, GNNs turned out to be universal approximators on graphs modulo the constraints enforced by 1-WL/unfolding equivalence. However, these results only apply to Static Undirected Homogeneous Graphs with node attributes. In contrast, real-life applications often involve a variety of graph properties, such as, e.g., dynamics or node and edge attributes. In this paper, we conduct a theoretical analysis of the expressive power of GNNs for these two graph types that are particularly of interest. Dynamic graphs are widely used in modern applications, and its theoretical analysis requires new approaches. The attributed type acts as a standard form for all graph types since it has been shown that all graph types can be transformed without loss to Static Undirected Homogeneous Graphs with attributes on nodes and edges (SAUHG). The study considers generic GNN models and proposes appropriate 1-WL tests for those domains. Then, the results on the expressive power of GNNs are extended by proving that GNNs have the same capability as the 1-WL test in distinguishing dynamic and attributed graphs, the 1-WL equivalence equals unfolding equivalence and that GNNs are universal approximators modulo 1-WL/unfolding equivalence. Moreover, the proof of the approximation capability holds for SAUHGs, which include most of those used in practical applications, and it is constructive in nature allowing to deduce hints on the architecture of GNNs that can achieve the desired accuracy

Genetic characterization of a multidrug-resistant Salmonella enterica serovar Agona isolated from a dietary supplement in Germany

Salmonella enterica subsp. enterica serovar Agona has a history of causing food-borne outbreaks and any emergence of multidrug-resistant (MDR) isolates in novel food products is of concern. Particularly, in food products frequently consumed without sufficient heating prior to consumption. Here, we report about the MDR isolate, 18-SA00377, which had been isolated from a dietary supplement in Germany in 2018 and submitted to the German National Reference Laboratory for Salmonella. WGS-based comparative genetic analyses were conducted to find a potential reservoir of the isolate itself or mobile genetic elements associated with MDR. As a phylogenetic analysis did not yield any closely related S. Agona isolates, either globally or from Germany, a detailed analysis of the largest plasmid (295,499 bp) was performed as it is the main carrier of resistances. A combined approach of long-read and short-read sequencing enabled the assembly of the isolate’s chromosome and its four plasmids. Their characterization revealed the presence of 23 different antibiotic resistance genes (ARGs), conferring resistance to 12 different antibiotic drug classes, as well as genes conferring resistance to six different heavy metals. The largest plasmid, pSE18-SA00377-1, belongs to the IncHI2 plasmid family and carries 16 ARGs, that are organized as two distinct clusters, with each ARG associated with putative composite transposons. Through a two-pronged approach, highly similar plasmids to pSE18-SA00377-1 were identified in the NCBI database and a search for Salmonella isolates with a highly similar ARG resistance profile was conducted. Mapping and structural comparisons between pSE18-SA00377-1 and these plasmids and Salmonella isolates showed that both the plasmid backbone and identical or similar ARG clusters can be found not only in Salmonella isolates, originating mostly from a wide variety of livestock, but also in a diverse range of bacterial genera of varying geographical origins and isolation sources. Thus, it can be speculated that the host range of pSE18-SA00377-1 is not restricted to Salmonella and its spread already occurred in different bacterial populations. Overall, this hints at a complex history for pSE18-SA00377-1 and highlights the importance of surveilling multidrug-resistant S. enterica isolates, especially in novel food items that are not yet heavily regulated

Metabolic control in patients with type 2 diabetes mellitus in a public hospital in Peru: a cross-sectional study in a low-middle income country

Objective The objective of this study was to assess patients’ achievement of ADA (American Diabetes Association) guideline recommendations for glycosylated hemoglobin, lipid profile, and blood pressure in a type 2 diabetes mellitus (T2DM) outpatient clinic in a low-middle income country (LMIC) setting. Methods This is a descriptive cross-sectional study with 123 ambulatory T2DM patients who are being treated at a public hospital in Lima, Peru. Data was gathered via standardized interviews, clinical surveys, and anthropomorphic measurements for each patient. Blood samples were drawn in fasting state for measures of glucose, glycosylated hemoglobin (HbA1c), and lipid profile. Laboratory parameters and blood pressure were evaluated according to ADA recommendations. Results Of the 123 patients, 81 were women and the mean age was 61.8 years. Glycemic control was abnormal in 82 (68.33%) participants, and 45 (37.50%) were unable to control their blood pressure. Lipid profile was abnormal in 73 (60.83%) participants. Only nine (7.50%) participants fulfilled ADA recommendations for glycemic, blood pressure, and lipid control. Conclusions Amongst individuals with type 2 diabetes, there was poor attainment of the ADA recommendations (HbA1c, blood pressure and LDL-cholesterol) for ambulatory T2DM patients. Interventions are urgently needed in order to prevent long-term diabetic complications

Is paternal age associated with transfer day, developmental stage, morphology, and initial hCG-rise of the competent blastocyst leading to live birth?:A multicenter cohort study

In this study we investigated whether age of men undergoing assisted reproductive technology (ART) treatment was associated with day of transfer, stage, morphology, and initial hCG-rise of the competent blastocyst leading to a live birth? The design was a multicenter historical cohort study based on exposure (age) and outcome data (blastocyst stage and morphology and initial hCG-rise) from men whose partner underwent single blastocyst transfer resulting in singleton pregnancy/birth. The ART treatments were carried out at sixteen private and university-based public fertility clinics. We included 7246 men and women, who between 2014 and 2018 underwent controlled ovarian stimulation (COS) or Frozen-thawed Embryo Transfer (FET) with a single blastocyst transfer resulting in singleton pregnancy were identified. 4842 men with a partner giving birth were included, by linking data to the Danish Medical Birth Registry. We showed that the adjusted association between paternal age and transfer day in COS treatments was OR 1.06, 95% CI (1.00;1.13). Meaning that for every increase of one year, men had a 6% increased probability that the competent blastocyst was transferred on day 6 compared to day 5. Further we showed that the mean difference in hCG values when comparing paternal age group 30–34, 35–39 and 40–45 with the age group 25–29 in those receiving COS treatment, all showed significantly lower adjusted values for older men. In conclusion we hypothesize that the later transfer (day 6) in female partners of older men may be due to longer time spent by the oocyte to repair fragmented DNA of the sperm cells, which should be a focus of future research in men

Maternal education and cognitive development in 15 European very-preterm birth cohorts from the RECAP Preterm platform

Background: Studies are sparse and inconclusive about the association between maternal education and cognitive development among children born very preterm (VPT). Although this association is well established in the general population, questions remain about its magnitude among children born VPT whose risks of medical and developmental complications are high. We investigated the association of maternal education with cognitive outcomes in European VPT birth cohorts. Methods: We used harmonized aggregated data from 15 population-based cohorts of children born at = 37 weeks of GA) were available in eight cohorts. Maternal education was classified as: low (primary/lower secondary); medium (upper secondary/short tertiary); high (bachelor's/higher). Pooled standardized mean differences (SMDs) in cognitive scores were estimated (reference: high educational level) for children assessed at ages 2-3, 4-7 and 8-15 years. Results: The study included 10 145 VPT children from 12 cohorts at 2-3 years, 8829 from 12 cohorts at 4-7 years and 1865 children from 6 cohorts at 8-15 years. Children whose mothers had low, compared with high, educational attainment scored lower on cognitive measures [pooled unadjusted SMDs: 2-3 years = -0.32 (95% confidence intervals: -0.43 to -0.21); 4-7 years = -0.57 (-0.67; -0.47); 8-15 years = -0.54 (-0.72; -0.37)]. Analyses by GA subgroups (= 27 weeks) in children without severe neonatal morbidity and term controls yielded similar results. Conclusions: Across diverse settings and regardless of the degree of prematurity, low maternal education was associated with lower cognition.Peer reviewe

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Long-Term Summertime Investigations of Pelagic and Benthic Realms with Continuous Observations of Vertical Particle Flux in the Fram Strait and the Central Arctic Ocean

Sea ice volume and extent currently experience massive reduction in the Arctic Ocean due to climate change. Our long-term study aims at tracing effects of environmental changes in pelagic and benthic systems and investigate accompanying impacts on the fate of organic matter produced in the upper water column on its way down to the seafloor. Since the start of our observations in 1999, we have already seen some effects and will present selected data sets from the upper water column and benthic data during summer expeditions as well as results from vertical particle flux measurements that were obtained from annually deployed sediment traps at the LTER (Long-Term Ecological Research) observatory HAUSGARTEN in the eastern Fram Strait (79°/4°E) and on fewer occasions in the central Arctic Ocean (CAO). Highest biomass was found in the eastern Fram Strait and lowest in the heavily ice-covered regions in the CAO. Flux rates of POC where at least one order of magnitude lower in the CAO than in the eastern Fram Strait. While in the CAO ice algae dominate the recognizable flux fraction, faecal material prevailed in eastern Fram Strait traps. This points towards different systems of organic matter production and modification and, thus, different mechanisms determine the efficiency of the biological carbon pump. These differences are also reflected in the benthic communities in the CAO and in the eastern Fram Strait. These first results have shown the importance of long-term observations and encouraged the continuation of the Arctic Ocean Observing System FRAM (FRontiers in Arctic marine Monitoring) to record environmental and biological data at high temporal and spatial resolution

ATM Regulates Differentiation of Myofibroblastic Cancer-Associated Fibroblasts and Can Be Targeted to Overcome Immunotherapy Resistance

Myofibroblastic cancer-associated fibroblast (myoCAF)-rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting the potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of the myoCAF phenotype. Differentiating myofibroblasts in vitro and myoCAFs cultured ex vivo display activated ATM signaling, and targeting ATM genetically or pharmacologically could suppress and reverse differentiation. ATM activation was regulated by the reactive oxygen species-producing enzyme NOX4, both through DNA damage and increased oxidative stress. Targeting fibroblast ATM in vivo suppressed myoCAF-rich tumor growth, promoted intratumoral CD8 T-cell infiltration, and potentiated the response to anti-PD-1 blockade and antitumor vaccination. This work identifies a novel pathway regulating myoCAF differentiation and provides a rationale for using ATM inhibitors to overcome CAF-mediated immunotherapy resistance.SignificanceATM signaling supports the differentiation of myoCAFs to suppress T-cell infiltration and antitumor immunity, supporting the potential clinical use of ATM inhibitors in combination with checkpoint inhibition in myoCAF-rich, immune-cold tumors