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Abstract We report time resolved observations of the crystallization from liquid hydrogen, supercooled to temperatures below the melting point, using 11.2 keV X-ray diffraction from the Linac Coherent Light Source (LCLS). Changes to the metastable solid and liquid structure factors have been dynamically measured. This allows for a direct determination of the lowest energy crystal polymorphs, the stacking probabilities, as well as the liquid and solid densities and temperatures. Such measurements provide experimental evidence of an Arrhenius-like growth kinetics along the stacking direction during supercooling.

Abstract Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)—a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis.

Infectious complications are common among heart transplant recipients due to immune suppressive therapy mandatorily given to prevent organ rejection. We share our experience regarding an orthotopic heart transplant recipient who underwent craniotomy and evacuation of intracerebral abscess under general anesthesia in our operation theater. An orthotopic heart transplant recipient presented with headache, fever, and left-sided homonymous hemianopia. Noncontrast computed tomography (NCCT) of the head showed a right occipital space-occupying lesion suggestive of an abscess. Craniotomy and evacuation of abscess was successfully performed under general anesthesia. There are several concerns pertinent to orthotopic heart transplant recipients mainly due to denervated heart status and immune suppressive therapy, which poses perioperative challenge. We report successful anesthetic management of this case.

Eosinophil-related diseases represent a group of pathologic conditions with highly heterogeneous clinical presentation and symptoms ranging from mild to critical. Both systemic and localized forms of disease are typically treated with glucocorticoids. The approval of novel biologic therapies targeting the interleukin-5 pathway can help reduce the use of systemic glucocorticoids (SGC) in eosinophilic diseases and reduce the risk of SGC-related adverse effects (AEs). In this article, a panel of experts from different medical specialties reviewed current evidence on the use of SGC in two systemic eosinophilic diseases: Eosinophilic Granulomatosis with PolyAngiitis (EGPA) and HyperEosinophilic Syndrome (HES); and in two single-organ (respiratory) eosinophilic diseases: Chronic RhinoSinusitis with Nasal Polyps (CRSwNP) and Severe Asthma with Eosinophil Phenotype (SA-EP), and contrasted it with their experience in clinical practice. Using nominal group technique, they reached consensus on key aspects related to the dose and tapering of SGC as well as on the initiation of biologics as SGC-sparing agents. Early treatment with biologics could help prevent AEs associated with medium and long-term use of SGC.

Abstract This study describes the composition and potential metabolic adaptation of microbial communities in northeastern Siberia, a repository of the oldest permafrost in the Northern Hemisphere. Samples of contrasting depth (1.75 to 25.1 m below surface), age (from ~ 10 kyr to 1.1 Myr) and salinity (from low 0.1–0.2 ppt and brackish 0.3–1.3 ppt to saline 6.1 ppt) were collected from freshwater permafrost (FP) of borehole AL1_15 on the Alazeya River, and coastal brackish permafrost (BP) overlying marine permafrost (MP) of borehole CH1_17 on the East Siberian Sea coast. To avoid the limited view provided with culturing work, we used 16S rRNA gene sequencing to show that the biodiversity decreased dramatically with permafrost age. Nonmetric multidimensional scaling (NMDS) analysis placed the samples into three groups: FP and BP together (10–100 kyr old), MP (105–120 kyr old), and FP (> 900 kyr old). Younger FP/BP deposits were distinguished by the presence of Acidobacteriota, Bacteroidota, Chloroflexota_A, and Gemmatimonadota, older FP deposits had a higher proportion of Gammaproteobacteria, and older MP deposits had much more uncultured groups within Asgardarchaeota, Crenarchaeota, Chloroflexota, Patescibacteria, and unassigned archaea. The 60 recovered metagenome-assembled genomes and un-binned metagenomic assemblies suggested that despite the large taxonomic differences between samples, they all had a wide range of taxa capable of fermentation coupled to nitrate utilization, with the exception of sulfur reduction present only in old MP deposits.

Abstract In recent years, more software engineering researchers have focussed on methods, techniques, tools, and processes to support software project management (SPM) addressing quality, cost, and time constraints. In this direction, the use of Bayesian belief networks (BBNs) has gained attention for providing a powerful mechanism for cause–effect analysis with both qualitative and quantitative data to support decision making under uncertainty. This work aims to provide an overview of the first 20 years of research in BBNs applied to SPM, and by so doing it contributes to the structuring of this research topic and the identification of new research opportunities. We conducted a systematic mapping (SM) study on the use of BBN as a decision‐support tool for SPM issues. We analysed over 109 relevant publications, from 1999 to 2018 (i.e., 20 years), to understand the motivations for using Bayesian networks (why), the problem domain and model scope addressed by researchers (what), the stage of the life cycle in which BBNs are being used (when), the venues of the publications (where), and the tools used to model the Bayesian networks (how). We draw the following conclusions from the results of our SM: (1) The application of Bayesian networks in SPM has been an active research topic since 1999. (2) Prediction and planning are the most common purposes in 60% of selected papers. (3) Software quality (55%) is the problem domain most investigated. (4) Most of the surveyed studies embrace the project (47%) and product (37%) scopes. And finally, (5) the development phase (86%) is when Bayesian networks have been more used. As future work, we highlight the need to further investigate methodologies that enable the use of BBNs in real software development contexts.

Cruzain, the main cysteine protease of Trypanosoma cruzi, plays key roles in all stages of the parasite’s life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of this validated target may lead to the development of novel drugs for the treatment of Chagas disease. In this study, a multiparameter optimization (MPO) approach, molecular modeling, and structure-activity relationships (SARs) were employed for the identification of new benzimidazole derivatives as potent competitive inhibitors of cruzain with trypanocidal activity and suitable pharmacokinetics. Extensive pharmacokinetic studies enabled the identification of metabolically stable and permeable compounds with high selectivity indices. CYP3A4 was found to be involved in the main metabolic pathway, and the identification of metabolic soft spots provided insights into molecular optimization. Compound 28, which showed a promising trade-off between pharmacodynamics and pharmacokinetics, caused no acute toxicity and reduced parasite burden both in vitro and in vivo.

A multistep synthesis of a novel arylidene 3­(2"H")-furanone has been designed and optimized for the second-year organic laboratory. The three-step sequence consists of a nucleophilic substitution, intramolecular cyclization, and acid-catalyzed aldol condensation, and can be carried out within two 3 h laboratory periods. The final product is a crystalline solid that does not require purification and bears structural resemblance to natural products with medicinal properties. Reactions are performed at room temperature, and the aldol condensation takes place without the need for organic solvent, providing students hands-on experience with chemical transformations that illustrate green chemistry principles.

Heart failure with preserved ejection fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune pathophysiology. Using a 2-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occurred concomitantly with cardiac pathology and that diastolic dysfunction, cardiomyocyte hypertrophy, and cardiac phospholamban phosphorylation were T cell dependent. Heart-infiltrating T cells were not restricted to cardiac antigens and were uniquely characterized by impaired activation of the inositol-requiring enzyme 1[alpha]/X-box-binding protein 1 (IRE1[alpha]/XBP1) arm of the unfolded protein response. Notably, selective ablation of XBP1 in T cells enhanced their persistence in the heart and lymphoid organs of mice with preclinical HFpEF. Furthermore, T cell IRE1[alpha]/XBP1 activation was restored after withdrawal of the 2 comorbidities inducing HFpEF, resulting in partial improvement of cardiac pathology. Our results demonstrated that diastolic dysfunction and cardiomyocyte hypertrophy in preclinical HFpEF were T cell dependent and that reversible dysregulation of the T cell IRE1[alpha]/ XBP1 axis was a T cell signature of HFpEF., Introduction Widely regarded as the greatest unmet need in cardiovascular medicine, heart failure with preserved ejection fraction (HFpEF) is a complex and heterogeneous syndrome accounting for roughly 50% of HF [...]

This article analyzes the optimal combination of ex ante and ex post regulation of an activity in a two-period model. Additional information about the sign and extent of the externality associated with the activity becomes available only once a private party undertakes the activity, but undoing the activity at that stage is costly. We characterize when the regulator should commit not to reevaluate the activity ex post. The case for ex post regulation is strengthened if the private party can signal its private information about the consequences of the activity, but it is weakened if the cost of undoing the activity can be manipulated. [ABSTRACT FROM AUTHOR]

The article "SHORTING YOUR RIVALS: NEGATIVE OWNERSHIP AS AN ANTITRUST REMEDY" proposes a unique antitrust remedy of negative ownership positions in remaining rivals as an alternative to divestiture in mergers. This remedy aims to restore competition levels by counteracting anticompetitive effects of mergers through various implementations like compensation based on relative performance and derivative contracts. The text explores the concept of negative ownership in antitrust enforcement, discussing its benefits in maintaining pre-merger competitive incentives and potentially allowing procompetitive transactions. It also delves into scenarios of asymmetry among firms, impact on innovation, and a detailed model of the JetBlue/Spirit merger to illustrate how negative ownership can influence pricing decisions, offering a versatile tool for antitrust enforcement. [Extracted from the article]

We report time resolved observations of the crystallization from liquid hydrogen, supercooled to temperatures below the melting point, using 11.2 keV X-ray diffraction from the Linac Coherent Light Source (LCLS). Changes to the metastable solid and liquid structure factors have been dynamically measured. This allows for a direct determination of the lowest energy crystal polymorphs, the stacking probabilities, as well as the liquid and solid densities and temperatures. Such measurements provide experimental evidence of an Arrhenius-like growth kinetics along the stacking direction during supercooling. [ABSTRACT FROM AUTHOR]

As states employ financial sanctions as a form of economic coercion, firms become the foot soldiers. This analysis bridges work on weaponized interdependence with work on extraterritorial authority to understand the de-risking behavior of these firms. Companies fearing extraterritorial enforcement are likely to limit exposure to third party jurisdictions, which may expose the firm to the sanctions regime. In particular, we identify two mechanisms – target leakage and political cascades – to understand which third-party jurisdictions are most likely to be affected. We test our hypotheses through analyses of multinational banks' lending before and after the 2010 sanctions on Iran. Using a difference-in-differences estimator to evaluate the sanction's impact on cross-border lending, our analysis shows that the sanction reduced multinational banks' lending to neighboring countries of Iran and its politically aligned states by approximately 14% and 12% respectively. Moreover, we observed lender heterogeneity as banks from offshore financial centers increased their lending to the affected jurisdictions by 32% and 33%. Our findings demonstrate the broader consequences of financial sanctions in terms of the impacted countries and the potential to drive lending to less regulated spaces. [ABSTRACT FROM AUTHOR]

Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)—a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis. Mice lacking A Disintegrin and Metalloproteinase 9 (ADAM9) do not mount Type 1 interferon responses against encephalomyocarditis infection. Here, Bazzone et al show that ADAM9 regulates innate immune responses via by MDA5. [ABSTRACT FROM AUTHOR]

Background: Glasgow coma scale (GCS) score is the most widely used clinical score for the initial assessment of neurologically injured patients and is also frequently used for prognostication. Other scores such as the Full Outline of UnResponsivness (FOUR) score and the Glasgow Coma Scale-Pupils (GCS-P) score have been more recently developed and are gaining popularity. This prospective cohort study was conducted to compare various scores in terms of their ability to predict outcomes at 3 months in patients with traumatic brain injury (TBI). Materials and methods: The study was carried out between October 2020 and March 2022. Patients who presented to the hospital with TBI were assessed for inclusion. Initial coma scores were assessed in the emergency department and again after 48 hours of admission. Outcome was assessed using the extended Glasgow outcome score (GOSE) at 3 months after injury. The receiver operating curve (ROC) was plotted to correlate coma scores with the outcome, and the area under the curve (AUC) was compared. Results: A total of 355 patients with TBI were assessed for eligibility, of which 204 patients were included in the study. The AUC values to predict poor outcomes for initial GCS, FOUR, and GCS-P scores were 0.75 each. The AUC values for 48-hour coma scores were 0.88, 0.87, and 0.88, respectively. Conclusion: The GCS, FOUR, and GCS-P scores were found to be comparable in predicting the functional outcome at 3 months as assessed by GOSE. However, coma scores assessed at 48 hours were better predictors of poor outcomes at 3 months than coma scores recorded initially at the time of hospital admission. [ABSTRACT FROM AUTHOR]

Regulation of gene expression plays a crucial role in developmental processes and adaptation to changing environments. expression quantitative trait locus (eQTL) mapping is a technique used to study the genetic regulation of gene expression using the transcriptomes of recombinant inbred lines (RILs). Typically, the age of the inbred lines at the time of RNA sampling is carefully controlled. This is necessary because the developmental process causes changes in gene expression, complicating the interpretation of eQTL mapping experiments. However, due to genetics and variation in ambient micro-environments, organisms can differ in their "developmental age," even if they are of the same chronological age. As a result, eQTL patterns are affected by developmental variation in gene expression. The model organism Caenorhabditis elegans is particularly suited for studying the effect of developmental variation on eQTL mapping patterns. In a span of days, C. elegans transitions from embryo through 4 larval stages to adult while undergoing massive changes to its transcriptome. Here, we use C. elegans to investigate the effect of developmental age variation on eQTL patterns and present a normalization procedure. We used dynamical eQTL mapping, which includes the developmental age as a cofactor, to separate the variation in development from genotypic variation and explain variation in gene expression levels. We compare classical single marker eQTL mapping and dynamical eQTL mapping using RNA-seq data of ∼200 multi-parental RILs of C. elegans. The results show that (1) many eQTLs are caused by developmental variation, (2) most trans-bands are developmental QTLs, and (3) dynamical eQTL mapping detects additional eQTLs not found with classical eQTL mapping. We recommend that correction for variation in developmental age should be strongly considered in eQTL mapping studies given the large impact of processes like development on the transcriptome. [ABSTRACT FROM AUTHOR]