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As managers of agricultural and natural resources are confronted with uncertainties in global change impacts, the complexities associated with the interconnected cycling of nitrogen, carbon, and water present daunting management challenges. Existing models provide detailed information on specific sub-systems (e.g., land, air, water, and economics). An increasing awareness of the unintended consequences of management decisions resulting from interconnectedness of these sub-systems, however, necessitates coupled regional earth system models (EaSMs). Decision makers’ needs and priorities can be integrated into the model design and development processes to enhance decision-making relevance and “usability” of EaSMs. BioEarth is a research initiative currently under development with a focus on the U.S. Pacific Northwest region that explores the coupling of multiple stand-alone EaSMs to generate usable information for resource decision-making. Direct engagement between model developers and non-academic stakeholders involved in resource and environmental management decisions throughout the model development process is a critical component of this effort. BioEarth utilizes a bottom-up approach for its land surface model that preserves fine spatial-scale sensitivities and lateral hydrologic connectivity, which makes it unique among many regional EaSMs. This paper describes the BioEarth initiative and highlights opportunities and challenges associated with coupling multiple stand-alone models to generate usable information for agricultural and natural resource decision-making.

Azo compounds find use in many areas of science, displaying crucial properties for important applications as photoconductive organic pigments, fluorescent quenchers, paints, cosmetics, inks, and in the large and valuable dye industry. Due to the unstable intermediates, and the exothermic and fast reactions used in their synthesis, high value azo compounds are excellent candidates for continuous flow manufacturing. This comprehensive review covers the progress made to date on developing continuous flow systems for azo synthesis and reflects on the main challenges still to be addressed, including scale up, conversion, product purity, and environmental impact. The further development of integrated continuous flow processes has the potential to help tackle these challenges and deliver improved methods for azo compound generation., Competing Interests: Competing InterestThe authors declare that the following financial interests/personal relationships which may be considered as potential competing interests: Adam McCormack reports financial support was provided by Prizer Ringaskiddy Ireland., (© The Author(s) 2024.)

In the past, pattern disciplines within forensic science have periodically faced criticism due to their subjective and qualitative nature and the perceived absence of research evaluating and supporting the foundations of their practices. Recently, however, forensic scientists and researchers in the field of pattern evidence analysis have developed and published approaches that are more quantitative, objective, and data driven. This effort includes automation, algorithms, and measurement sciences, with the end goal of enabling conclusions to be informed by quantitative models. Before employing these tools, forensic evidence must be digitized in a way that adequately balances high-quality detail and content capture with minimal background noise imparted by the selected technique. While the current work describes the process of optimizing a method to digitize physical documentary evidence for use in semi-automated trash mark examinations, it could be applied to assist other disciplines where the digitization of physical items of evidence is prevalent. For trash mark examinations specifically, it was found that high-resolution photography provided optimal digital versions of evidentiary items when compared to high-resolution scanning., (© 2023 American Academy of Forensic Sciences. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

The founder population of Newfoundland and Labrador (NL) is a unique genetic resource, in part due to its geographic and cultural isolation, where historical records describe a migration of European settlers, primarily from Ireland and England, to NL in the 18th and 19th centuries. Whilst its historical isolation, and increased prevalence of certain monogenic disorders are well appreciated, details of the fine-scale genetic structure and ancestry of the population are lacking. Understanding the genetic origins and background of functional, disease causing, genetic variants would aid genetic mapping efforts in the Province. Here, we leverage dense genome-wide SNP data on 1,807 NL individuals to reveal fine-scale genetic structure in NL that is clustered around coastal communities and correlated with Christian denomination. We show that the majority of NL European ancestry can be traced back to the south-east and south-west of Ireland and England, respectively. We date a substantial population size bottleneck approximately 10-15 generations ago in NL, associated with increased haplotype sharing and autozygosity. Our results reveal insights into the population history of NL and demonstrate evidence of a population conducive to further genetic studies and biomarker discovery., (© 2023. The Author(s).)

Moving beyond technocratic approaches to climate action, climate justice articulates a paradigm shift in how organizations think about their response to the climate crisis. This paper makes a conceptual contribution by exploring the potential of this paradigm shift in higher education. Through a commitment to advancing transformative climate justice, colleges and universities around the world could realign and redefine their priorities in teaching, research, and community engagement to shape a more just, stable, and healthy future. As inequitable climate vulnerabilities increase, higher education has multiple emerging opportunities to resist, reverse, and repair climate injustices and related socioeconomic and health disparities. Rather than continuing to perpetuate the concentration of wealth and power by promoting climate isolationism's narrow focus on technological innovation and by prioritizing the financial success of alumni and the institution, colleges and universities have an opportunity to leverage their unique role as powerful anchor institutions to demonstrate climate justice innovations and catalyze social change toward a more equitable, renewable-based future. This paper explores how higher education can advance societal transformation toward climate justice, by teaching climate engagement, supporting impactful justice-centered research, embracing non-extractive hiring and purchasing practices, and integrating community-engaged climate justice innovations across campus operations. Two climate justice frameworks, Green New Deal-type policies and energy democracy, provide structure for reviewing a breadth of proposed transformational climate justice initiatives in higher education., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2023.)

GPR21 is an orphan and constitutively active receptor belonging to the superfamily of G-Protein Coupled Receptors (GPCRs). GPR21 couples to the G q family of G proteins and is expressed in macrophages. Studies of GPR21 knock-out mice indicated that GPR21 may be involved in promoting macrophage migration. The aim of this study was to evaluate the role of GPR21 in human macrophages, analyzing (i) its involvement in cell migration and cytokine release and (ii) the consequence of its pharmacological inhibition by using the inverse agonist GRA2. THP-1 cells were activated and differentiated into either M 1 or M 2 macrophages. GPR21 expression was evaluated at gene and protein level, the signalling pathway was investigated by an IP 1 assay, and cytokine release by ELISA. Cell migration was detected by the Boyden chamber migration assay, performed on macrophages derived from both the THP-1 cell line and human peripheral blood monocytes. In addition, we compared the effect of the pharmacological inhibition of GPR21 with the effect of the treatment with a specific GPR21 siRNA to downregulate the receptor expression, thus confirming that GRA2 acts as an inverse agonist of GPR21. GRA2 does not affect cell viability at the tested concentrations, but significantly reduces the release of TNF-α and IL-1β from M 1 macrophages. The analysis of the migratory ability highlighted opposite effects of GRA2 on M 1 and M 2 macrophages since it decreased M 1 , while it promoted M 2 cell migration. Therefore, the pharmacological inhibition of GPR21 could be of interest for pathological conditions characterized by low grade chronic inflammation., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Trash marks are unintentional markings observed on printed, scanned, or photocopied documents that result from permanent defects or transient material in office machines and can be used for source attribution of questioned documents. Trash mark examinations have been in use in forensic laboratories for decades, yet the method remains relatively untested and relies on training, experience, and anecdotal information to support its validity. This study generated and harnessed objective data to empirically test one of the foundational theories for assessing the origin of photocopied documents: provided trash marks are present in sufficient quantity and/or quality, no two machines will exhibit a constellation of trash marks that is indistinguishable from another. In this project, objective trash mark location and size data was generated for 50 known photocopiers using both a traditional and a novel, automated method. Inter-machine comparisons were conducted using a novel variant of the Hausdorff distance algorithm to generate a quantitative assessment of how similar or different the 2450 pairs of trash mark constellations were from one another. This study found that each of the machines bearing one or more trash marks exhibited objective differences in their trash mark constellations, ultimately providing support for the tested hypothesis., Competing Interests: Declarations of interest none., (Published by Elsevier B.V.)

Many U.S. states have taken significant action on climate change in recent years, demonstrating their commitment despite federal policy gridlock and rollbacks. Yet, there is still much we do not know about the agents, discourses, and strategies of those seeking to delay or obstruct state-level climate action. We first ask,  what are the obstacles to strong and effective climate policy within U.S. states? We review the political structures and interest groups that slow action, and we examine emerging tensions between climate justice and the technocratic and/or market-oriented approaches traditionally taken by many mainstream environmental groups. Second, what are potential solutions for overcoming these obstacles? We suggest strategies for overcoming opposition to climate action that may advance more effective and inclusive state policy, focusing on political strategies, media framing, collaboration, and leveraging the efforts of ambitious local governments., (© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2022.)

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour in adults. Treatments include surgical resection, radiotherapy, and chemotherapy. Despite this, the prognosis remains poor, with an impacted quality of life during treatment coupled with brain tumour recurrence; thus, new treatments are desperately needed. In this review, we focus on recent advances in G-protein-coupled receptor (GPCR) targets. To date, the most promising targets are the chemokine, cannabinoid, and dopamine receptors, but future work should further examine the melanocortin receptor-4 (MC4R), adhesion, lysophosphatidic acid (LPA) and smoothened (Smo) receptors to initiate new drug-screening strategies and targeted delivery of safe and effective GBM therapies., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pyrazolopyrimidinones are fused nitrogen-containing heterocyclic systems, which act as a core scaffold in many pharmaceutically relevant compounds. Pyrazolopyrimidinones have been demonstrated to be efficient in treating several diseases, including cystic fibrosis, obesity, viral infection and cancer. In this study using glioblastoma U-251MG cell line, we tested the cytotoxic effects of 15 pyrazolopyrimidinones, synthesised via a two-step process, in combination with cold atmospheric plasma (CAP). CAP is an adjustable source of reactive oxygen and nitrogen species as well as other unique chemical and physical effects which has been successfully tested as an innovative cancer therapy in clinical trials. Significantly variable cytotoxicity was observed with IC 50 values ranging from around 11 μM to negligible toxicity among tested compounds. Interestingly, two pyrazolopyrimidinones were identified that act in a prodrug fashion and display around 5-15 times enhanced reactive-species dependent cytotoxicity when combined with cold atmospheric plasma. Activation was evident for direct CAP treatment on U-251MG cells loaded with the pyrazolopyrimidinone and indirect CAP treatment of the pyrazolopyrimidinone in media before adding to cells. Our results demonstrated the potential of CAP combined with pyrazolopyrimidinones as a programmable cytotoxic therapy and provide screened scaffolds that can be used for further development of pyrazolopyrimidinone prodrug derivatives., 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 © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT (Ser473) /tot-AKT and phGSK-3β (Ser9) /tot-GSK-3β, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance.

A remote-operated apparatus for testing the detonation sensitivity of energetic materials is detailed. Using an air ram and rotating disk, the normal force and transverse velocity of the impact plane are controlled independently, enabling the exploration of varying impact conditions over a wide parameter space. A microcontroller local to the apparatus is used to automate apparatus operation and ensure temporal alignment of the impacting ram head with the rotating disk. Calculation of the firing parameters and issuing of operational commands are handled by a remote computer and relayed to the local microcontroller for execution at the hardware level. Impact forces are taken from fast strain measurements obtained from gauges incorporated into the ram head. Infrared imaging of explosive samples provides insight into the peak thermal temperatures experienced at the sample surface during the impact event.

Background - Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. Results - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor ( KDR ) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR . Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions - The Bayesian inference approach allowed us to independently validate KDR , which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease., (© 2020 by The American Society of Hematology.)

The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC 50  = 27 μM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes., 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 © 2020 Elsevier Masson SAS. All rights reserved.)

The heterogeneous manifestations of MYH9-related disorder (MYH9-RD), characterized by macrothrombocytopenia, Döhle-like inclusion bodies in leukocytes, bleeding of variable severity with, in some cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE-BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9-RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9-RD should always be considered. A HTS-based strategy is a reliable method to reach a conclusive diagnosis of MYH9-RD in clinical practice., (© 2019 The Authors. Human Mutation published by Wiley Periodicals, Inc.)

This Letter reports the successful experimental demonstration of amplification of subterahertz radiation in a klystron with photonic crystal cavities. The klystron has six cavities, with each cavity having a series of oversized photonic crystal cells made up of a 5×3 array of square posts. The center post is removed from each cell to form a highly oversized (0.8  mm∼λ/4) beam tunnel, with power coupling from cell to cell through the tunnel. The pulsed electron beam is operated at 23.5 kV, 330 mA in a 0.5 T solenoidal field. At 93.7 GHz, a small-signal gain of 26 dB and a saturated output power of 30 W are obtained. Experimental results are in very good agreement with the predictions of a particle-in-cell code. The successful achievement of high gain operation of a photonic crystal klystron amplifier is promising for the future extension of klystron operation well into the terahertz frequency region.

To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing data from 13 037 individuals enrolled in the National Institute for Health Research (NIHR) BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor-encoding gene IKZF5 and thrombocytopenia. We report 5 causal missense variants in or near IKZF5 zinc fingers, of which 2 occurred de novo and 3 co-segregated in 3 pedigrees. A canonical DNA-zinc finger binding model predicts that 3 of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared with wild-type IKZF5, and electron microscopy revealed a reduced quantity of α granules in normally sized platelets. Proplatelet formation was reduced in megakaryocytes from 7 cases relative to 6 controls. Comparison of RNA-sequencing data from platelets, monocytes, neutrophils, and CD4+ T cells from 3 cases and 14 healthy controls showed 1194 differentially expressed genes in platelets but only 4 differentially expressed genes in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans., (© 2019 by The American Society of Hematology.)

There is a continuing rise in the occurrence of multidrug-resistant bacterial infections. Antibiotic resistance to currently available antibiotics has become a global health issue leading to an urgent need for alternative antibacterial strategies. There has been a renewed interest in the development of antibacterial agents from natural sources, and trans-cinnamaldehyde is an example of a naturally occurring compound that has received significant attention in recent years. Trans-Cinnamaldehyde has been shown to possess substantial antimicrobial activity, as well as an array of other medicinal properties, and represents an intriguing hit compound from which a number of derivatives have been developed. In some cases, these derivatives have been shown to possess improved activity, not only compared to trans-cinnamaldehyde but also to commonly used antibiotics. Therefore, understanding the antibacterial mechanisms of action that these compounds elicit is imperative in order to facilitate their development and the development of new antibacterial agents that could exploit similar mechanistic approaches. The purpose of this review is to provide an overview of current knowledge on the antibacterial activity and mechanisms of action of cinnamaldehyde and its derivatives, and to highlight significant contributions made in this research area. It is hoped that the findings presented in this work will aid the future development of new antibacterial agents., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Oosporein was first identified from the insect pathogen Beauveria bassiana >50 y ago. Here, we investigate the insecticidal, anti-feedant and immunomodulation effects of oosporein produced by Beauveria caledonica on the forestry pest Hylobius abietis and model insect Galleria mellonella. We report a novel feedback induction mechanism regulating oosporein production in B. caledonica; exogenous oosporein induces the expression of the oosporein cluster, leading to increased abundance of oosporein biosynthetic enzymes, as shown by label-free quantitative proteomics. Oosporein did not have an anti-feedant effect on H. abietis adults - on the contrary, insects exposed to oosporein-treated food fed more than those exposed to untreated food only. Injected oosporein did not kill insect larvae but increased susceptibility of H. abietis to a subsequent infection. Oosporein did not act as a contact toxin on H. abietis adults and G. mellonella larvae at the concentrations tested. Therefore, it appears that oosporein promotes infection rather than directly killing insects; this could be mediated both by a reduction in haemocyte numbers and by alterations to the humoral immune system. This work makes a case for future research into the potential use of B. caledonica as a biocontrol agent through combinations with oosporein or with enhanced production of oosporein., (Copyright © 2019 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

A laser-driven semiconductor switch (LDSS) employing silicon (Si) and gallium arsenide (GaAs) wafers has been used to produce nanosecond-scale pulses from a 3 μ s, 110 GHz gyrotron at the megawatt power level. Photoconductivity was induced in the wafers using a 532 nm laser, which produced 6 ns, 230 mJ pulses. Irradiation of a single Si wafer by the laser produced 110 GHz RF pulses with a 9 ns width and >70% reflectance. Under the same conditions, a single GaAs wafer yielded 24 ns 110 GHz RF pulses with >78% reflectance. For both semiconductor materials, a higher value of reflectance was observed with increasing 110 GHz beam intensity. Using two active wafers, pulses of variable length down to 3 ns duration were created. The switch was tested at incident 110 GHz RF power levels up to 600 kW. A 1-D model is presented that agrees well with the experimentally observed temporal pulse shapes obtained with a single Si wafer. The LDSS has many potential uses in high power millimeter-wave research, including testing of high-gradient accelerator structures., (Copyright © 2019 Author(s).)

A simple one-pot method for the microwave-assisted synthesis of substituted pyrazolo[1,5- a ]pyrimidinones, a core scaffold in many bioactive and pharmaceutically relevant compounds, has been established. A variety of substituents was tolerated at the 2 and 5 positions, including functionalized aryls, heterocycles, and alkyl groups.

Mounting evidence that even aggressive reductions in net emissions of greenhouse gases will be insufficient to limit global climate risks is increasing calls for atmospheric experiments to better understand the risks and implications of also deploying solar geoengineering technologies to reflect sunlight and rapidly lower surface temperatures. But solar geoengineering research itself poses significant environmental and geopolitical risks. Given limited societal awareness and public dialogue about this climate response option, conducting such experiments without meaningful societal engagement could galvanize opposition to solar geoengineering research from civil society, including the most climate vulnerable communities who are among its intended beneficiaries. Here, we explore whether and how a solar geoengineering research enterprise might be developed in a way that promotes legitimacy as well as scientific credibility and policy relevance. We highlight the distinctive responsibilities of researchers and research funders to ensure that solar geoengineering research proposals are subject to legitimate societal review and scrutiny, recommend steps they can take to strive towards legitimacy and call on them to be explicitly open to multiple potential outcomes, including the societal rejection or considerable alteration of the solar geoengineering research enterprise.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'., (© 2018 The Authors.)

The linear and nonlinear theory of a gyroamplifier using a confocal waveguide is presented. A quasi-optical approach to describing the modes of a confocal waveguide is derived. Both the equations of motion and the mode excitation equation are derived in detail. The confocal waveguide circuit has the advantage of reducing mode competition but the lack of azimuthal symmetry presents challenges in calculating the gain. In the linear regime, the gain calculated using the exact form factor for the confocal waveguide agrees with an azimuthally averaged form factor. A beamlet code including velocity spread effects has been written to calculate the linear and nonlinear (saturated) gain. It has been successfully benchmarked against the MAGY code for azimuthally symmetric cases. For the confocal waveguide, the beamlet code shows that the saturated gain is reduced when compared with results obtained using an azimuthally averaged form factor. The beamlet code derived here extends the capabilities of nonlinear gyroamplifier theory to configurations that lack azimuthal symmetry.

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibβ, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, GP1BA, GP1BB, and GP9) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in GP1BB By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in GP1BB., (© 2017 by The American Society of Hematology.)

Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insight into the autoregulation of DIAPH1 activity., (© 2016 by The American Society of Hematology.)

Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD., (© 2016 by The American Society of Hematology.)

Metformin is the main drug of choice for treating type 2 diabetes, yet the therapeutic regimens and side effects of the compound are all undesirable and can lead to reduced compliance. The aim of this study was to elucidate the mechanism of action of two novel compounds which improved glucose handling and weight gain in mice on a high-fat diet. Wildtype C57Bl/6 male mice were fed on a high-fat diet and treated with novel, anti-diabetic compounds. Both compounds restored the glucose handling ability of these mice. At a cellular level, these compounds achieve this by inhibiting complex I activity in mitochondria, leading to AMP-activated protein kinase activation and subsequent increased glucose uptake by the cells, as measured in the mouse C2C12 muscle cell line. Based on the inhibition of NADH dehydrogenase (IC50 27µmolL(-1)), one of these compounds is close to a thousand fold more potent than metformin. There are no indications of off target effects. The compounds have the potential to have a greater anti-diabetic effect at a lower dose than metformin and may represent a new anti-diabetic compound class. The mechanism of action appears not to be as an insulin sensitizer but rather as an insulin substitute., (© 2016 Society for Endocrinology.)

The Src family kinase (SFK) member SRC is a major target in drug development because it is activated in many human cancers, yet deleterious SRC germline mutations have not been reported. We used genome sequencing and Human Phenotype Ontology patient coding to identify a gain-of-function mutation in SRC causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in nine cases. Modeling of the E527K substitution predicts loss of SRC's self-inhibitory capacity, which we confirmed with in vitro studies showing increased SRC kinase activity and enhanced Tyr(419) phosphorylation in COS-7 cells overexpressing E527K SRC. The active form of SRC predominates in patients' platelets, resulting in enhanced overall tyrosine phosphorylation. Patients with myelofibrosis have hypercellular bone marrow with trilineage dysplasia, and their stem cells grown in vitro form more myeloid and megakaryocyte (MK) colonies than control cells. These MKs generate platelets that are dysmorphic, low in number, highly variable in size, and have a paucity of α-granules. Overactive SRC in patient-derived MKs causes a reduction in proplatelet formation, which can be rescued by SRC kinase inhibition. Stem cells transduced with lentiviral E527K SRC form MKs with a similar defect and enhanced tyrosine phosphorylation levels. Patient-derived and E527K-transduced MKs show Y419 SRC-positive stained podosomes that induce altered actin organization. Expression of mutated src in zebrafish recapitulates patients' blood and bone phenotypes. Similar studies of platelets and MKs may reveal the mechanism underlying the severe bleeding frequently observed in cancer patients treated with next-generation SFK inhibitors., (Copyright © 2016, American Association for the Advancement of Science.)

We report the synthesis, antibacterial evaluation of a series of thiourea-containing compounds. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)-((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea 5, was the most active against a range of Gram-positive and Gram-negative bacteria, and exhibited bacteriostatic activity against methicillin resistant Staphylococcus aureus (MRSA) comparable to that of the well-known antibacterial agent vancomycin. Quinoline thiourea 5 was subjected to a detailed structure-activity relationship study, with 5 and its derivatives evaluated for their bacteriostatic activity against both Gram-negative and Gram-positive bacteria. A number of structural features important for the overall activity of quinoline thiourea 5 have been identified. A selection of compounds, including 5, was also evaluated for their in vivo toxicity using the larvae of the Greater wax moth, Galleria mellonella. Compound 5, and a number of derivatives, were found to be non-toxic to the larvae of Galleria mellonella. A new class of antibiotic can result from the further development of this family of compounds., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Heritable bleeding and platelet disorders (BPD) are heterogeneous and frequently have an unknown genetic basis. The BRIDGE-BPD study aims to discover new causal genes for BPD by high throughput sequencing using cluster analyses based on improved and standardised deep, multi-system phenotyping of cases., Methods: We report a new approach in which the clinical and laboratory characteristics of BPD cases are annotated with adapted Human Phenotype Ontology (HPO) terms. Cluster analyses are then used to characterise groups of cases with similar HPO terms and variants in the same genes., Results: We show that 60% of index cases with heritable BPD enrolled at 10 European or US centres were annotated with HPO terms indicating abnormalities in organ systems other than blood or blood-forming tissues, particularly the nervous system. Cases within pedigrees clustered closely together on the bases of their HPO-coded phenotypes, as did cases sharing several clinically suspected syndromic disorders. Cases subsequently found to harbour variants in ACTN1 also clustered closely, even though diagnosis of this recently described disorder was not possible using only the clinical and laboratory data available to the enrolling clinician., Conclusions: These findings validate our novel HPO-based phenotype clustering methodology for known BPD, thus providing a new discovery tool for BPD of unknown genetic basis. This approach will also be relevant for other rare diseases with significant genetic heterogeneity.

Neuronal nitric oxide synthase (nNOS) produces the key signalling mediator nitric oxide, (NO). This gaseous, free radical molecule modulates a vast array of biological processes, from vascular pressure to immune responses and neurological signalling cascades. Overproduction of NO has been implicated in conditions including Alzheimer's disease, Parkinson's disease and schizophrenia. Inhibition of nNOS therefore offers a potential therapeutic approach for treatment of these conditions. This endeavour is made more complex by the fact that there are two other isoforms of nitric oxide synthase (NOS), endothelial NOS (eNOS) and inducible NOS (iNOS). The selectivity of nNOS inhibitors is therefore a key concern for therapeutic development. This review explores recent advances in the field of selective nNOS inhibition. A particular focus is placed on computational approaches towards the rational design of selective nNOS ligands with improved pharmacokinetic properties. These ligands have been targeted at four key binding sites of the nNOS enzyme - the tetrahydrobiopterin, calmodulin, nicotinamide adenine dinucleotide phosphate (NADPH) and arginine binding sites. The binding sites, and the compounds used to inhibit them, will be discussed in turn, along with the computational methods which have been employed in the field of nNOS inhibition.

In recent years, multiple loci dispersed on the genome have been shown to be associated with coronary artery disease (CAD). We investigated whether these common genetic variants also hold value for CAD prediction in a large cohort of patients with familial hypercholesterolemia (FH). We genotyped a total of 41 single-nucleotide polymorphisms (SNPs) in 1701 FH patients, of whom 482 patients (28.3%) had at least one coronary event during an average follow up of 66 years. The association of each SNP with event-free survival time was calculated with a Cox proportional hazard model. In the cardiovascular disease risk factor adjusted analysis, the most significant SNP was rs1122608:G>T in the SMARCA4 gene near the LDL-receptor (LDLR) gene, with a hazard ratio for CAD risk of 0.74 (95% CI 0.49-0.99; P-value 0.021). However, none of the SNPs reached the Bonferroni threshold. Of all the known CAD loci analyzed, the SMARCA4 locus near the LDLR had the strongest negative association with CAD in this high-risk FH cohort. The effect is contrary to what was expected. None of the other loci showed association with CAD.

Objectives: This case report describes the endoscopic transsphenoidal management of a cholesterol granuloma situated in a technically challenging part of the petrous apex, and the associated peri- and post-operative complications that arose. The literature on diagnosis and management of petrous apex cholesterol granulomas is reviewed., Method and Results: Surgical intervention was attempted on three occasions, each time via an endoscopic, transsphenoidal approach with image guidance. The procedure was abandoned on the first occasion as there was a significant risk to the carotid artery; only a small drainage ostium was created because of the proximity of the carotid artery. The second attempt, complicated by copious bleeding from the clival venous plexus, was arrested prematurely. Successful drainage was achieved at the third attempt, but recovery was complicated by tension pneumocephalus., Conclusion: The transnasal route is less invasive than a lateral labyrinthine or cochlear approach, and spares cochlear and vestibular function. However, this approach is not without risk. It is important to consider the natural anatomical variance of vasculature when planning surgical intervention for a lesion situated in a technically challenging part of the petrous apex. Additional magnetic resonance venography is recommended to circumnavigate the venous plexus, thereby avoiding an unexpected breach.

Asymmetric organocatalytic annulation of E/Z isomeric mixtures of bis(alkyl carboxylate)buta-1,3-dienes and aldehydes has been realized via enamine catalysis. In the presence of α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether, excellent stereo- and enantioselectivities were achieved for a broad spectrum of substrates.