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We present the results of remote sensing analysis of U.S. Geological Survey digital elevation models, Landsat spectral data, and National Agriculture Imagery Program orthophotos to generate a preliminary geologic map that significantly aided our boots-on-the-ground geologic mapping of the southwest portion of the Three Peaks 7.5ʹ quadrangle in southwest Utah. Sedimentary rocks, intrusive rocks, and a variety of geologic contacts, including unconformities and faults, as well as unconsolidated alluvium are recognized in the study area. We constructed a series of geologic maps using remote sensing data and analysis techniques that are readily available to geoscientists. These techniques include band-ratioing, random forest analysis, and these analyses. Resolution of the resulting geologic maps generated by random forest analysis and principal component analysis were greatly improved by incorporating both the high resolution orthophoto and the 1/3 arc second digital elevation model into the principal component analysis. Our final remotely sensed geologic map integrated results from each technique. We used this remotely sensed geologic map to develop our preliminary plan for the field campaign. We preselected high priority targets (e.g., previously unrecognized units and faults) for in-person field analysis. We also identified highly accessible areas that allowed for efficient use of in-person field time needed for evaluation of large areas covered by relatively homogeneous units. The authors spent 25 days in the field over a seven-week field season, mapping the same area. Here, we compare the remote-sensed geologic maps with the final in-person field checked geologic map and discuss the utility of remote sensing data for detailed geologic field investigations. Preparing a remote sensing geologic map prior to field work has several advantages, including identification of mappable units, recognition of geologic contacts, and selection of priority target areas for direct evaluation of hypothesized field relationships, thereby promoting more efficient geologic mapping.

New mutations conferring resistance to SARS-CoV-2 therapeutics have important clinical implications. We describe the first cases of an independently acquired V792I RNA-dependent RNA polymerase mutation developing in renal transplant recipients after remdesivir exposure. Our work underscores the need for augmented efforts to identify concerning mutations and address their clinical implications.

In this experiment, we manipulated what men believed about their own penis size, relative to others. We gave them false information, stating that the average penis size was larger than it in fact is, reasoning that, on average, these males will feel that relatively and subjectively their own penis was smaller; compared to those told that the average penis size was smaller than true average. We then asked them to rate how much they would like to own a sports car. These facts and questions were buried amongst other items giving information and asking for product ratings, so that our hypothesis was masked from participants. We found that males, and males over 30 in particular, rated sports cars as more desirable when they were made to feel that they had a small penis.

Space-based biomanufacturing has the potential to improve the sustainability of deep space exploration. To advance biomanufacturing, bioprocessing systems need to be developed for space applications. Here, commercial technologies were assessed to design space bioprocessing systems to supply a liquid amine carbon dioxide scrubber with active carbonic anhydrase produced recombinantly. Design workflows encompassed biomass dewatering of 1 L Escherichia coli cultures through to recombinant protein purification. Equivalent system mass (ESM) analyses had limited utility for selecting specific technologies. Instead, bioprocessing system designs focused on minimizing complexity and enabling system versatility. Three designs that differed in biomass dewatering and protein purification approaches had nearly equivalent ESM of 357-522 kg eq. Values from the system complexity metric (SCM), technology readiness level (TRL), and degree of crew assistance metric identified a simpler, less costly, and easier to operate design for automated biomass dewatering, cell lysis, and protein affinity purification.

The medical community currently lacks robust data regarding the incidence, prevalence, and clinical significance of mutations associated with resistance to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) therapeutics. This report describes two renal transplant recipients who, after remdesivir exposure, developed a de novo V792I RNA-dependent RNA polymerase (RdRp) mutation that has recently been found to confer resistance to remdesivir in vitro. To the best of our knowledge, this publication is the first to document the emergence of V792I in patients treated with remdesivir. Our work underscores the critical need for augmented efforts to identify concerning mutations and address their clinical implications.

The temporal and spatial distribution of strain associated with the Sevier orogeny in western North America is significantly different in the southern end of the belt, at the latitude of Las Vegas, Nevada, than farther to the north at the latitude of Salt Lake City, Utah. Reasons for these differences have been speculative as a lack of temporal constraints on thrusting in the intervening region hindered along-strike correlation across the belt. We determined a crystallization age of 100.18 ± 0.04 Ma for zircons extracted from a recently recognized dacite lapilli ash-fall tuff near the base of the synorogenic Iron Springs Formation. We propose the name “Three Peaks Tuff Member” for this unit, and identify a type stratigraphic section on the western flank of the “Three Peaks,” a topographic landmark in Iron County, Utah. Field relationships and this age constrain movement on the Iron Springs thrust and the end of the sub-Cretaceous unconformity in the critical intervening area to latest Albian/earliest Cenomanian. Movement on the Iron Springs thrust was synchronous with movement on multiple Sevier thrusts at ~100 Ma, indicating that the mid-Cretaceous was a period of extensive thrust-fault movement. This mid-Cretaceous thrusting event coincided with a period of global plate reorganization and increased convergence, and hence an increased subduction rate for the Farallon Plate beneath North America. The accelerated subduction contributed to a Cordilleran arc flare-up event and steepening of the orogenic wedge, which triggered widespread thrusting across the retroarc Sevier deformation belts. Additionally, based on temporal constraints and the strong spatial connection of mid-Cretaceous thrusts to lineaments interpreted as pre-orogenic transform faults, we suggest that temporal and spatial variations along the strike of the orogenic belt reflect tectonic inheritance of basement structures associated with the edge of the rifted Precambrian craton.

IntroductionExtracellular vesicles (EVs) from human Alzheimer’s disease (AD) biospecimens contain amyloid-β peptide (Aβ) and tau. While AD EVs are known to affect brain disease pathobiology, their biochemical and molecular characterizations remain ill defined.MethodsEVs were isolated from the cortical grey matter of 20 AD and 18 control brains. Tau and Aβ levels were measured by immunoassay. Differentially expressed EV proteins were assessed by quantitative proteomics and machine learning.ResultsLevels of pS396 tau and Aβ were significantly elevated in AD EVs. High levels of neuron- and glia- specific factors are detected in control and AD EVs, respectively. Machine learning identified ANXA5, VGF, GPM6A and ACTZ in AD EV compared to controls. They distinguished AD EVs from controls in the test sets with 88% accuracy.DiscussionIn addition to Aβ and tau, ANXA5, VGF, GPM6A and ACTZ are new signature proteins in AD EVs.

Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Despite continued efforts to understand the pathophysiology of sepsis, no effective therapies are currently available. While singular components of the aberrant immune response have been investigated, comprehensive studies linking different data layers are lacking. Using an integrated systems immunology approach, we evaluated neutrophil phenotypes and concomitant changes in cytokines and metabolites in patients with sepsis. Our findings identify differentially expressed mature and immature neutrophil subsets in patients with sepsis. These subsets correlate with various proteins, metabolites, and lipids, including pentraxin-3, angiopoietin-2, and lysophosphatidylcholines, in patients with sepsis. These results enabled the construction of a statistical model based on weighted multi-omics linear regression analysis for sepsis biomarker identification. These findings could help inform early patient stratification and treatment options, and facilitate further mechanistic studies targeting the trifecta of surface marker expression, cytokines, and metabolites.

We describe a vaccinated lung transplant recipient who experienced a fatal outcome associated with coronavirus disease 2019 (COVID-19). Tocilizumab was administered. The patient exhibited clinical and radiographic evidence of colitis during the course of multiple secondary infections. This report emphasizes the need for more conservative precautions to prevent COVID-19 infection in transplant recipients.

A 21-year-old man with a history of psychiatric comorbidities, primary vesicoureteral reflux, recurrent pyelonephritis requiring bilateral native nephrectomies, and deceased-donor kidney transplantation at age two experienced few infectious complications for several years after transplant. Both the donor and recipient were seronegative for cytomegalovirus at the time of transplant. A few days after engaging in his first lifetime unprotected sexual contact, receptive anal intercourse with a casual partner, the patient presented to an outside hospital emergency room with burning perianal pain. He denied any history of similar symptoms in the past and also denied any gastrointestinal or systemic symptoms at that time. He reported no previous sexual partners. A superficial swab of perianal ulcers confirmed a diagnosis of HSV-2 by immunofluorescence assay, and the patient was treated with a 10-day course of valacyclovir. Although the patient experienced some improvement in symptoms, residual ulcerative changes persisted at the end of his valacyclovir course, and his painful perianal lesions progressed soon after stopping antiviral therapy. Three weeks later, the patient experienced the new onset of malaise, intermittent fever, morbilliform rash, abdominal discomfort, and voluminous, watery, non-hemorrhagic diarrhea.

Reliance on π-diagrams and tangent plots to describe fold geometry has created an unwarranted status for conical folds at the expense of periclines. Analysis of virtual periclines using synthetic stereograms, tangent diagrams, and geologic curvature analysis demonstrates small portions of periclines are “cylindrical.” The more significant “non-cylindrical” portion of periclines allows for a mathematically permissible, but unrealistic, geometrical representation as portions of cones. We demonstrate cones are an extremely poor geometric representation of both the virtual periclines and examples of natural non-cylindrical folds. “Conical folds,” if they exist, terminate at a point; the amplitude to width ratio and the plunge of the crestal line must remain constant towards the fold terminus, with a Gaussian curvature of zero. In contrast, the amplitude to width ratio, plunge along the crestal line, and Gaussian curvature of periclines vary towards the fold terminus. These differences have important implications for the rheological modeling of folds, and while realistic dynamic models for periclines exist, models for conical fold formation remain conceptual. We suggest that in order to advance our understanding of how folds form, it may be “pointless” to continue the misconception of conical folds as an accurate geometric representation of how folds end.

Graphical abstract, High-resolution visualization of surfaces of geologic interest, at a multitude of scales, using 3D point cloud technologies provides an opportunity to analyze spatial relationships of surfaces using orientation data. We present a MATLAB® script that produces planar geologic attitude data (e.g., strike, dip, and dip-direction data) from 3D datasets (e.g., point clouds, 3D scanning). The method utilizes Cartesian coordinates of triangular planar surfaces and converts them into matrices of conventional geologic attitude data. Spatial relationships among data points can be investigated, using polar tangent diagrams, stereographic analysis, or geologic curvature analysis. We utilize this script to create “synthetic” graphical plots (e.g., stereograms, tangent diagrams) from geomechanically realistic, virtual, folded surfaces produced by dynamic modeling. Synthetic graphical diagrams are of considerable usefulness in interpreting graphical plots (e.g., stereograms) of attitude data from natural folded rock surfaces, particularly in locations with poor exposure. • This script outputs attitude data (strike, dip, and dip direction) in a spreadsheet and as a text file for use in other visualization software. • A tangent diagram is created and displayed in this script for rapid visualization and fold shape assessment. • The MATLAB script is readily modified to accept multiple data formats for input (e.g., MATLAB variables, *.csv files, etc.) and output (e.g., *.csv files, *.txt files, etc.).

The characterization of folds is often limited to two-dimensional cross-sectional views where folds are approximated as cylindrical. This enables simplification of fold shape analysis (using principles such as dip isogons, stereographs, tangent diagrams, and Bezier curve analysis), allows for a simplified analysis of the distribution of stress and strain, and enables and the analysis and visualization of folding associated fractures. However, in a heterogenous medium folds have to terminate somewhere, resulting in more complex three-dimensional geometries. In this study, a 3D finite element modeling approach using a Maxwell visco-elastic rheology is utilized to simulate 3D periclinal folds resulting from single layer buckle folding. With respect to fold shape analysis, we use the forward modeled pericline geometries to demonstrate that geometrical attitude data collected for various cross sections and plotted using traditional 2D methods such as stereographs and tangent diagrams may lead to the misinterpretation of the fold shape as conical. In contrast 3D geometric data such as Gaussian curvature can describe and quantify the 3D fold geometry in its entirety. With respect to folding associated fracture analysis, the 3D modeling results show that shear fractures of various orientations in the fold limb, which cannot be intuitively explained by the strain/stress regimes during 2D buckling and require unrealistic boundary conditions, are feasible to occur during a single deformation event during the development of a pericline. In summary, accounting for the true 3D geometry of buckle fold structures will lead to a better classification of folds, a better understanding of the processes and parameters affecting their development, and enable post-folding failure analysis.

Acute pneumonia continues to represent a major source of morbidity, mortality, and healthcare expenditure in the U.S. It is imperative that clinicians at all levels of training have a firm understanding of this potentially deadly infection and its numerous complications. The current state of our diagnostic capabilities often dictates that clinicians will need to make important therapeutic decisions in patients presenting with acute pneumonia before identifying a culprit pathogen. Only after understanding the pathogenesis of pneumonia under different clinical circumstances can one devise rational empiric therapeutic regimens. In this practical review we offer a succinct description of the epidemiology and pathogenesis of acute pneumonia. We then proceed to discuss the evaluation and management of patients presenting with acute pneumonia with emphasis on the most valuable clinical trials and major guidelines that we use to inform our clinical decisions. Despite significant advances in the field of infectious disease over the past century, clinicians continue to recognize pneumonia, the infection of the pulmonary parenchyma, as a major source of morbidity and mortality. In this article we attempt to provide the general practitioner with a practical review of acute pneumonia and its complications. Prioritizing the needs of the general practitioner, we most thoroughly address community acquired pneumonia (CAP). Though we do not intend for this review to be completely comprehensive, in this article we also briefly discuss healthcare associated pneumonia (HCAP), hospital associated pneumonia (HAP), and ventilator associated pneumonia (VAP). Focusing much of our attention on the most important clinical trials and guidelines underpinning the diagnosis and management of this common problem, we hope that this publication will serve as a useful review to aid in clinical decision making. This review contains 65 references, 1 figure and 6 tables. Key Words: Pneumonia, viral pneumonia, bacterial pneumonia, community-acquired pneumonia, ventilator-associated pneumonia, VAP, healthcare-associated pneumonia, hospital-acquired pneumonia

The sulfated glycosaminoglycans (GAGs) are long, linear polysaccharide chains that are typically found as the glycan portion of proteoglycans. These GAGs are characterized by repeating disaccharide units with variable sulfation and acetylation patterns along the chain. GAG length and modification patterns have profound impacts on growth factor signaling mechanisms central to numerous physiological processes. Electron activated dissociation tandem mass spectrometry is a very effective technique for assigning the structures of GAG saccharides; however, manual interpretation of the resulting complex tandem mass spectra is a difficult and time-consuming process that drives the development of computational methods for accurate and efficient sequencing. We have recently published GAGfinder, the first peak picking and elemental composition assignment algorithm specifically designed for GAG tandem mass spectra. Here, we present GAGrank, a novel network-based method for determining GAG structure using information extracted from tandem mass spectra using GAGfinder. GAGrank is based on Google’s PageRank algorithm for ranking websites for search engine output. In particular, it is an implementation of BiRank, an extension of PageRank for bipartite networks. In our implementation, the two partitions comprise every possible sequence for a given GAG composition and the tandem MS fragments found using GAGfinder. Sequences are given a higher ranking if they link to many important fragments. Using the simulated annealing probabilistic optimization technique, we optimized GAGrank’s parameters on ten training sequences. We then validated GAGrank’s performance on three validation sequences. We also demonstrated GAGrank’s ability to sequence isomeric mixtures using two mixtures at five different ratios., Graphical abstract, Highlights • GAGfinder assigns glycosaminoglycan EDD and NETD product ions. • GAGrank assigns the most probable sequence from the tandem MS. • GAGrank ranks nodes using a bipartite network’s structure. • GAGrank ranks glycosaminoglycan sequences based on their importance in the network., In Brief We demonstrate GAGrank, an algorithm that uses a bipartite graph model for sequencing glycosaminoglycans from EDD or NETD tandem mass spectra. The process involves first assigning glycosaminoglycan product ions using the GAGfinder algorithm. The second step is to rank possible sequences using GAGrank. We show GAGrank’s ability to sequence isomeric mixtures.

Previous studies on Parkinson’s disease mechanisms have shown dysregulated extracellular transport of α-synuclein and growth factors in the extracellular space. In the human brain these consist of perineuronal nets, interstitial matrices, and basement membranes, each composed of a set of collagens, non-collagenous glycoproteins, proteoglycans, and hyaluronan. The manner by which amyloidogenic proteins spread extracellularly, become seeded, oligomerize, and are taken up by cells, depends on intricate interactions with extracellular matrix molecules. We sought to assess the alterations to structure of glycosaminoglycans and proteins that occur in PD brain relative to controls of similar age. We found that PD differs markedly from normal brain in upregulation of extracellular matrix structural components including collagens, proteoglycans and glycosaminoglycan binding molecules. We also observed that levels of hemoglobin chains, possibly related to defects in iron metabolism, were enriched in PD brains. These findings shed important new light on disease processes that occur in association with PD.

Social contextualist analysis, by contrast to much of the existing research on international negotiations, emphasizes the social and organizational environment in which negotiations take place and the effect that it can have on the decision-making of participants. This paper applies a social contextualist lens to negotiations held to decide upon the form and function of the African Peace and Security Architecture (APSA). Certain elements of the Architecture, which is one of the central pillars of the African Union (AU), present something of a puzzle for theorists, given the cession of sovereignty they represent on a continent where leaders have traditionally been very protective of their authority. After illustrating the limited value of the most prominent approaches to negotiation analysis, the social contextualist framework is outlined. The analysis incorporates negotiations held to decide upon a number of features of APSA. Its findings rest upon interviews conducted with representatives from AU member states and AU officials, as well as examination of a broad range of primary and secondary documents. In highlighting the significance of factors that are generally overlooked by traditional approaches, a case is made for greater consideration of social contextual factors in analysis of international negotiations.

Parkinson's disease (PD) is a neurological disorder characterized by the progressive loss of functional dopaminergic neurons in the nigrostriatal pathway in the brain. Although current treatments provide only symptomatic relief, gene therapy has the potential to slow or halt the degeneration of nigrostriatal dopamine neurons in PD patients. Adeno-associated viruses (AAV) are vectors of choice in gene therapy because of their well-characterized safety and efficacy profiles; however, although gene therapy has been successful in preclinical models of the disease, clinical trials in humans have failed to demonstrate efficacy. Significantly, all primary AAV receptors of the virus are glycans. We thus hypothesize that age related changes in glycan receptors of heparan sulfate (HS) proteoglycans (receptor for rAAV2), and/or N-glycans with terminal galactose (receptor for rAAV9) results in poor adeno-associated virus binding in either the striatum or substantia nigra, or both, affecting transduction and gene delivery. To test our hypothesis we analyzed the striatum and substantia nigra for changes in HS, N-glycans and proteomic signatures in young versus aged rat brain striatum and substantia nigra. We observed different brain region-specific HS disaccharide profiles in aged compared with young adult rats for brain region-specific profiles in striatum versus substantia nigra. We observed brain region- and age-specific N-glycan compositional profiles with respect to the terminal galactose units that serve as receptors for AAV9. We also observed brain region-specific changes in protein expression in the aging nigrostriatal pathway. These studies provide insight into age- and brain region-specific changes in glycan receptors and proteome that will inform design of improved viral vectors for Parkinson Disease (PD) gene therapy.

In the southeast Western Desert of Egypt, a prominent set of E-W faults and co-located domes and basins involve sedimentary cover rock as young as the early Eocene. Although earlier Mesozoic slip on faults in southern Egypt has been widely mentioned in the literature and attributed to repeated reactivation of basement faults, evidence is indirect and based on the idea that regional stresses associated with tectonic events in the Syrian Arc would likely have reactivated basement faults in south Egypt in dextral strike slip during the Mesozoic as well as the Cenozoic. Here, we present direct evidence from the rock record for the sequence of development of features along these faults. Southwest of Aswan, a small structural dome in Mesozoic Nubia facies rocks occurs where the Seiyal Fault bends northward from west to east. The dome is cut by strands of the Seiyal Fault and a related set of cataclastic deformation bands showing dominantly right lateral strike slip, as well as by younger calcite veins with related patchy poikilotopic cement. High resolution satellite image analysis of the remote southwest Kharga Valley shows a similar sequence of events: older structural domes and basins located where E-W faults bend northward from west to east, right lateral offset of domes and basins along the E-W faults, and two sets of deformation band faults that lack co-located domes and basins. We suggest that field data, image analysis, and burial depth estimates are best explained by diachronous development of features along the E-W fault system. We propose that Late Mesozoic right lateral strike slip produced domes and basins in Nubia facies rocks in stepover regions above reactivated basement faults. We further suggest that the extensively linked segments of the E-W fault system in Nubia facies rocks, plus the deformation band systems, formed during the late Eocene when basement faults were again reactivated in dominantly right lateral strike slip.

Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.

Embryonic development is arguably the most complex process an organism undergoes during its lifetime, and understanding this complexity is best approached with a systems-level perspective. The sea urchin has become a highly valuable model organism for understanding developmental specification, morphogenesis, and evolution. As a non-chordate deuterostome, the sea urchin occupies an important evolutionary niche between protostomes and vertebrates.Lytechinus variegatus(Lv) is an Atlantic species that has been well studied, and which has provided important insights into signal transduction, patterning, and morphogenetic changes during embryonic and larval development. The Pacific species,Strongylocentrotus purpuratus(Sp), is another well-studied sea urchin, particularly for gene regulatory networks (GRNs) andcis-regulatory analyses. A well-annotated genome and transcriptome for Sp are available, but similar resources have not been developed for Lv. Here, we provide an analysis of the Lv transcriptome at 11 timepoints during embryonic and larval development. The data indicate that the gene regulatory networks that underlie specification are well-conserved among sea urchin species. We show that the major transitions in variation of embryonic transcription divide the developmental time series into four distinct, temporally sequential phases. Our work shows that sea urchin development occurs via sequential intervals of relatively stable gene expression states that are punctuated by abrupt transitions.