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Background: Malignant peripheral nerve sheath tumors (MPNSTs) are rare yet highly aggressive soft tissue sarcomas of mesenchymal origin, characterized by a heterogeneous pathological spectrum, limited therapeutic options, and high metastatic potential., Methods: Here, the authors conducted a comprehensive bibliometric analysis of the 100 most-cited MPNST articles by utilizing Elsevier's Scopus to identify all relevant published and indexed articles referring to MPNST, thereby aiming to elucidate the pertinent research findings regarding the disease's pathophysiology and therapeutic advancements. Articles were classified as basic science or clinical and analyzed for various bibliometric parameters., Results: The majority of articles (75%) focused on clinical aspects, reflecting the extensive clinicopathological characterization of MPNSTs. Notable studies investigated prognostic factors, histological and immunohistochemical features, and diagnostic modalities. The identification of loss of function mutations in the polycomb repressive complex 2 emerged as a pivotal role, as it opened avenues for potential targets for novel therapeutic interventions. Newer articles (published in or after 2006) demonstrated higher citation rates, suggesting evolving impact and collaboration., Conclusions: This bibliometric analysis showed how developments in the understanding of MPNST pathophysiology and the creation of novel therapeutic strategies occurred throughout time. Changes that have been noticed recently could portend future innovative therapeutic approaches., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Medulloblastoma, the most common malignant brain tumor in children, presents a complex treatment challenge due to its propensity for infiltrative growth within the posterior fossa and its potential attachment to critical anatomical structures. Central to the management of medulloblastoma is the surgical resection of the tumor, which is a key determinant of patient prognosis. However, the extent of surgical resection (EOR), ranging from gross total resection (GTR) to subtotal resection (STR) or even biopsy, has been the subject of extensive debate and investigation within the medical community. Today, the impact of neurosurgical EOR on the prognosis of medulloblastoma patients remains a complex and evolving area of investigation. The conflicting findings in the literature, the challenges posed by critical surrounding anatomical structures, the potential for surgical complications and neurologic morbidity, and the nuanced interactions with molecular subgroups all contribute to the complexity of this issue. As the field continues to advance, the imperative to strike a delicate balance between maximizing resection and preserving quality of life remains central to the management of medulloblastoma patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Increased age is a strong and unfavorable prognostic factor for patients with glioblastoma (GBM). However, the relationships between stratified patient age, comorbidities, and medications have yet to be explored in GBM patient survival analyses., Objective: To evaluate co-morbid conditions, tumor-related symptoms, medication prescriptions, and subject age for patients with GBM and to establish potential targets for prospective studies., Methods: Electronic health records for 565 patients with IDHwt GBM were evaluated at a single center between January 1, 2000 and August 9, 2021 were retrospectively assessed. Data were stratified by MGMT promoter methylation status when available and were used to construct multivariable time-dependent cox models and intra-cohort hazards., Results: Younger (<65 years of age) but not older (≥65 years) GBM patients demonstrated a worse prognosis with movement related disabilities (P < 0.0001), gait/balance difficulty (P = 0.04) and weakness (P = 0.007), as well as psychiatric conditions, mental health disorders (P = 0.002) and anxiety (P = 0.001). In contrast, older but not younger GBM patients demonstrated a worse prognosis with epilepsy (P = 0.039). Both groups had worse survival with confusion/altered mental status (P = 0.023 vs < 0.000) and an improved survival with a Temozolomide prescription. Older but not younger GBM patients experienced an improved hazard with a prescription of ace-inhibitor medications (P = 0.048)., Conclusion: Age-dependent novel associations between clinical symptoms and medications prescribed for co-morbid conditions were demonstrated in patients with GBM. The results of the current work support future mechanistic studies that investigate the negative relationship(s) between increased age, comorbidities, and drug therapies for differential clinical decision-making across the lifespan of patients with GBM., Competing Interests: All co-authors report no financial or otherwise conflicts of interest., (© 2024 Published by Elsevier Inc.)

Purpose: Choroid plexus tumors (CPT) are relatively rare CNS tumors that primarily occur in children. They are classified as low-grade choroid plexus papilloma, including atypical ones, and high-grade choroid plexus carcinoma based on histological characteristics. There has been extensive academic research regarding these complex tumors. The goal of this work was to identify the 100 most-cited articles pertaining to CPTs in order to better understand the most impactful studies to date., Methods: In August 2023, Elsevier's Scopus database was searched for the 100 most-cited articles about CPT. To look for trends, articles were classified as either basic science or clinical, and the earliest 50 articles were separated from the latest 50 articles and then were compared. Various bibliometric parameters were summarized and compared using Pearson's chi-square exact test and Wilcoxon rank sum test/Mann-Whitney U test., Results: The 100 most-cited articles were published between 1955 and 2016 in 53 different scientific journals, originating from 16 distinct countries. Over 75% of the articles were clinical in nature, and overall mean (range) values were as follows: citation count 78.5 (42-371), citation rate per year 3.4 (0.9-12), number of authors 6.2 (1-28). Newer articles had statistically higher citation rate (P < 0.01) and number of authors (P < 0.01) compared to their older counterparts. Additionally, while there was no significant difference in article focus (P = 0.64), there was a difference in study design (P < 0.01)., Conclusion: This study used citation number as a surrogate for article impact and identified the 100 most-cited CPT articles. New mutational analyses have allowed for further subgrouping and positive trends in collaboration shine hope for improvement in treatment outcomes and long-term survival., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: H3 K27-altered diffuse midline glioma (DMG) is the most common malignant brainstem tumor in the pediatric population. Despite enormous preclinical and clinical efforts, the prognosis remains dismal, with fewer than 10% of patients surviving for two years after diagnosis. Fractionated radiation remains the only standard treatment options for DMG. Developing novel treatments and therapeutic delivery methods is critical to improving outcomes in this devastating disease., Areas Covered: This review addresses recent advances in molecularly targeted pharmacotherapy and immunotherapy in DMG. The clinical presentation, diagnostic workup, unique pathological challenges, and current clinical trials are highlighted throughout., Expert Opinion: Promising pharmacotherapies targeting various components of DMG pathology and the application of immunotherapies have the potential to improve patient outcomes. However, novel approaches are needed to truly revolutionize treatment for this tumor. First, combinational therapy should be employed, as DMG can develop resistance to single-agent approaches and many therapies are susceptible to rapid clearance from the brain. Second, drug-tumor residence time, i.e. the time for which a therapeutic is present at efficacious concentrations within the tumor, must be maximized to facilitate a durable treatment response. Engineering extended drug delivery methods with minimal off-tumor toxicity should be a focus of future studies.

To address claims of human exceptionalism, we determine where humans fit within the greater mammalian distribution of reproductive inequality. We show that humans exhibit lower reproductive skew (i.e., inequality in the number of surviving offspring) among males and smaller sex differences in reproductive skew than most other mammals, while nevertheless falling within the mammalian range. Additionally, female reproductive skew is higher in polygynous human populations than in polygynous nonhumans mammals on average. This patterning of skew can be attributed in part to the prevalence of monogamy in humans compared to the predominance of polygyny in nonhuman mammals, to the limited degree of polygyny in the human societies that practice it, and to the importance of unequally held rival resources to women's fitness. The muted reproductive inequality observed in humans appears to be linked to several unusual characteristics of our species-including high levels of cooperation among males, high dependence on unequally held rival resources, complementarities between maternal and paternal investment, as well as social and legal institutions that enforce monogamous norms.

Background: H3K27-altered diffuse midline glioma (DMG) is the deadliest pediatric brain tumor; despite intensive research efforts, every clinical trial to date has failed. Is this because we are choosing the wrong drugs? Or are drug delivery and other pharmacokinetic variables at play? We hypothesize that the answer is likely a combination, where optimization may result in a much needed novel therapeutic approach., Methods: We used in vitro drug screening, patient samples, and shRNA knockdown models to identify an upregulated target in DMG. A single small molecule protein kinase inhibitor with translational potential was selected for systemic and direct, loco-regional delivery to patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM). Pharmacokinetic studies were conducted in non-tumor bearing rats., Results: Aurora kinase (AK) inhibitors demonstrated strong antitumor effects in DMG drug screens. Additional in vitro studies corroborated the importance of AK to DMG survival. Systemic delivery of alisertib showed promise in subcutaneous PDX but not intracranial GEMM and PDX models. Repeated loco-regional drug administration into the tumor through convection-enhanced delivery (CED) was equally inefficacious, and pharmacokinetic studies revealed rapid clearance of alisertib from the brain. In an effort to increase the drug to tumor residence time, continuous CED over 7 days improved drug retention in the rodent brainstem and significantly extended survival in both orthotopic PDXs and GEMMs., Conclusions: These studies provide evidence for increasing drug-tumor residence time of promising targeted therapies via extended CED as a valuable treatment strategy for DMG., Competing Interests: The authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Helping behaviour is thought to play a major role in the evolution of group-living animals. Yet, it is unclear to what extent human males and human females use the same strategies to secure support. Accordingly, we investigate help-seeking over a 5-year period in relation to gender using data from virtually all adults in two Tamil villages ( N = 782). Simulations of network dynamics (i.e. stochastic actor-oriented models) calibrated to these data broadly indicate that women are more inclined than men to create and maintain supportive bonds via multiple mechanisms of cooperation (e.g. reciprocity, kin bias, friend bias, generalized exchange). However, gender-related differences in the simulated dynamics of help-seeking are modest, vary based on structural position (e.g. out-degree), and do not appear to translate to divergence in the observed structure of respondents' egocentric networks. Findings ultimately suggest that men and women in the two villages are similarly social but channel their sociality differently. This article is part of the theme issue 'Cooperation among women: evolutionary and cross-cultural perspectives'.

Introduction: Despite much progress, the prognosis for H3K27-altered diffuse midline glioma (DMG), previously known as diffuse intrinsic pontine glioma when located in the brainstem, remains dark and dismal., Areas Covered: A wealth of research over the past decade has revolutionized our understanding of the molecular basis of DMG, revealing potential targetable vulnerabilities for treatment of this lethal childhood cancer. However, obstacles to successful clinical implementation of novel therapies remain, including effective delivery across the blood-brain barrier (BBB) to the tumor site. Here, we review relevant literature and clinical trials and discuss direct drug delivery via convection-enhanced delivery (CED) as a promising treatment modality for DMG. We outline a comprehensive molecular, pharmacological, and procedural approach that may offer hope for afflicted patients and their families., Expert Opinion: Challenges remain in successful drug delivery to DMG. While CED and other techniques offer a chance to bypass the BBB, the variables influencing successful intratumoral targeting are numerous and complex. We discuss these variables and potential solutions that could lead to the successful clinical implementation of preclinically promising therapeutic agents.

Background: H3K27M-mutant diffuse midline glioma (DMG) is a lethal brain tumor that usually occurs in children. Despite advances in our understanding of its underlying biology, efficacious therapies are severely lacking., Methods: We screened a library of drugs either FDA-approved or in clinical trial using a library of patient-derived H3K27M-mutant DMG cell lines with cell viability as the outcome. Results were validated for clinical relevance and mechanistic importance using patient specimens from biopsy and autopsy, patient-derived cell lines, inhibition by gene knockdown and small molecule inhibitors, and patient-derived xenografts., Results: Kinase inhibitors were highly toxic to H3K27M-mutant DMG cells. Within this class, STAT3 inhibitors demonstrated robust cytotoxic activity in vitro. Mechanistic analyses revealed one form of activated STAT3, phospho-tyrosine- 705 STAT3 (pSTAT3), was selectively upregulated in H3K27M-mutant cell lines and clinical specimens. STAT3 inhibition by CRISPR/Cas9 knockout, shRNA or small molecule inhibition reduced cell viability in vitro, and partially restored expression of the polycomb repressive mark H3K27me3, which is classically lost in H3K27M-mutant DMG. Putative STAT3-regulated genes were enriched in an H3K27M-knockout DMG cell line, indicating relative gain of STAT3 signaling in K27M-mutant cells. Treatment of patient-derived intracranial xenografts with WP1066, a STAT3 pathway inhibitor currently in clinical use for pediatric brain tumors, resulted in stasis of tumor growth, and increased overall survival. Finally, pSTAT3(Y705) was detected in circulating plasma extracellular vesicles of patients with H3K27M-mutant DMG., Conclusions: STAT3 is a biologically relevant therapeutic target in H3K27M-mutant DMG. STAT3 inhibition should be considered in future clinical trials., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Important challenges in developing drugs that target central nervous system (CNS) tumors include overcoming barriers for CNS delivery and reducing systemic side effects. Alisertib, an aurora A kinase inhibitor, has been examined for treatment of several CNS tumors in preclinical and clinical studies. In this study, we investigated the distribution of alisertib into the CNS, the site of efficacy for brain tumors, and into the bone marrow, the site of dose-limiting toxicity leading to myelosuppression. Mechanisms influencing site-specific distribution, such as active transport mediated by the efflux proteins, p-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), were examined. Alisertib exposure to the brain in wild-type mice was less than 1% of that in the plasma, and was evenly distributed throughout various brain regions and the spinal cord. Studies using transporter knockout mice and pharmacological inhibition show that alisertib CNS distribution is influenced by P-gp, but not Bcrp. Conversely, upon systemic administration, alisertib distribution to the bone marrow occurred rapidly, was not significantly limited by efflux transporters, and reached higher concentrations than in the CNS. This study demonstrates that, given an equivalent distributional driving force exposure in plasma, the exposure of alisertib in the brain is significantly less than that in the bone marrow, suggesting that targeted delivery may be necessary to guarantee therapeutic efficacy with minimal risk for adverse events.Therefore, these data suggest that, to improve the therapeutic index when using alisertib for brain tumors, a localized regional delivery, such as convection-enhanced delivery, may be warranted. SIGNIFICANCE STATEMENT: The CNS penetration of alisertib is limited with uniform distribution in various regions of the brain, and P-gp efflux is an important mechanism limiting that CNS distribution. Alisertib rapidly distributes into the bone marrow, a site of toxicity, with a greater exposure than in the CNS, a possible site of efficacy. These results suggest a need to design localized delivery strategies to improve the CNS exposure of alisertib and limit systemic toxicities in the treatment of brain tumors., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Even though the last decade has seen a surge in the identification of molecular targets and targeted therapies in pediatric brain tumors, the blood brain barrier (BBB) remains a significant challenge in systemic drug delivery. This continues to undermine therapeutic efficacy. Recent efforts have identified several strategies that can facilitate enhanced drug delivery into pediatric brain tumors. These include invasive methods such as intra-arterial, intrathecal, and convection enhanced delivery and non-invasive technologies that allow for transient access across the BBB, including focused ultrasound and nanotechnology. This review discusses current strategies that are being used to enhance delivery of different therapies across the BBB to the tumor site - a major unmet need in pediatric neuro-oncology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Research in various disciplines has highlighted that humans are uniquely able to solve the problem of cooperation through the informal mechanisms of reputation and gossip. Reputation coordinates the evaluative judgments of individuals about one another. Direct observation of actions and communication are the essential routes that are used to establish and update reputations. In large groups, where opportunities for direct observation are limited, gossip becomes an important channel to share individual perceptions and evaluations of others that can be used to condition cooperative action. Although reputation and gossip might consequently support large-scale human cooperation, four puzzles need to be resolved to understand the operation of reputation-based mechanisms. First, we need empirical evidence of the processes and content that form reputations and how this may vary cross-culturally. Second, we lack an understanding of how reputation is determined from the muddle of imperfect, biased inputs people receive. Third, coordination between individuals is only possible if reputation sharing and signaling is to a large extent reliable and valid. Communication, however, is not necessarily honest and reliable, so theoretical and empirical work is needed to understand how gossip and reputation can effectively promote cooperation despite the circulation of dishonest gossip. Fourth, reputation is not constructed in a social vacuum; hence we need a better understanding of the way in which the structure of interactions affects the efficiency of gossip for establishing reputations and fostering cooperation., (© 2021. The Author(s).)

Across species, social hierarchies are often governed by dominance relations. In humans, where there are multiple culturally valued axes of distinction, social hierarchies can take a variety of forms and need not rest on dominance relations. Consequently, humans navigate multiple domains of status, i.e. relative standing. Importantly, while these hierarchies may be constructed from dyadic interactions, they are often more fundamentally guided by subjective peer evaluations and group perceptions. Researchers have typically focused on the distinct elements that shape individuals' relative standing, with some emphasizing individual-level attributes and others outlining emergent macro-level structural outcomes. Here, we synthesize work across the social sciences to suggest that the dynamic interplay between individual-level and meso-level properties of the social networks in which individuals are embedded are crucial for understanding the diverse processes of status differentiation across groups. More specifically, we observe that humans not only navigate multiple social hierarchies at any given time but also simultaneously operate within multiple, overlapping social networks. There are important dynamic feedbacks between social hierarchies and the characteristics of social networks, as the types of social relationships, their structural properties, and the relative position of individuals within them both influence and are influenced by status differentiation. This article is part of the theme issue 'The centennial of the pecking order: current state and future prospects for the study of dominance hierarchies'.

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor. While there are a number of in vivo rodent models for evaluating tumor biology and response to therapy, these models require significant time and resources. Here, we established the chick-embryo chorioallantoic (CAM) assay as an affordable and time efficient xenograft model for testing a variety of treatment approaches for DIPG. We found that patient-derived DIPG tumors develop in the CAM and maintain the same genetic and epigenetic characteristics of native DIPG tumors. We monitored tumor response to pharmaco- and radiation therapy by 3-D ultrasound volumetric and vasculature analysis. In this study, we established and validated the CAM model as a potential intermediate xenograft model for DIPG and its use for testing novel treatment approaches that include pharmacotherapy or radiation., Competing Interests: The authors have declared that no competing interests exist.

Large-scale non-kin cooperation is a unique ingredient of human success. This type of cooperation is challenging to explain in a world of self-interested individuals. There is overwhelming empirical evidence from different disciplines that reputation and gossip promote cooperation in humans in different contexts. Despite decades of research, important details of reputation systems are still unclear. Our goal with this theme issue is to promote an interdisciplinary approach that allows us to explore and understand the evolution and maintenance of reputation systems with a special emphasis on gossip and honest signalling. The theme issue is organized around four main questions: What are the necessary conditions for reputation-based systems? What is the content and context of reputation systems? How can reputations promote cooperation? And, what is the role of gossip in maintaining reputation systems and thus cooperation? This article is part of the theme issue 'The language of cooperation: reputation and honest signalling'.

Performing a dramatic act of religious devotion, creating an art exhibit, or releasing a new product are all examples of public acts that signal quality and contribute to building a reputation. Signalling theory predicts that these public displays can reliably reveal quality. However, data from ethnographic work in South India suggests that more prominent individuals gain more from reputation-building religious acts than more marginalized individuals. To understand this phenomenon, we extend signalling theory to include variation in people's social prominence or social capital, first with an analytical model and then with an agent-based model. We consider two ways in which social prominence/capital may alter signalling: (i) it impacts observers' priors, and (ii) it alters the signallers' pay-offs. These two mechanisms can result in both a 'reputational shield,' where low quality individuals are able to 'pass' as high quality thanks to their greater social prominence/capital, and a 'reputational poverty trap,' where high quality individuals are unable to improve their standing owing to a lack of social prominence/capital. These findings bridge the signalling theory tradition prominent in behavioural ecology, anthropology and economics with the work on status hierarchies in sociology, and shed light on the complex ways in which individuals make inferences about others. This article is part of the theme issue 'The language of cooperation: reputation and honest signalling'.

Reputation has been shown to provide an informal solution to the problem of cooperation in human societies. After reviewing models that connect reputations and cooperation, we address how reputation results from information exchange embedded in a social network that changes endogenously itself. Theoretical studies highlight that network topologies have different effects on the extent of cooperation, since they can foster or hinder the flow of reputational information. Subsequently, we review models and empirical studies that intend to grasp the coevolution of reputations, cooperation and social networks. We identify open questions in the literature concerning how networks affect the accuracy of reputations, the honesty of shared information and the spread of reputational information. Certain network topologies may facilitate biased beliefs and intergroup competition or in-group identity formation that could lead to high cooperation within but conflicts between different subgroups of a network. Our review covers theoretical, experimental and field studies across various disciplines that target these questions and could explain how the dynamics of interactions and reputations help or prevent the establishment and sustainability of cooperation in small- and large-scale societies. This article is part of the theme issue 'The language of cooperation: reputation and honest signalling'.

Performing costly helpful behaviours can allow individuals to improve their reputation. Those who gain a good reputation are often preferred as interaction partners and are consequently better able to access support through cooperative relationships with others. However, investing in prosocial displays can sometimes yield social costs: excessively generous individuals risk losing their good reputation, and even being vilified, ostracised or antisocially punished. As a consequence, people frequently try to downplay their prosocial actions or hide them from others. In this review, we explore when and why investments in prosocial behaviour are likely to yield social costs. We propose two key features of interactions that make it more likely that generous individuals will incur social costs when: (a) observers infer that helpful behaviour is motivated by strategic or selfish motives; and (b) observers infer that helpful behaviour is detrimental to them. We describe how the cognition required to consider ulterior motives emerges over development and how these tendencies vary across cultures - and discuss how the potential for helpful actions to result in social costs might place boundaries on prosocial behaviour as well as limiting the contexts in which it might occur. We end by outlining the key avenues and priorities for future research., Competing Interests: NR is the author of the forthcoming trade book, The Social Instinct: How Cooperation Shaped the World., (© The Author(s) 2021.)

Community detection in networks is commonly performed using information about interactions between nodes. Recent advances have been made to incorporate multiple types of interactions, thus generalizing standard methods to multilayer networks. Often, though, one can access additional information regarding individual nodes, attributes, or covariates. A relevant question is thus how to properly incorporate this extra information in such frameworks. Here we develop a method that incorporates both the topology of interactions and node attributes to extract communities in multilayer networks. We propose a principled probabilistic method that does not assume any a priori correlation structure between attributes and communities but rather infers this from data. This leads to an efficient algorithmic implementation that exploits the sparsity of the dataset and can be used to perform several inference tasks; we provide an open-source implementation of the code online. We demonstrate our method on both synthetic and real-world data and compare performance with methods that do not use any attribute information. We find that including node information helps in predicting missing links or attributes. It also leads to more interpretable community structures and allows the quantification of the impact of the node attributes given in input.

Many aspects of religious rituals suggest they provide adaptive benefits. Studies across societies consistently find that investments in ritual behaviour return high levels of cooperation. Another line of research finds that alloparental support to mothers increases maternal fertility and improves child outcomes. Although plausible, whether religious cooperation extends to alloparenting and/or affects child development remains unclear. Using 10 years of data collected from the Avon Longitudinal Study of Parents and Children (ALSPAC), we test the predictions that church attendance is positively associated with social support and fertility ( n = 8207 to n = 8209), and that social support is positively associated with fertility and child development ( n = 1766 to n = 6561). Results show that: (i) relative to not attending, church attendance is positively related to a woman's social network support and aid from co-religionists, (ii) aid from co-religionists is associated with increased family size, while (iii) fertility declines with extra-religious social network support. Moreover, while extra-religious social network support decreased over time, co-religionist aid remained constant. These findings suggest that religious and secular networks differ in their longevity and have divergent influences on a woman's fertility. We find some suggestive evidence that support to mothers and aid from co-religionists is positively associated with a child's cognitive ability at later stages of development. Findings provide mixed support for the premise that ritual, such as church attendance, is part of a strategy that returns high levels of support, fertility and improved child outcomes. Identifying the diversity and scope of cooperative breeding strategies across global religions presents an intriguing new horizon in the evolutionary study of religious systems. This article is part of the theme issue 'Ritual renaissance: new insights into the most human of behaviours'.

Objective: Convection-enhanced delivery (CED) and osmotic pump delivery both have been promoted as promising techniques to deliver drugs to pediatric diffuse intrinsic pontine gliomas (DIPGs). Correspondingly, the aim of this study was to understand how infusate molecular weight (MW), duration of delivery, and mechanism of delivery (CED or osmotic pump) affect volume of distribution (Vd) in the brainstem, to better inform drug selection and delivery in future DIPG investigations., Methods: A series of in vivo experiments were conducted using rat models. CED and osmotic pump delivery systems were surgically implanted in the brainstem, and different MW fluorescent dextran beads were infused either once (acute) or daily for 5 days (chronic) in a volume infused (Vi). Brainstems were harvested after the last infusion, and Vd was quantified using serial sectioning and fluorescence imaging., Results: Fluorescence imaging showed infusate uptake within the brainstem for both systems without complication. A significant inverse relationship was observed between infusate MW and Vd in all settings, which was distinctly exponential in nature in the setting of acute delivery across the 570-Da to 150-kDa range. Chronic duration and CED technique resulted in significantly greater Vd compared to acute duration or osmotic pump delivery, respectively. When accounting for Vi, acute infusion yielded significantly greater Vd/Vi than chronic infusion. The distribution in CED versus osmotic pump delivery was significantly affected by infusate MW at higher weights., Conclusions: Here the authors demonstrate that infusate MW, duration of infusion, and infusion mechanism all impact the Vd of an infused agent and should be considered when selecting drugs and infusion parameters for novel investigations to treat DIPGs.

Purpose: Diffuse intrinsic pontine glioma (DIPG) is a lethal high-grade pediatric brainstem tumor without a cure. Despite numerous clinical trials over the last decades, the prognosis has remained poor. The aim of this update was to report on the status and outcomes of all clinical trials for DIPG performed to better understand the landscape of research efforts for this diagnosis to date., Methods: The ClinicalTrials.gov database was reviewed in May 2019 for all possible interventional clinical trials that included DIPG as a diagnosis of primary investigation. These were then screened against selection criteria to identify pertinent clinical trials., Results: Ninety-five clinical trials satisfied all inclusion criteria, with 55 (58%) trials specific to the DIPG diagnosis only. In terms of the most prevalent design features, 42 (44%) were phase I trials, with median expected start and completion years in 2011 (range, 1994-2020) and 2018 (range, 2005-2047), respectively. Median target number of patients to enroll was 38 (range, 1-1500), and the most common primary outcome was safety and toxicity (56%). There were 69 (73%) trials originating from the USA, with 49 (52%) of them being single institutional. Only 10 (11%) trials have reported results to date., Conclusions: To date, 95 clinical trials investigating DIPG with specific emphasis have been registered on ClinicalTrials.gov. There were only a small number of trials that had study results available, and they uniformly reported non-significant improvement to prognosis. Given the rarity and lethality of DIPG, which limits the accumulation of large cohorts, our results mandate the need for more robust, systematic clinical trial design to minimize redundancies and maximize yield in the future.

Purpose: Although the dismal clinical prognosis of diffuse intrinsic pontine glioma (DIPG) has not changed, there has been significant progress in the academic literature made in the biological understanding of this brainstem tumor. The aim of this analysis was to evaluate citation and other bibliometric characteristics of the 100 most-cited DIPG articles in the current literature in order to better understand the current state of our academic efforts in this area., Methods: Elsevier's Scopus database was searched for the 100 most-cited articles that focussed on DIPG. Articles were dichotomized as either primarily basic science (BSc) or clinical (CL) articles. Various bibliometric parameters were summarized and comparison between BSc and CL articles was performed using Pearson's chi-square and Mann-Whitney U tests., Results: Of the 100 most-cited articles, 36 (36%) were BSc and 64 (64%) were CL articles. Overall median values were as follows: citation count, 52 (range, 27-261); citation rate per year, 8.6 (range, 1.7-104); number of authors, 9 (range, 1-63); and publication year, 2011 (range, 1997-2017). Articles were published in a total of 43 different journals and predominately originated in the USA (n = 67, 67%). When compared with CL articles, BSc articles reported significantly greater citation count (P = 0.03), citations rate per year (P < 0.01), number of authors (P < 0.01), and more recent years of publication (P < 0.01)., Conclusions: The 100 most-cited articles about DIPG were characterized in this analysis. Although smaller in overall proportion, BSc articles demonstrated significantly increased bibliometric parameters, supporting the recent dominance of BSc in this field, primarily involving histone biology of the H3K27M mutation. Moving forward, it will be of great interest to see how the findings of these high-impact BSc articles will translate into future high-impact CL articles.

Pathogens can spread epidemically through populations. Beneficial contagions, such as viruses that enhance host survival or technological innovations that improve quality of life, also have the potential to spread epidemically. How do the dynamics of beneficial biological and social epidemics differ from those of detrimental epidemics? We investigate this question using a breadth-first modeling approach involving three distinct theoretical models. First, in the context of population genetics, we show that a horizontally-transmissible element that increases fitness, such as viral DNA, spreads superexponentially through a population, more quickly than a beneficial mutation. Second, in the context of behavioral epidemiology, we show that infections that cause increased connectivity lead to superexponential fixation in the population. Third, in the context of dynamic social networks, we find that preferences for increased global infection accelerate spread and produce superexponential fixation, but preferences for local assortativity halt epidemics by disconnecting the infected from the susceptible. We conclude that the dynamics of beneficial biological and social epidemics are characterized by the rapid spread of beneficial elements, which is facilitated in biological systems by horizontal transmission and in social systems by active spreading behavior of infected individuals.

Diffuse intrinsic pontine glioma (DIPG), otherwise known as diffuse midline glioma with H3K27M mutation, is a devastating brainstem glioma without a cure. Efforts are currently underway to better optimize molecular diagnoses through biological sampling, which today remains largely limited to surgical biopsy sampling. Surgical intervention is not without its risks, and therefore a preference remains for a less invasive modality that can provide biological information about the tumor. There is emerging evidence to suggest that a liquid biopsy, targeting biofluids such as CSF and blood plasma, presents an attractive alternative for brain tumors in general. In this update, the authors provide a summary of the progress made to date regarding the use of liquid biopsy to diagnose and monitor DIPG, and they also propose future development and applications of this technique moving forward, given its unique histone biology.

Evolutionary ecologists have shown that relatives are important providers of support across many species. Among humans, cultural reckonings of kinship are more than just relatedness, as they interact with systems of descent, inheritance, marriage and residence. These cultural aspects of kinship may be particularly important when a person is determining which kin, if any, to call upon for help. Here, we explore the relationship between kinship and cooperation by drawing upon social support network data from two villages in South India. While these Tamil villages have a nominally male-biased kinship system (being patrilocal and patrilineal), matrilateral kin play essential social roles and many women reside in their natal villages, letting us tease apart the relative importance of genetic relatedness, kinship and residence in accessing social support. We find that people often name both their consanguineal and affinal kin as providing them with support, and we see some weakening of support with lesser relatedness. Matrilateral and patrilateral relatives are roughly equally likely to be named, and the greatest distinction instead is in their availability, which is highly contingent on post-marital residence patterns. People residing in their natal village have many more consanguineal relatives present than those who have relocated. Still, relocation has only a small effect on an individual's network size, as non-natal residents are more reliant on the few kin that they have present, most of whom are affines. In sum, marriage patterns have an important impact on kin availability, but the flexibility offered by the broadening of the concept of kin helps people develop the cooperative relationships that they rely upon, even in the absence of genetic relatives. This article is part of the theme issue 'The evolution of female-biased kinship in humans and other mammals'.

Humans frequently perform extravagant and seemingly costly behaviors, such as widely sharing hunted resources, erecting conspicuous monumental structures, and performing dramatic acts of religious devotion. Evolutionary anthropologists and archeologists have used signaling theory to explain the function of such displays, drawing inspiration from behavioral ecology, economics, and the social sciences. While signaling theory is broadly aimed at explaining honest communication, it has come to be strongly associated with the handicap principle, which proposes that such costly extravagance is in fact an adaptation for signal reliability. Most empirical studies of signaling theory have focused on obviously costly acts, and consequently anthropologists have likely overlooked a wide range of signals that also promote reliable communication. Here, we build on recent developments in signaling theory and animal communication, developing an updated framework that highlights the diversity of signal contents, costs, contexts, and reliability mechanisms present within human signaling systems. By broadening the perspective of signaling theory in human systems, we strive to identify promising areas for further empirical and theoretical work., (© 2019 Wiley Periodicals, Inc.)

Acts of prosociality, such as donating to charity, are often analysed in a similar way to acts of conspicuous advertising; both involve costly signals revealing hidden qualities that increase the signaller's prestige. However, experimental work suggests that grand gestures, even if prosocial, may damage one's reputation for trustworthiness and cooperativeness if they are perceived as prestige enhancing: individuals may gain some types of cooperative benefits only when they perform prosocial acts in particular ways. Here, we contrast subtle, less obviously costly, interpersonal forms of prosocial behaviour with high-cost displays to a large audience, drawing on the example of food sharing in subsistence economies. This contrast highlights how highly visible prosocial displays may be effective for attracting new partners, while subtle signals may be crucial for ensuring trust and commitment with long-term partners. Subtle dyadic signals may be key to understanding the long-term maintenance of interpersonal networks that function to reduce unanticipated risks.

The scholarship on religion has long argued that collective worship helps foster social cohesion. Despite the pervasiveness of this contention, rigorous quantitative evaluations of it have been surprisingly limited. Here, I draw on network data representing the ties of social support among Hindu residents of a South Indian village to evaluate the association between collective religious ritual and social cohesion. I find that those who partake in collective religious rituals together have a higher probability of having a supportive relationship than those who do not. At the structural level, this corresponds to denser connections among co-participants. At the individual level, participants are more embedded in the local community of co-religionists, but are not disassociating themselves from members of other religious denominations. These patterns hold most strongly for co-participation in the recurrent, low-arousal monthly worships at the temple, and are suggestive for co-participation in the intense and dysphoric ritual acts carried out as part of an annual festival. Together, these findings provide clear empirical evidence of the lasting relationship between collective religious ritual and social cohesion., (© 2018 The Authors.)

Complex systems are often characterized by distinct types of interactions between the same entities. These can be described as a multilayer network where each layer represents one type of interaction. These layers may be interdependent in complicated ways, revealing different kinds of structure in the network. In this work we present a generative model, and an efficient expectation-maximization algorithm, which allows us to perform inference tasks such as community detection and link prediction in this setting. Our model assumes overlapping communities that are common between the layers, while allowing these communities to affect each layer in a different way, including arbitrary mixtures of assortative, disassortative, or directed structure. It also gives us a mathematically principled way to define the interdependence between layers, by measuring how much information about one layer helps us predict links in another layer. In particular, this allows us to bundle layers together to compress redundant information and identify small groups of layers which suffice to predict the remaining layers accurately. We illustrate these findings by analyzing synthetic data and two real multilayer networks, one representing social support relationships among villagers in South India and the other representing shared genetic substring material between genes of the malaria parasite.

Assembly of kinetochore complexes, involving greater than one hundred proteins, is essential for chromosome segregation and genome stability. Neocentromeres, or new centromeres, occur when kinetochores assemble de novo, at DNA loci not previously associated with kinetochore proteins, and they restore chromosome segregation to chromosomes lacking a functional centromere. Neocentromeres have been observed in a number of diseases and may play an evolutionary role in adaptation or speciation. However, the consequences of neocentromere formation on chromosome missegregation rates, gene expression, and three-dimensional (3D) nuclear structure are not well understood. Here, we used Candida albicans, an organism with small, epigenetically-inherited centromeres, as a model system to study the functions of twenty different neocentromere loci along a single chromosome, chromosome 5. Comparison of neocentromere properties relative to native centromere functions revealed that all twenty neocentromeres mediated chromosome segregation, albeit to different degrees. Some neocentromeres also caused reduced levels of transcription from genes found within the neocentromere region. Furthermore, like native centromeres, neocentromeres clustered in 3D with active/functional centromeres, indicating that formation of a new centromere mediates the reorganization of 3D nuclear architecture. This demonstrates that centromere clustering depends on epigenetically defined function and not on the primary DNA sequence, and that neocentromere function is independent of its distance from the native centromere position. Together, the results show that a neocentromere can form at many loci along a chromosome and can support the assembly of a functional kinetochore that exhibits native centromere functions including chromosome segregation accuracy and centromere clustering within the nucleus., Competing Interests: The authors have declared that no competing interests exist.