Mechanistic interactions as the origin of modularity in biological networks.

Biological networks are often modular. Explanations for this peculiarity either assume an adaptive advantage of a modular design such as higher robustness, or attribute it to neutral factors such as constraints underlying network assembly. Interestingly, most insights on the origin of modularity stem from models in which interactions are either determined by highly simplistic mechanisms, or have no mechanistic basis at all. Yet, empirical knowledge suggests that biological interactions are often mediated by complex structural or behavioural traits. Here, we investigate the origins of modularity using a model in which interactions are determined by potentially complex traits. Specifically, we model system elements-such as the species in an ecosystem-as finite-state machines (FSMs), and determine their interactions by means of communication between the corresponding FSMs. Using this model, we show that modularity probably emerges for free. We further find that the more modular an interaction network is, the less complex are the traits that mediate the interactions. Altogether, our results suggest that the conditions for modularity to evolve may be much broader than previously thought.

Azacitidine as epigenetic priming for chemotherapy is safe and well-tolerated in infants with newly diagnosed KMT2A-rearranged acute lymphoblastic leukemia: Children's Oncology Group trial AALL15P1.

Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of remission failure, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies. The Children's Oncology Group trial AALL15P1 tested the safety and tolerability of five days of azacitidine immediately prior to the start of chemotherapy on day six, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was welltolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells (PBMCs) demonstrated decreased DNA methylation in 87% of samples tested following five days of azacitidine. Event-free survival was similar to prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of PBMCs in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358.

Socioeconomic status and risk for child psychopathology: exploring gene-environment interaction in the presence of gene-environment correlation using extended families in the Norwegian Mother, Father and Child Birth Cohort Study.

BACKGROUND: Low socioeconomic status (SES) is associated with increased risk for emotional and behavioural problems among children. Evidence from twin studies has shown that family SES moderates genetic and environmental influences on child mental health. However, it is also known that SES is itself under genetic influence and previous gene-environment interaction (G×E) studies have not incorporated the potential genetic overlap between child mental health and family SES into G×E analyses. We applied a novel approach using extended family data to investigate the moderation of aetiological influences on child emotional and behavioural problems by parental socioeconomic status in the presence of modelled gene-environment correlation. METHODS: The sample comprised >28,100 children in extended-family units drawn from the Norwegian Mother, Father and Child Cohort Study (MoBa). Mothers reported children's emotional and behavioural symptoms. Parents' income and educational attainment were obtained through linkage to administrative register data. Bivariate moderation Multiple-Children-of-Twins-and-Siblings (MCoTS) models were used to analyse relationships between offspring outcomes (emotional and behavioural symptom scores) and parental socioeconomic moderators (income rank and educational attainment). RESULTS: The aetiology of child emotional symptoms was moderated by maternal and paternal educational attainment. Shared environmental influences on child emotional symptoms were greater at lower levels of parents' education. The aetiology of child behavioural symptoms was moderated by maternal, but not paternal, socioeconomic factors. Genetic factors shared between maternal income and child behavioural symptoms were greater in families with lower levels maternal income. Nonshared environmental influences on child behavioural symptoms were greater in families with higher maternal income and education. CONCLUSIONS: Parental socioeconomic indicators moderated familial influences and nonshared environmental influences on child emotional and behavioural outcomes. Maternal SES and child mental health share aetiological overlap such that shared genetic influence was greater at the lower end of the socioeconomic distribution. Our findings collectively highlight the role that family socioeconomic factors play in shaping the origins of child emotional and behavioural problems.

Cheating in Mutualisms Promotes Diversity and Complexity.

AbstractMutualisms such as those between flowering plants and their pollinators are common in nature. Yet understanding their persistence in the face of cheaters and identifying the mechanisms behind their stunning diversity provide formidable challenges for evolutionary biologists. To shed light onto these questions, we introduce an individual-based model of two coevolving species in which individuals of one species use a Boolean circuit to discriminate between cooperators and cheaters in the other species. This conveys the idea that interactions are often mediated by complex biological processes rather than the matching of a single trait, as often assumed in models of coevolution. Our results show that cheating promotes diversification and complex discrimination mechanisms at the cost of a higher risk for mutualism to collapse. This result is mediated by an inverse relationship between mutational robustness and organismal complexity.

High-throughput qPCR and 16S rRNA gene amplicon sequencing as complementary methods for the investigation of the cheese microbiota.

BACKGROUND: Next-generation sequencing (NGS) methods and especially 16S rRNA gene amplicon sequencing have become indispensable tools in microbial ecology. While they have opened up new possibilities for studying microbial communities, they also have one drawback, namely providing only relative abundances and thus compositional data. Quantitative PCR (qPCR) has been used for years for the quantification of bacteria. However, this method requires the development of specific primers and has a low throughput. The constraint of low throughput has recently been overcome by the development of high-throughput qPCR (HT-qPCR), which allows for the simultaneous detection of the most prevalent bacteria in moderately complex systems, such as cheese and other fermented dairy foods. In the present study, the performance of the two approaches, NGS and HT-qPCR, was compared by analyzing the same DNA samples from 21 Raclette du Valais protected designation of origin (PDO) cheeses. Based on the results obtained, the differences, accuracy, and usefulness of the two approaches were studied in detail. RESULTS: The results obtained using NGS (non-targeted) and HT-qPCR (targeted) show considerable agreement in determining the microbial composition of the cheese DNA samples studied, albeit the fundamentally different nature of these two approaches. A few inconsistencies in species detection were observed, particularly for less abundant ones. The detailed comparison of the results for 15 bacterial species/groups measured by both methods revealed a considerable bias for certain bacterial species in the measurements of the amplicon sequencing approach. We identified as probable origin to this PCR bias due to primer mismatches, variations in the number of copies for the 16S rRNA gene, and bias introduced in the bioinformatics analysis. CONCLUSION: As the normalized microbial composition results of NGS and HT-qPCR agreed for most of the 21 cheese samples analyzed, both methods can be considered as complementary and reliable for studying the microbial composition of cheese. Their combined application proved to be very helpful in identifying potential biases and overcoming methodological limitations in the quantitative analysis of the cheese microbiota.

Retrospective Diagnosis of Ataxia-Telangiectasia in an Adolescent Patient With a Remote History of T-Cell Leukemia.

Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar degeneration that is typically diagnosed in early childhood. A-T is associated with a predisposition to malignancies, particularly lymphoid tumors in childhood and early adulthood. An adolescent girl with minimal neurologic symptoms was diagnosed with A-T 8 years after completing therapy for T-cell acute lymphoblastic leukemia, following a diagnosis of ATM-mutated breast cancer in her mother. We highlight the importance of recognizing ATM mutations in T-cell acute lymphoblastic leukemia, appreciating the phenotypic heterogeneity of A-T, and defining optimal cancer screening in A-T patients.

Wet-Chemically Prepared Porphyrin Layers on Rutile TiO2(110).

Porphyrins are large organic molecules that are interesting for different applications, such as photovoltaic cells, gas sensors, or in catalysis. For many of these applications, the interactions between adsorbed molecules and surfaces play a crucial role. Studies of porphyrins on surfaces typically fall into one of two groups: (1) evaporation onto well-defined single-crystal surfaces under well-controlled ultrahigh vacuum conditions or (2) more application-oriented wet chemical deposition onto less well-defined high surface area surfaces under ambient conditions. In this study, we will investigate the wet chemical deposition of 5-(monocarboxyphenyl)-10,15,20-triphenylporphyrin (MCTPP) on well-defined rutile TiO2(110) single crystals under ambient conditions. Prior to deposition, the TiO2(110) crystals were also cleaned wet-chemically under ambient conditions, meaning none of the preparation steps were done in ultrahigh vacuum. However, after each preparation step, the surfaces were characterized in ultrahigh vacuum with X-ray photoelectron spectroscopy (XPS) and the result was compared with porphyrin layers prepared in ultrahigh vacuum (UHV) by evaporation. The differences of both preparations when exposed to zinc ion solutions will also be discussed.

Probing the Roughness of Porphyrin Thin Films with X-ray Photoelectron Spectroscopy.

Thin-film growth of molecular systems is of interest for many applications, such as for instance organic electronics. In this study, we demonstrate how X-ray photoelectron spectroscopy (XPS) can be used to study the growth behavior of such molecular systems. In XPS, coverages are often calculated assuming a uniform thickness across a surface. This results in an error for rough films, and the magnitude of this error depends on the kinetic energy of the photoelectrons analyzed. We have used this kinetic-energy dependency to estimate the roughnesses of thin porphyrin films grown on rutile TiO2 (110). We used two different molecules: cobalt (II) monocarboxyphenyl-10,15,20-triphenylporphyrin (CoMCTPP), with carboxylic-acid anchor groups, and cobalt (II) tetraphenylporphyrin (CoTPP), without anchor groups. We find CoMCTPP to grow as rough films at room temperature across the studied coverage range, whereas for CoTPP the first two layers remain smooth and even; depositing additional CoTPP results in rough films. Although, XPS is not a common technique for measuring roughness, it is fast and provides information of both roughness and thickness in one measurement.

Very late recurrence of B-cell acute lymphoblastic leukemia masquerading as a pituitary tumor.

Involvement of the pituitary gland by leukemic infiltration is exceedingly rare. Here, we describe a very late recurrence of B-cell acute lymphoblastic leukemia masquerading as a pituitary tumor and review the literature for previously reported cases. Our female patient presented 13 years after completion of therapy for B-ALL with headache, amenorrhea, galactorrhea and a pituitary mass. Subsequent studies revealed recurrence of her leukemia, and the pituitary lesion resolved after induction chemotherapy. Our case highlights the importance of considering leukemic infiltrate in the differential diagnosis of pituitary mass, particularly in a patient with a history of hematologic malignancy, sparing unnecessary surgical intervention and informing endocrine evaluation. In addition, the case also highlights difficulties with characterizing this recurrence as a very late relapse or clonal evolution of the original leukemia.

Interfacial Reactions of Tetraphenylporphyrin with Cobalt-Oxide Thin Films.

We have studied the adsorption and interfacial reactions of 2H-tetraphenylporphyrin (2HTPP) with cobalt-terminated Co3 O4 (111) and oxygen-terminated CoO(111) thin films using synchrotron-radiation X-ray photoelectron spectroscopy. Already at 275 K, we find evidence for the formation of a metalated species, most likely CoTPP, on both surfaces. The degree of self-metalation increases with temperature on both surfaces until 475 K, where the metalation is almost complete. At 575 K the porphyrin coverage decreases drastically on the reducible cobalt-terminated Co3 O4 (111) surface, while higher temperatures are needed on the non-reducible oxygen-terminated CoO(111). The low temperature self-metalation is similar to that observed on MgO(100) surfaces, but drastically different from that observed on TiO2 (110), where no self-metalation is observed at room temperature.

Thresholds in the resilience of modular social networks to invasion by defectors.

Cooperative interactions constitute the backbone of many biological and social systems. Since cooperation is prone to exploitation, these systems must incorporate mechanisms that prevent the spreading of defective behaviors. One such mechanism is modularity, i.e., the tendency of a social network to be organized in modules, where individuals within a module tend to interact strongly among themselves while avoiding interacting with individuals from other modules. This structure allows cooperation to prevail by having modules of cooperative individuals with a limited exposure to defectors. To address the rate and shape of the effect of modularity on the resilience of cooperation, here we study a variant of the Prisoner's Dilemma on modular networks. Our simulations reveal a sharp transition between a resilient and a vulnerable regime as modularity exceeds a critical threshold. By using a simplified mathematical model, we show that the observed threshold is equivalent to the epidemic threshold found in a certain class of SIR models. This allows us to derive an explicit condition under which a cooperative society is expected to be resilient to invasive defectors.

Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on treatment and management considerations for AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for AYA Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

Isolated Central Nervous System Chloroma as a Presenting Sign of Relapsed Pediatric Acute Lymphoblastic Leukemia.

Central nervous system (CNS) chloromas are an exceedingly rare presentation of CNS relapse in acute lymphoblastic leukemia (ALL). We report a relapsed ALL patient who presented with 2 separate chloromas and cerebrospinal fluid lymphoblastocytosis, and outline a treatment plan of systemic chemotherapy and CNS-directed radiation therapy. A review of the literature indicates that multiagent chemotherapy combined with CNS radiotherapy is effective, with hematopoietic stem cell transplantation used in half of reported cases. We conclude that intensive systemic multiagent chemotherapy with CNS-directed radiation therapy can be successfully used to treat relapsed pediatric ALL with CNS lymphoblastic chloroma.

Interfacial interactions between CoTPP molecules and MgO(100) thin films.

We have investigated the interactions between cobalt(ii)-tetraphenylporphyrin (CoTPP) molecules and MgO(100) thin films on Ag(100) by means of Synchrotron Radiation X-Ray and Ultra-Violet Photoelectron Spectroscopy (SR-XPS and SR-UPS). At room temperature, the CoTPP monolayer consists of two different species. A minority of molecules exhibits a strong electronic interaction with the substrate, whereas for the majority a similar spectroscopic signature as for multilayer molecules is observed. Based on the lateral inhomogeneity of the surface electronic structure, we tentatively suggest that the strongly interacting molecules adsorb with their metal center directly above oxygen ions. Unlike for metal substrates, where a monolayer can be prepared upon heating to above 500 K, most of the monolayer on MgO desorbs at 550 K together with the multilayers. This indicates either a weaker molecule-substrate bond than for most metal surfaces or a higher activation energy barrier for dehydrogenation. The remaining molecules are presumably MgTPP molecules, originating from a 2HTPP impurity in CoTPP.

A CALM-derived nuclear export signal is essential for CALM-AF10-mediated leukemogenesis.

The t(10;11) chromosomal translocation gives rise to the CALM-AF10 fusion gene and is found in patients with aggressive and difficult-to-treat hematopoietic malignancies. CALM-AF10-driven leukemias are characterized by HOXA gene up-regulation and a global reduction in H3K79 methylation. DOT1L, the H3K79 methyltransferase, interacts with the octapeptide/leucine zipper domain of AF10, and this region has been shown to be necessary and sufficient for CALM-AF10-mediated transformation. However, the precise role of CALM in leukemogenesis remains unclear. Here, we show that CALM contains a nuclear export signal (NES) that mediates cytoplasmic localization of CALM-AF10 and is necessary for CALM-AF10-dependent transformation. Fusions of the CALM NES (NES(CALM)-AF10) or NES motifs from heterologous proteins (ABL1, Rev, PKIA, APC) in-frame with AF10 are sufficient to immortalize murine hematopoietic progenitors in vitro. The CALM NES is essential for CALM-AF10-dependent Hoxa gene up-regulation and aberrant H3K79 methylation, possibly by mislocalization of DOT1L. Finally, we observed that CALM-AF10 leukemia cells are selectively sensitive to inhibition of nuclear export by Leptomycin B. These findings uncover a novel mechanism of leukemogenesis mediated by the nuclear export pathway and support further investigation of the utility of nuclear export inhibitors as therapeutic agents for patients with CALM-AF10 leukemias.

WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.

WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling.

Coverage- and temperature-dependent metalation and dehydrogenation of tetraphenylporphyrin on Cu(111).

Using temperature-programmed desorption, supported by X-ray photoelectron spectroscopy and scanning tunneling microscopy, a comprehensive overview of the main reactions of 5,10,15,20-tetraphenyl-21H,23H-porphyrin (2HTPP) on Cu(111) as a function of coverage and temperature is obtained. Three reactions were identified: metalation with Cu substrate atoms, stepwise partial dehydrogenation, and finally complete dehydrogenation. At low coverage the reactions are independent of coverage, but at higher coverage metalation becomes faster and partial dehydrogenation slower. This behavior is explained by a weaker interaction between the iminic nitrogen atoms and the Cu(111) surface in the high-coverage checkerboard structure, leading to faster metalation, and the stabilizing effect of T-type interactions in the CuTPP islands formed at high coverage after metalation, leading to slower dehydrogenation. Based on the amount of hydrogen released and the appearance in STM, a structure of the partially dehydrogenated molecule is suggested.