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In the dynamic landscape of scientific research, imaging core facilities are vital hubs propelling collaboration and innovation at the technology development and dissemination frontier. Here, we present a collaborative effort led by Global BioImaging (GBI), introducing international recommendations geared towards elevating the careers of Imaging Scientists in core facilities. Despite the critical role of Imaging Scientists in modern research ecosystems, challenges persist in recognising their value, aligning performance metrics and providing avenues for career progression and job security. The challenges encompass a mismatch between classic academic career paths and service-oriented roles, resulting in a lack of understanding regarding the value and impact of Imaging Scientists and core facilities and how to evaluate them properly. They further include challenges around sustainability, dedicated training opportunities and the recruitment and retention of talent. Structured across these interrelated sections, the recommendations within this publication aim to propose globally applicable solutions to navigate these challenges. These recommendations apply equally to colleagues working in other core facilities and research institutions through which access to technologies is facilitated and supported. This publication emphasises the pivotal role of Imaging Scientists in advancing research programs and presents a blueprint for fostering their career progression within institutions all around the world.

In the dynamic landscape of scientific research, imaging core facilities are vital hubs propelling collaboration and innovation at the technology development and dissemination frontier. Here, we present a collaborative effort led by Global BioImaging (GBI), introducing international recommendations geared towards elevating the careers of Imaging Scientists in core facilities. Despite the critical role of Imaging Scientists in modern research ecosystems, challenges persist in recognising their value, aligning performance metrics and providing avenues for career progression and job security. The challenges encompass a mismatch between classic academic career paths and service-oriented roles, resulting in a lack of understanding regarding the value and impact of Imaging Scientists and core facilities and how to evaluate them properly. They further include challenges around sustainability, dedicated training opportunities and the recruitment and retention of talent. Structured across these interrelated sections, the recommendations within this publication aim to propose globally applicable solutions to navigate these challenges. These recommendations apply equally to colleagues working in other core facilities and research institutions through which access to technologies is facilitated and supported. This publication emphasises the pivotal role of Imaging Scientists in advancing research programs and presents a blueprint for fostering their career progression within institutions all around the world.

Currently trade sanctions are drastically affecting world commerce, economies, industries, companies, and potentially the well-being of individuals around the world. Even global peace is threatened by the growing frictions among major countries. The question we explore is how politically motivated economic sanctions affect commercial interactions within targeted countries. We focus on the case of American economic sanctions of the last half century. To the task we apply findings regarding negotiation processes and outcomes between more than 1200 experienced businesspeople in twenty-one cultural regions and countries around the world. Economic outcomes in intracultural buyer-seller negotiation simulations were found to be lower in the six cultural regions on which the United States has applied broadly comprehensive sanctions. We conclude that this “hidden” damage done can hurt international cooperation well beyond the period of the sanctions. The scope and relevance of the work is very broad, connecting concepts and theories from political science, economics, trade, anthropology, marketing science, negotiation, and, of course, business ethics. Our findings are useful for theorists, policy makers and managers of firms considering market entry to recently sanctioned countries. Specific guidance for amelioration of the negative and largely unintended consequences of sanctions on target countries are provided.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or DTRs). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

The Acquisition Modernization Integration (AMI) team within the ASA(ALT) office is critical in the Army decision-making process. The AMI creates reports that include actionable knowledge rendered to Army strategic leaders. These reports include vital data on critical Army programs integrated into the modernization efforts. Part of this necessary data are the First Unit Issued (FUI) and the First Unit Equipped (FUE) dates. These reported dates directly affect Army units’ training, deployment, and logistics support timelines as they become part of the data-driven analytics on reports provided to decision-makers. Because of the initiatives to improve efficiency in the acquisition process, realignment, and creation of new organizations, the AMI needs a system that facilitates accurate and consistent FUI and FUE dates reporting. This research used several systems engineering (SE) concepts and methods such as stakeholders’ analysis, functional analysis, mapping of functions to systems’ parameters, modeling-based systems engineering, and analysis of alternatives. The application of these SE tools resulted in identifying a system/process that will accurately and consistently facilitate FUI and FUE date reporting to meet the AMI’s needs. This system/process provides a reporting capability for current and future acquisition programs and could be implemented across the DOD and all other government agencies and departments., Major, United States Army, Captain, United States Army, Captain, United States Army, Captain, United States Army, Captain, United States Army, Approved for public release. Distribution is unlimited.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5Brelated neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Our study examines the effects of culture on negotiation behaviors and outcomes. We also explore how culture moderates the relationships between those behaviors and outcomes, a subject that has been neglected by most researchers. Our work integrates theories and methods from many areas of the behavioral sciences: marketing science, decision analysis, behavioral economics, game theory, social psychology, anthropology, sociolinguistics, linguistics, content analysis, and structural equations modeling. The data were created in a laboratory setting in which 1,197 businesspeople from 20 cultural groups participated in a three-product buyer–seller negotiation simulation. In this article we first describe how our database was developed. Second, we look at how observed behaviors are associated with questionnaire-derived negotiation processes and outcomes. Third, we develop a new tool for understanding cultural differences and use it to investigate how culture influences negotiation behaviors, processes, and outcomes across the 20 cultural groups included in our database.

In the past four decades, the importance of international trade has burgeoned, from 17 percent of world gross domestic product to over 37 percent now. The academic literature on international commercial negotiations has not kept up. This chapter begins with a brief review of the extant literature on the topic of international business negotiations. It describes the methods used in our laboratory studies of negotiation behaviors, processes and outcomes in 22 countries. This is followed by applications of two advances in measurement, linguistic distance and facial expression coding technologies. It continues with a discussion of qualitative approaches that include methods focused on emic (versus etic) interpretation. The chapter closes with a third theory of negotiation, one that goes beyond the American views of competitive and integrative bargaining theories, and one that emphasizes relationships over agreements and the search for mutual opportunities over problem solving.

Steve Jobs used it to cut a better deal with Disney. George Mitchell and Mary Robinson used it to help end a decades-long war in Northern Ireland. And you can use it in your life and work to get better outcomes for years to come. AND? Inventive Negotiation provides a concrete set of steps that can help build long-term relationships instead of lasting enmity. Lavishly illustrated with real life stories from around the world, plus the latest neuroscience and behavioral economics, this book will show you how to get more than your share of the pie - it gives you the tools to build a pie factory.Learn what hostage negotiators and clowns have in common. How a teen bested the phone company. What it takes to talk your way into a prison in Bolivia, or out of a terrorist camp in Colombia. Why you need to handle your chairs carefully in Korea. Every example demonstrates a principle perfected by the authors' decades of experience in everything from oil-pipelines to international peace. Once you've learned the art and science of Inventive Negotiation, you'll never be satisfied with transactional or integrative bargaining again.

Steve Jobs used it to cut a better deal with Disney. George Mitchell and Mary Robinson used it to help end a decades-long war in Northern Ireland. And you can use it in your life and work to get better outcomes for years to come. AND? Inventive Negotiation provides a concrete set of steps that can help build long-term relationships instead of lasting enmity. Lavishly illustrated with real life stories from around the world, plus the latest neuroscience and behavioral economics, this book will show you how to get more than your share of the pie - it gives you the tools to build a pie factory.Learn what hostage negotiators and clowns have in common. How a teen bested the phone company. What it takes to talk your way into a prison in Bolivia, or out of a terrorist camp in Colombia. Why you need to handle your chairs carefully in Korea. Every example demonstrates a principle perfected by the authors' decades of experience in everything from oil-pipelines to international peace. Once you've learned the art and science of Inventive Negotiation, you'll never be satisfied with transactional or integrative bargaining again.

Although numerous predictions have been developed regarding climate change, many current tools and methods represent a reductionist approach and are insufficient to fully assess the ecological impact of climate change, and the adaptive capacity of species to mitigate these impacts. A complex systems approach is required: assessing the impacts of climate change on species is flawed without consideration of variation in behaviour and social organisation. The aim of this study is to evaluate the utility of using simulations to understand how the full range of behavioural variation, and social organisation, contributes to the adaptive capacity of species to respond to climate change. A high-resolution agent-based model was developed to simulate behavioural variation within a community of antelope species in Mokala National Park, South Africa, subject to different climate change scenarios. The model was then extended to evaluate and compare the effectiveness of two separate management interventions (habitat management and park expansion), in conserving the community under climate change. Comparisons were based on individuals’ energy levels and whether there were selection pressures for specific behaviour or social groups. The results suggest both types of intervention show promise for mitigation of climate change effects but both schemes also selected for specific behaviour types and social groups. This may impact on populations ability to adapt to change and may affect the social cohesion of these populations.

The Compact Muon Solenoid (CMS) experiment at the CERN Large Hadron Collider (LHC) distributes its data by leveraging a diverse array of National Research and Education Networks (NRENs), which CMS is forced to treat as an opaque resource. Consequently, CMS sees highly variable performance that already poses a challenge for operators coordinating the movement of petabytes around the globe. This kind of unpredictability, however, threatens CMS with a logistical nightmare as it barrels towards the High Luminosity LHC (HL-LHC) era in 2030, which is expected to produce roughly 0.5 exabytes of data per year. This paper explores one potential solution to this issue: software-defined networking (SDN). In particular, the prototypical interoperation of SENSE, an SDN product developed by the Energy Sciences Network, with Rucio, the data management software used by the LHC, is outlined. In addition, this paper presents the current progress in bringing these technologies together.

Although numerous predictions have been developed regarding climate change, many current tools and methods represent a reductionist approach and are insufficient to fully assess the ecological impact of climate change, and the adaptive capacity of species to mitigate these impacts. A complex systems approach is required: assessing the impacts of climate change on species is flawed without consideration of variation in behaviour and social organisation. The aim of this study is to evaluate the utility of using simulations to understand how the full range of behavioural variation, and social organisation, contributes to the adaptive capacity of species to respond to climate change. A high-resolution agent-based model was developed to simulate behavioural variation within a community of antelope species in Mokala National Park, South Africa, subject to different climate change scenarios. The model was then extended to evaluate and compare the effectiveness of two separate management interventions (habitat management and park expansion), in conserving the community under climate change. Comparisons were based on individuals’ energy levels and whether there were selection pressures for specific behaviour or social groups. The results suggest both types of intervention show promise for mitigation of climate change effects but both schemes also selected for specific behaviour types and social groups. This may impact on populations ability to adapt to change and may affect the social cohesion of these populations.

Bycatch, the incidental capture of non-target species in active fishing gear, is the most significant human threat to coastal marine mammals and a severe conservation problem. Characterizing the effects of bycatch through space and time is similar to finding a needle in a haystack: relatively small populations and limited interactions with dispersed fishing vessels. The behaviors of both parties are unpredictable, and therefore a challenge for researchers to collect data and managers to effectively manage. Further adding to the problem, a lack of risk frameworks that can integrate and visualize existing datasets has hindered the ability to describe and quantify bycatch risk. There are spatio-temporal patterns in bycatch occurrence that can be identified, even in data-limited SSF. Therefore, is it possible to design and apply an assessment framework for evaluating harmful interactions between marine mammals and fisheries using existing information only? This is the main question I attempt to answer in this thesis. This is a knowledge gap worth exploring because ocean data and the systems developed to monitor marine ecosystems are now more sophisticated and cheaper to deploy. More broadly, I investigate the ways in which international policies have, or have not, translated into effective management strategies for the monitoring and mitigation of marine mammal bycatch in data-limited fisheries.

Knowledge of stock structure is a priority for effective assessment of commercially-fished cephalopods. Loligo forbesii squid are thought to migrate inshore for breeding and offshore for feeding and long-range movements are implied from past studies showing genetic homogeneity in the entire neritic population. Only offshore populations (Faroe and Rockall Bank) were considered distinct. The present study applied mitchondrial and microsatellite markers (nine loci) to samples from Rockall Bank, north Scotland, North Sea, various shelf locations in Ireland, English Channel, northern Bay of Biscay, north Spain, and Bay of Cadiz. No statistically significant genetic sub-structure was found, although some non-significant trends involving Rockall were seen using microsatellite markers. Differences in L. forbesii statolith shape were apparent at a subset of locations, with most locations showing pairwise differences and statoliths from north Ireland being highly distinct. This suggests that (i) statolith shape is highly sensitive to local conditions and (ii) L. forbesii forms distinguishable groups (based on shape statistics), maintaining these groups over sufficiently long periods for local conditions to affect the shape of the statolith. Overall evidence suggests that L. forbesii forms separable (ecological) groups over short timescales with a semi-isolated breeding group at Rockall whose distinctiveness varies over time.

Identifiable food remains were analyzed from 46 stomachs of striped dolphins (Stenella coeruleoalba) stranded in southern Spain between 2007 and 2014. Results suggest that the species feeds mainly on mesopelagic and neritic fish, but also on oceanic squids. Fish species of the family Myctophidae were the main prey in terms of numerical importance and reconstructed prey weight (62% N and 29% W), followed by squids of the family Ommastrephidae (20% W) and bogue (Boops boops) (15% W). The most important prey taxa according to the General Importance Index (GII) were C. maderensis, Ommastrephidae gen. spp., Notoscopelus spp., and M. punctatum. Higher number of mesopelagic myctophids were found in dolphins from the Mediterranean (73% vs. 29% N), while more demersal gobiids and European hake (Merluccius merluccius) were found in those from the Atlantic (44% vs. 1% and 8% vs. <1% N), where a more varied diet was also observed. Differences were also seen in the seasonal importance of some prey, as well as between years, sexes, and maturity states. The diet composition suggests that most of feeding occurred in oceanic regions, during twilight and night hours, while the observed dietary variation may reflect differences in topography, and changes in the prey availability.

Monitoring marine mammal populations is essential to permit assessment of population status as required by both national and international legislation. Traditional monitoring methods often rely on visual and/or acoustic detections from vessels and aircraft, but limitations including cost, errors in the detection of some species and dependence on taxonomic expertise, as well as good weather and visibility conditions often limit the temporal and spatial scale of effective, long-term monitoring programs. In recent years, environmental DNA (eDNA) has emerged as a revolutionary tool for cost-effective, sensitive, noninvasive species monitoring in both terrestrial and aquatic realms. eDNA is a rapidly developing field and a growing number of studies have successfully implemented this approach for the detection and identification of marine mammals. Here, we review 21 studies published between 2012 and 2021 that employed eDNA for marine mammal monitoring including single species detection, biodiversity assessment and genetic characterization. eDNA has successfully been used to infer species presence (especially useful for rare, elusive or threatened species) and to characterize the population genetic structure, although additional research is needed to support the interpretation of non-detections. Finally, we discuss the challenges and the opportunities that eDNA could bring to marine mammal monitoring as a complementary tool to support visual and acoustic methods.

Dolphins play a key role in marine food webs as predators of mid-trophic level consumers. Because of their mobility and relatively long life span, they can be used as indicators of large scale changes in the ecosystem. In this study, we calculated the trophic position (TP) of five dolphin species from the Canary, Madeira and Azores Islands using bulk and compound-specific stable isotope ratios from muscle tissue to assess trophic adaptations to recent changes in the availability of feeding resources. Dolphin TP values were then compared with those of seven other species of cetaceans from this region. Analysis of stable nitrogen isotopes in amino acids of the common dolphin indicated non-significant effects of changes in the basal resources of the food web and thus supported the use of bulk samples for TP estimations. Dolphins occupied an intermediate TP (mean 3.91 to 4.20) between fin (3.25) and sperm whales (4.95). Species-specific TP were equivalent among islands. However, TP increased for the common dolphin and decreased for the striped dolphin (the latter also becoming more oceanic) between 2000 and 2018 in the Canary Islands. These results suggest different impacts of recent changes in the oceanography and in the pelagic food web of the Macaronesian region on the trophic ecology of dolphin species.

Influenced by the advances in data and computing, the scientific practice increasingly involves machine learning and artificial intelligence driven methods which requires specialized capabilities at the system-, science- and service-level in addition to the conventional large-capacity supercomputing approaches. The latest distributed architectures built around the composability of data-centric applications led to the emergence of a new ecosystem for container coordination and integration. However, there is still a divide between the application development pipelines of existing supercomputing environments, and these new dynamic environments that disaggregate fluid resource pools through accessible, portable and re-programmable interfaces. New approaches for dynamic composability of heterogeneous systems are needed to further advance the data-driven scientific practice for the purpose of more efficient computing and usable tools for specific scientific domains. In this paper, we present a novel approach for using composable systems in the intersection between scientific computing, artificial intelligence (AI), and remote sensing domain. We describe the architecture of a first working example of a composable infrastructure that federates Expanse, an NSF-funded supercomputer, with Nautilus, a Kubernetes-based GPU geo-distributed cluster. We also summarize a case study in wildfire modeling, that demonstrates the application of this new infrastructure in scientific workflows: a composed system that bridges the insights from edge sensing, AI and computing capabilities with a physics-driven simulation., Comment: 18th IEEE International Conference on eScience (2022)

Unique scientific instruments designed and operated by large global collaborations are expected to produce Exabyte-scale data volumes per year by 2030. These collaborations depend on globally distributed storage and compute to turn raw data into science. While all of these infrastructures have batch scheduling capabilities to share compute, Research and Education networks lack those capabilities. There is thus uncontrolled competition for bandwidth between and within collaborations. As a result, data "hogs" disk space at processing facilities for much longer than it takes to process, leading to vastly over-provisioned storage infrastructures. Integrated co-scheduling of networks as part of high-level managed workflows might reduce these storage needs by more than an order of magnitude. This paper describes such a solution, demonstrates its functionality in the context of the Large Hadron Collider (LHC) at CERN, and presents the next-steps towards its use in production., Comment: Submitted to the proceedings of the XLOOP workshop held in conjunction with Supercomputing 22

Background: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. Methods: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. Results: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. Conclusions: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies m

This paper describes a vision and work in progress to elevate network resources and data transfer management to the same level as compute and storage in the context of services access, scheduling, life cycle management, and orchestration. While domain science workflows often include active compute resource allocation and management, the data transfers and associated network resource coordination is not handled in a similar manner. As a result data transfers can introduce a degree of uncertainty in workflow operations, and the associated lack of network information does not allow for either the workflow operations or the network use to be optimized. The net result is that domain science workflow processes are forced to view the network as an opaque infrastructure into which they inject data and hope that it emerges at the destination with an acceptable Quality of Experience. There is little ability for applications to interact with the network to exchange information, negotiate performance parameters, discover expected performance metrics, or receive status/troubleshooting information in real time. Developing mechanisms to allow an application workflow to obtain information regarding the network services, capabilities, and options, to a degree similar to what is possible for compute resources is the primary motivation for this work. The initial focus is on the Open Science Grid (OSG)/Compact Muon Solenoid (CMS) Large Hadron Collider (LHC) workflows with Rucio/FTS/XRootD based data transfers and the interoperation with the ESnet SENSE (Software-Defined Network for End-to-end Networked Science at the Exascale) system., Comment: contribution to Snowmass 2022

Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous entities have been grouped as PIK3CA-Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low-level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient-specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi-system and often complex medical issues seen with PROS. In March 2019, macrocephaly-capillary malformation (M-CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M-CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge.

Several approaches have been developed to measure instantaneous friction between the piston assembly and cylinder in internal combustion (IC) engines, such as floating-liner, reciprocating liner, instantaneous mean effective pressure (IMEP), fixed sleeve, and (P-ω) method and tribological bench tests. However, the “floating-liner method” and the “(IMEP) method” are the most common methods used to measure instantaneous friction between the piston assembly and IC engines. This paper critically evaluates different approaches to the design of the “floating-liner”. The paper begins by discussing piston assembly frictional losses and their significance and then discuss the development of instantaneous piston-friction measurements. After that, it reviews the main design challenges in the floating-liner approach. “Methods of cylinder sealing” and “force balancing methods” are also reviewed. Design challenges associated with firing operation were presented. Floating-liner designs were classified into different categories with a detailed presentation of the features of each. The paper ends by presenting a range of broad recommendations for further work which would benefit future designs.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

HTCondor is a major workload management system used in distributed high throughput computing (dHTC) environments, e.g., the Open Science Grid. One of the distinguishing features of HTCondor is the native support for data movement, allowing it to operate without a shared filesystem. Coupling data handling and compute scheduling is both convenient for users and allows for significant infrastructure flexibility but does introduce some limitations. The default HTCondor data transfer mechanism routes both the input and output data through the submission node, making it a potential bottleneck. In this document we show that by using a node equipped with a 100 Gbps network interface (NIC) HTCondor can serve data at up to 90 Gbps, which is sufficient for most current use cases, as it would saturate the border network links of most research universities at the time of writing., Comment: 2 pages, 2 figures, to be published in proceedings of eScience 2021

International commerce has always driven human progress. Its inherent cultural diversity has maximized the new ideas that improve consumers’ lives around the world. The best international business relationships are maintained over the long term and managed through inventive negotiation processes. Investments in time and money are required to build the trust and honest information exchange that allow for exploitation of mutually beneficial opportunities. This article provides a database and associated tools to help international negotiators understand the cultural differences that may impact buyer–seller relationships between parties from twenty countries and cultures including the United States and Iran.

We present post-jet-break Hubble Space Telescope, Very Large Array, and Chandra observations of the afterglow of the long gamma-ray bursts GRB 160625B (between 69 and 209 days) and GRB 160509A (between 35 and 80 days). We calculate the post-jet-break decline rates of the light curves and find the afterglow of GRB 160625B is inconsistent with a simple t(-3/4) steepening over the break, expected from the geometric effect of the jet edge entering our line of sight. However, the favored optical post-break decline is also inconsistent with the f(nu) proportional to t(-p) decline (where p 2.3 from the pre-break light curve), which is expected from exponential lateral expansion of the jet; perhaps suggesting lateral expansion that only affects a fraction of the jet. The post-break decline of GRB 160509A is consistent with both the t(-3/4) steepening and with f(nu) proportional to t(-p). We also use boxfit to fit afterglow models to both light curves and find both to be energetically consistent with a millisecond magnetar central engine, but the magnetar parameters need to be extreme (i.e., E similar to 3 x 10(52) erg). Finally, the late-time radio light curves of both afterglows are not reproduced well by boxfit and are inconsistent with predictions from the standard jet model; instead, both are well represented by a single power-law decline (roughly f(nu) proportional to t(-1)) with no breaks. This requires a highly chromatic jet break and possibly a two-component jet for both bursts.© 2020. The American Astronomical Society. All rights reserved.

This paper describes the design of a test apparatus which simulates the lubrication of large, slow, two‐stroke marine engines in which the ring pack is lubricated by means of injectors supplying lubricant above the piston. The equipment is able to control lubricant injection parameters (volume, frequency, etc.) and employs capacitance based lubricant film thickness transducers to allow instantaneous oil film thickness and film extent around the compression ring to be investigated on a stroke‐by‐stroke basis. It is demonstrated that the equipment can be used to study the development of lubricating films on successive strokes under differing injection strategies. Time varying changes in lubricating film thickness and film extent have been measured and the rate at which the lubricant spreads across the cylinder wall has also been investigated. It has been observed that increases in oil‐film thickness are strongly linked to the transition from starved to fully‐flooded inlet conditions and that net lubricant transport rates along different parts of the cylinder can be evaluated from measured data.

This paper describes the design of a test apparatus which simulates the lubrication of large, slow, two‐stroke marine engines in which the ring pack is lubricated by means of injectors supplying lubricant above the piston. The equipment is able to control lubricant injection parameters (volume, frequency, etc.) and employs capacitance based lubricant film thickness transducers to allow instantaneous oil film thickness and film extent around the compression ring to be investigated on a stroke‐by‐stroke basis. It is demonstrated that the equipment can be used to study the development of lubricating films on successive strokes under differing injection strategies. Time varying changes in lubricating film thickness and film extent have been measured and the rate at which the lubricant spreads across the cylinder wall has also been investigated. It has been observed that increases in oil‐film thickness are strongly linked to the transition from starved to fully‐flooded inlet conditions and that net lubricant transport rates along different parts of the cylinder can be evaluated from measured data.

This paper describes the design of a test apparatus which simulates the lubrication of large, slow, two‐stroke marine engines in which the ring pack is lubricated by means of injectors supplying lubricant above the piston. The equipment is able to control lubricant injection parameters (volume, frequency, etc.) and employs capacitance based lubricant film thickness transducers to allow instantaneous oil film thickness and film extent around the compression ring to be investigated on a stroke‐by‐stroke basis. It is demonstrated that the equipment can be used to study the development of lubricating films on successive strokes under differing injection strategies. Time varying changes in lubricating film thickness and film extent have been measured and the rate at which the lubricant spreads across the cylinder wall has also been investigated. It has been observed that increases in oil‐film thickness are strongly linked to the transition from starved to fully‐flooded inlet conditions and that net lubricant transport rates along different parts of the cylinder can be evaluated from measured data.

PurposeDetermination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND).MethodsFifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex.ResultsSubjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners.ConclusionsA consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.

This paper describes the design of a test apparatus which simulates the lubrication of large, slow, two-stroke marine engines in which the ring pack is lubricated by means of injectors supplying lubricant above the piston. The equipment is able to control lubricant injection parameters (volume, frequency, etc.) and employs capacitance based lubricant film thickness transducers to allow instantaneous oil film thickness and film extent around the compression ring to be investigated on a stroke-by-stroke basis. It is demonstrated that the equipment can be used to study the development of lubricating films on successive strokes under differing injection strategies. Time varying changes in lubricating film thickness and film extent have been measured and the rate at which the lubricant spreads across the cylinder wall has also been investigated. It has been observed that increases in oil-film thickness are strongly linked to the transition from starved to fully-flooded inlet conditions and that net lubricant transport rates along different parts of the cylinder can be evaluated from measured data.

This paper describes the design of a test apparatus which simulates the lubrication of large, slow, two‐stroke marine engines in which the ring pack is lubricated by means of injectors supplying lubricant above the piston. The equipment is able to control lubricant injection parameters (volume, frequency, etc.) and employs capacitance based lubricant film thickness transducers to allow instantaneous oil film thickness and film extent around the compression ring to be investigated on a stroke‐by‐stroke basis. It is demonstrated that the equipment can be used to study the development of lubricating films on successive strokes under differing injection strategies. Time varying changes in lubricating film thickness and film extent have been measured and the rate at which the lubricant spreads across the cylinder wall has also been investigated. It has been observed that increases in oil‐film thickness are strongly linked to the transition from starved to fully‐flooded inlet conditions and that net lubricant transport rates along different parts of the cylinder can be evaluated from measured data.

This paper describes the design of a test apparatus which simulates the lubrication of large, slow, two‐stroke marine engines in which the ring pack is lubricated by means of injectors supplying lubricant above the piston. The equipment is able to control lubricant injection parameters (volume, frequency, etc.) and employs capacitance based lubricant film thickness transducers to allow instantaneous oil film thickness and film extent around the compression ring to be investigated on a stroke‐by‐stroke basis. It is demonstrated that the equipment can be used to study the development of lubricating films on successive strokes under differing injection strategies. Time varying changes in lubricating film thickness and film extent have been measured and the rate at which the lubricant spreads across the cylinder wall has also been investigated. It has been observed that increases in oil‐film thickness are strongly linked to the transition from starved to fully‐flooded inlet conditions and that net lubricant transport rates along different parts of the cylinder can be evaluated from measured data.

This paper describes the design of a test apparatus which simulates the lubrication of large, slow, two‐stroke marine engines in which the ring pack is lubricated by means of injectors supplying lubricant above the piston. The equipment is able to control lubricant injection parameters (volume, frequency, etc.) and employs capacitance based lubricant film thickness transducers to allow instantaneous oil film thickness and film extent around the compression ring to be investigated on a stroke‐by‐stroke basis. It is demonstrated that the equipment can be used to study the development of lubricating films on successive strokes under differing injection strategies. Time varying changes in lubricating film thickness and film extent have been measured and the rate at which the lubricant spreads across the cylinder wall has also been investigated. It has been observed that increases in oil‐film thickness are strongly linked to the transition from starved to fully‐flooded inlet conditions and that net lubricant transport rates along different parts of the cylinder can be evaluated from measured data.

Commercial Cloud computing is becoming mainstream, with funding agencies moving beyond prototyping and starting to fund production campaigns, too. An important aspect of any scientific computing production campaign is data movement, both incoming and outgoing. And while the performance and cost of VMs is relatively well understood, the network performance and cost is not. This paper provides a characterization of networking in various regions of Amazon Web Services, Microsoft Azure and Google Cloud Platform, both between Cloud resources and major DTNs in the Pacific Research Platform, including OSG data federation caches in the network backbone, and inside the clouds themselves. The paper contains both a qualitative analysis of the results as well as latency and throughput measurements. It also includes an analysis of the costs involved with Cloud-based networking., Comment: 7 pages, 1 figure, 5 tables, to be published in CHEP19 proceedings