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Laboratory hydration of obsidian is based on the principle that the measurement of water penetration at high temperatures allows computation of hydration rates at archaeological temperatures. Accuracy of the laboratory hydration method is sensitive to the details of the laboratory and analysis protocols employed. We present the results of a simulation study showing that accuracy of the standard protocol is poor, but is improved by longer hot-soak times, more accurate hydration rim measurements, and use of statistical weighting factors in the analysis. A revised protocol is proposed which permits hydration rate development with accuracies of 10–15%. However, inherent limitations of optical microscopy make further improvements difficult and the measurement of hydration layers using alternate technologies is recommended.

Introduction and purposeAccurate and reproducible patient positioning is a critical step in radiotherapy for breast cancer. This has seen the use of permanent skin markings becoming standard practice in many centres. Permanent skin markings may have a negative impact on long-term cosmetic outcome, which may in turn, have psychological implications in terms of body image. The aim of this study was to investigate the feasibility of using a semi-permanent tattooing device for the administration of skin marks for breast radiotherapy set-up.Materials and methodsThis was designed as a phase II double-blinded randomised-controlled study comparing our standard permanent tattoos with the Precision Plus Micropigmentation (PPMS) device method. Patients referred for radical breast radiotherapy were eligible for the study. Each study participant had three marks applied using a randomised combination of the standard permanent and PPMS methods and was blinded to the type of each mark. Follow up was at routine appointments until 24 months post radiotherapy. Participants and a blind assessor were invited to score the visibility of each tattoo at each follow-up using a Visual Analogue Scale. Tattoo scores at each time point and change in tattoo scores at 24 months were analysed by a general linear model using the patient as a fixed effect and the type of tattoo (standard or research) as covariate. A simple questionnaire was used to assess radiographer feedback on using the PPMS.ResultsIn total, 60 patients were recruited to the study, of which 55 were available for follow-up at 24 months. Semi-permanent tattoos were more visible at 24 months than the permanent tattoos. Semi-permanent tattoos demonstrated a greater degree of fade than the permanent tattoos at 24 months (final time point) post completion of radiotherapy. This was not statistically significant, although it was more apparent for the patient scores (p=0·071) than the blind assessor scores (p=0·27). No semi-permanent tattoos required re-marking before the end of radiotherapy and no adverse skin reactions were observed.ConclusionThe PPMS presents a safe and feasible alternative to our permanent tattooing method. An extended period of follow-up is required to fully assess the extent of semi-permanent tattoo fade.

This study explored the impact of COVID‐19 on adults with type 2 diabetes mellitus (T2DM) self‐management behaviours and service experiences within an ethnically diverse UK sample. A cross‐sectional survey design was employed. An 18‐item survey was administered to suitable patients attending the Lambeth Diabetes Intermediate Care Team (South East London, UK) via text message (n=993) or post (n=62). A total of 150 participants completed the survey, which revealed that 30% had changed their diabetes medication taking behaviour since the start of the COVID‐19 pandemic for a number of reasons. Negative changes in physical activity levels and dietary behaviours were also reported. Of those who received a telephone consultation, high satisfaction levels were reported but a clear preference for face‐to‐face consultations was still present. Our findings suggest that the COVID‐19 pandemic is having a negative impact on individuals with T2DM physical activity levels and dietary behaviours. Additionally, the findings indicate that although telephone consultations were highly accepted, many would prefer to receive a face‐to‐face consultation in future. Copyright © 2021 John Wiley & Sons.

Key Points Question What is the association between the bitter taste receptor phenotype and outcomes after infection with SARS-CoV-2? Findings In this cohort study of 1935 adults, 266 tested positive for SARS-CoV-2, and those who experienced low intensity of bitter tastes or no bitter tastes (nontasters) were significantly more likely to test positive for SARS-CoV-2, to be hospitalized, and to be symptomatic for a longer duration. Conversely, those who experienced greater intensity of bitter tastes (supertasters) represented 5.6% of patients infected with SARS-CoV-2, suggesting enhanced innate immune protection. Meaning This study suggests that bitter taste receptor allelic variants are associated with innate immune fitness toward SARS-CoV-2 and can be used to correlate with clinical course and prognosis of COVID-19., Importance Bitter taste receptors (T2Rs) have been implicated in sinonasal innate immunity, and genetic variation conferred by allelic variants in T2R genes is associated with variation in upper respiratory tract pathogen susceptibility, symptoms, and outcomes. Bitter taste receptor phenotype appears to be associated with the clinical course and symptom duration of SARS-CoV-2 infection. Objective To evaluate the association between T2R phenotype and patient clinical course after infection with SARS-CoV-2. Design, Setting, and Participants A prospective cohort study was performed from July 1 through September 30, 2020, at a tertiary outpatient clinical practice and inpatient hospital in the United States among 1935 participants (patients and health care workers) with occupational exposure to SARS-CoV-2. Exposure Exposure to SARS-CoV-2. Main Outcomes and Measures Participants underwent T2R38 phenotype taste testing to determine whether they were supertasters (those who experienced greater intensity of bitter tastes), tasters, or nontasters (those who experienced low intensity of bitter tastes or no bitter tastes) and underwent evaluation for lack of infection with SARS-CoV-2 via polymerase chain reaction (PCR) testing and IgM and IgG testing. A group of participants was randomly selected for genotype analysis to correlate phenotype. Participants were followed up until confirmation of infection with SARS-CoV-2 via PCR testing. Phenotype of T2R38 was retested after infection with SARS-CoV-2. The results were compared with clinical course. Results A total of 1935 individuals (1101 women [56.9%]; mean [SD] age, 45.5 [13.9] years) participated in the study. Results of phenotype taste testing showed that 508 (26.3%) were supertasters, 917 (47.4%) were tasters, and 510 (26.4%) were nontasters. A total of 266 participants (13.7%) had positive PCR test results for SARS-CoV-2. Of these, 55 (20.7%) required hospitalization. Symptom duration among patients with positive results ranged from 0 to 48 days. Nontasters were significantly more likely than tasters and supertasters to test positive for SARS-CoV-2 (odds ratio, 10.1 [95% CI, 5.8-17.8]; P, This cohort study evaluates the association between bitter taste receptor phenotype and patient clinical course after infection with SARS-CoV-2.

Nanozerovalent iron (nZVI) is widely used for its ability to remove or degrade environmental contaminants. However, the effect of nZVI-pollutant complexes on organisms has not been tested. We demonstrate the ability of a sulfidized derivative of nZVI (FeSSi) to sorb cadmium (Cd) from aqueous media and alleviate Cd toxicity to a freshwater alga for 32 days. FeSSi particles removed over 80% of the aqueous Cd in the first hour and nearly the same concentration of free Cd remained unbound at the end of the experiment. We found that FeSSi particles with Cd sorbed onto them are an order of magnitude more toxic than FeSSi alone. Further, algal-produced organic material facilitates safer remediation of Cd by FeSSi by decreasing the toxicity of FeSSi itself. We developed a dynamic model to predict the maximum Cd concentration FeSSi can remediate without replacing Cd toxicity with its own. FeSSi can remediate four times as much Cd to phytoplankton populations when organic material is present compared to the absence of organic material. We demonstrate the effectiveness of FeSSi as an environmental remediator and the strength of our quantitative model of the mitigation of nanoparticle toxicity by algal-produced organic material.

Given that stakeholders often commit more than capital to a startup, they commonly stress how important it is for entrepreneurs to be “coachable.” To date, however, coachability has received little attention in entrepreneurship research. We address this gap by first establishing the entrepreneurial coachability construct and validating a measurement scale. Then, drawing on social exchange and signaling theories, we develop and test a novel framework in which coachability influences a potential investor’s willingness to invest. We find that entrepreneurial coachability functions as a viable signal in a pitch setting, but this impact is conditional on the investor’s prior coaching experience.

Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacotherapy for mood and anxiety disorders. The common mechanism of drugs in this class is antagonism of the serotonin transporter. Within the serotonin transporter gene SLC6A4, two polymorphic sites termed 5-HTTLPR and STin2 are proposed to have functional consequences and thus have been attractive candidates for pharmacogenetic studies of SSRI efficacy and tolerability. This review summarizes approximately 15 years of study of these polymorphisms as they relate to SSRI tolerability phenotypes. Four online databases (PubMed, Cochrane CENTRAL, PsycINFO, and PharmGKB) were searched for articles on polymorphisms of SLC6A4 including 5-HTTLPR and STin2 by using a systematic approach. Specific and general psychopharmacology terms, along with adverse effect and tolerability concepts, added to the search strategy. The Human Gene Mutation Database was checked for additional references. Forty studies met the inclusion criteria. While null and occasionally opposite associations are reported, the low expression 5-HTTLPR S allele is generally associated with greater adverse drug reaction burden during SSRI therapy. The most convincing evidence is in studies of antidepressant-induced mania and gastrointestinal adverse events. Studies of STin2 are sparse and have conflicting findings. In conclusion, the S allele of 5-HTTLPR may be predictive of increased adverse event burden, and this effect appears specific to certain classes of adverse events. Limitations and challenges in interpreting this body of evidence include assay errors, dissimilar grouping of genotypes, the role of ethnicity in associations, and study methodological differences. The clinical utility of serotonin transporter genotypes is not yet delineated but will ultimately depend on genotypic effects on both tolerability and efficacy of SSRIs.

Background: Total hip arthroplasty (THA) is now an increasingly common procedure for people sustaining acetabular fractures. The incidence of acetabular fractures among the elderly population is increasing, and contemporary treatment aims to avoid the risks of prolonged incumbency associated with poor bone stock for fixation or inability to comply with limited weightbearing in this patient group. The concept of acute hip arthroplasty as a treatment for acetabular fracture is, therefore, becoming more topical and relevant. Our systematic review investigates whether THAs for acetabular fractures should be performed acutely, with a short delay, or as a late procedure for posttraumatic osteoarthritis (PTOA) if it develops. Materials and Methods: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed when undertaking this systematic review. Detailed searches were performed on three different databases, using keywords, such as “acetabular fracture,” “acetabular trauma,” “total hip arthroplasty,” “hip arthroplasty,” and “hip prosthesis.” Studies from 1975 to September 2016 were included in the study. All studies included in the review were independently critically appraised by two of the authors. Results: Forty three studies were included in this review. Only two of them actually compared acute and delayed THAs for acetabular fractures with the rest focusing on one or the other. Results were comparable between acute and late THAs in terms of aseptic loosening, operative time, blood loss, Harris Hip Score, and ability to mobilize postoperatively without aid. Complication rates, however, were much higher in the acute group. Conclusion: Evidence based on this topic is scarce and therefore we have to be cautious about drawing a definitive conclusion. The findings of this systematic review do suggest, however, that acute THAs should be considered in elderly patients, where fixation is not possible, or when their health and ability to rehabilitate are poor. It should also be considered in patients where PTOA is very likely, or where there is already some preexisting degenerative osteoarthritis.

Recent collections of Ceratozamia from the Sierra Norte of Puebla, Mexico, point to a new undescribed species, which was previously subsumed under the concept of C. mexicana. Identification of this new species resulted from a review of three associated species: C. mexicana, C. tenuis, and C. delucana. Here we describe Ceratozamia totonacorum and provide information regarding its distribution and natural history. The Ceratozamia species from the Sierra Madre Oriental, Mexico, are circumscribed using morphological characters, including a detailed evaluation of reproductive structures such as the apex, position, color and shape of the ovulate strobilus.

Clostridium thermocellum rapidly deconstructs cellulose and ferments resulting hydrolysis products into ethanol and other products, and is thus a promising platform organism for the development of cellulosic biofuel production via consolidated bioprocessing. While recent metabolic engineering strategies have targeted eliminating canonical fermentation products (acetate, lactate, formate, and H2), C. thermocellum also secretes amino acids, which has limited ethanol yields in engineered strains to approximately 70% of the theoretical maximum. To investigate approaches to decrease amino acid secretion, we attempted to reduce ammonium assimilation by deleting the Type I glutamine synthetase (glnA) in an essentially wild type strain of C. thermocellum. Deletion of glnA reduced levels of secreted valine and total amino acids by 53% and 44% respectively, and increased ethanol yields by 53%. RNA-seq analysis revealed that genes encoding the RNF-complex were more highly expressed in ΔglnA and may have a role in improving NADH-availability for ethanol production. While a significant up-regulation of genes involved in nitrogen assimilation and urea uptake suggested that deletion of glnA induces a nitrogen starvation response, metabolomic analysis showed an increase in intracellular glutamine levels indicative of nitrogen-rich conditions. We propose that deletion of glnA causes deregulation of nitrogen metabolism, leading to overexpression of nitrogen metabolism genes and, in turn, elevated glutamine levels. Here we demonstrate that perturbation of nitrogen assimilation is a promising strategy to redirect flux from the production of nitrogenous compounds toward biofuels in C. thermocellum.

Alkyl phosphates in crude oils originate from their use as gellants used in some hydraulic fracturing processes or as additives used to improve physical properties of the oil for transportation. Alkyl phosphates are a potential issue for used oil re-refining and recycling operations because of their use as flame-retardants in, for example, aviation hydraulic fluids. The primary concern with alkyl phosphates in the refinery is their association with refinery fouling, including deposit formation and catalyst deactivation. A comprehensive two-dimensional gas chromatography method, with nitrogen phosphorus detection (GC × GC-NPD) and post-column Deans switching, was previously developed by our group for quantitative analysis of alkyl phosphates in petroleum samples. The original method employed an apolar/polar GC × GC column configuration and was shown to provide trace speciation of alkyl phosphates in distillate samples and some crude oils. However, when petroleum samples having a high concentration of heavy nitrogen-containing species were encountered, coelutions with alkyl phosphates ensued. Even in a phosphorus-optimized NPD configuration, the background signal from nitrogen-containing species masked the signals of some alkyl phosphates. Thus, a new column configuration using a polar/apolar GC × GC column set was developed. The results of this study are presented, showing the applicability of this method to the analysis of alkyl phosphates in petroleum samples with a high concentration of nitrogen-containing species. This method effectively separates the alkyl phosphates from nitrogen containing species with which they previously co-eluted. Additionally, it allows for trace speciation and quantification of alkyl phosphates in crude-oil with detection limits ranging from 0.001 to 0.02 μg phosphorus per mL.

A Cr-photocatalyzed [4 + 2] cycloaddition between dienes and electron-deficient alkenes is reported, accessed by up to three converging pathways to yield the “meta” adducts., A chromium-catalyzed, visible light-activated net [4 + 2] cycloaddition between dienes and electron-deficient alkenes is described. Gathered evidence, via control experiments, isolated intermediates, and measured redox potentials, points to several converging reaction pathways that afford the cyclohexene adducts, including a photochemical [2 + 2] cycloaddition/vinylcyclobutane rearrangement cascade and a substrate excitation/oxidation sequence to a radical cation intermediate. Notably, the accompanying mechanistic stipulations result in a process that yields regioisomeric compounds from those generated by traditional Diels–Alder cycloadditions.

Primary infection with the gastrointestinal nematode Heligmosomoides polygyrus bakeri is chronic in C57BL/6 (B6) mice whereas challenge infection is rapidly eliminated. F4/80-CD11b+Gr+ cells, presumed to be neutrophils, were reported to accumulate around encysting larvae in intestinal tissue during primary infection, but their exact identity and role remain unclear. We observed significant increases in F4/80-CD11bhiGr1hi cells in mesenteric lymph nodes (MLNs) and spleen after primary but not challenge infection; a high proportion of these cells expressed Ly6G and Ly6C. These cells, which phenotypically resemble myeloid-derived suppressor cells (MDSC), increased in lamina propria (LP) early during primary infection. Increased MDSC were associated with low numbers of alternatively activated macrophages (AAMO) in LP and CD4+GATA3+ T cells and AAMO in MLN and spleen. Purified CD11c-CD11b+Gr1+ cells from H. polygyrus bakeri-infected mice suppressed OVA-specific CD4+ T-cell proliferation via a nitric oxide-dependent mechanism and parasite-specific IL-4 secretion in vitro. Adoptive transfer of CD11c-CD11b+Gr1+ cells from mice with primary infection resulted in significantly higher adult worm burdens and increased egg production in naive B6 recipients infected with H. polygyrus bakeri. Altogether, these findings indicate that primary H. polygyrus bakeri infection induces a novel subset of MDSC that suppress CD4+ Th2 responses and promote chronic infection.

Trehalose-6-phosphate synthase OtsA from streptomycetes is unusual in that it uses GDP-glucose as the donor substrate rather than the more commonly used UDP-glucose. We now confirm that OtsA from Streptomyces venezuelae has such a preference for GDP-glucose and can utilize ADP-glucose to some extent too. A crystal structure of the enzyme shows that it shares twin Rossmann-like domains with the UDP-glucose-specific OtsA from Escherichia coli. However, it is structurally more similar to Streptomyces hygroscopicus VldE, a GDP-valienol-dependent pseudoglycosyltransferase enzyme. Comparison of the donor binding sites reveals that the amino acids associated with the binding of diphosphoribose are almost all identical in these three enzymes. By contrast, the amino acids associated with binding guanine in VldE (Asn, Thr, and Val) are similar in S. venezuelae OtsA (Asp, Ser, and Phe, respectively) but not conserved in E. coli OtsA (His, Leu, and Asp, respectively), providing a rationale for the purine base specificity of S. venezuelae OtsA. To establish which donor is used in vivo, we generated an otsA null mutant in S. venezuelae. The mutant had a cell density-dependent growth phenotype and accumulated galactose 1-phosphate, glucose 1-phosphate, and GDP-glucose when grown on galactose. To determine how the GDP-glucose is generated, we characterized three candidate GDP-glucose pyrophosphorylases. SVEN_3027 is a UDP-glucose pyrophosphorylase, SVEN_3972 is an unusual ITP-mannose pyrophosphorylase, and SVEN_2781 is a pyrophosphorylase that is capable of generating GDP-glucose as well as GDP-mannose. We have therefore established how S. venezuelae can make and utilize GDP-glucose in the biosynthesis of trehalose 6-phosphate. Fil: Asención Diez, Matías Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; Argentina Fil: Miah, Farzana. John Innes Institute; Reino Unido Fil: Stevenson, Clare E. M.. John Innes Institute; Reino Unido Fil: Lawson, David M.. John Innes Institute; Reino Unido Fil: Iglesias, Alberto Alvaro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; Argentina Fil: Bornemann, Stephen. John Innes Institute; Reino Unido

OBJECTIVES/GOALS: HIV-specific CD8+ T-cells play a critical role in partially controlling viral replication in infected-individuals, but ultimately fail to eliminate infection. Enhancing these T-cell responses through lymphocyte engineering approaches has the potential as a novel therapy capable of achieving durable control or eradication of infection. METHODS/STUDY POPULATION: IL-15 Superagonist (IL-15SA) potently supports the in vivo persistence and antiviral activity of adoptively transferred CD8+ T-cells. The Deep-PrimingTM technology platform, developed by Torque, allows for loading of immunomodulators onto the surface of T-cells via electrostatic ‘nanogels’, which slowly release to deliver sustained autocrine immune stimulation without the harmful effects of systemic exposure. Here, we investigate the impact of IL-15SA Deep-Priming on HIV-specific CD8+ T-cells in a humanized mouse model of HIV infection. Humanized mice were generated by engrafting NOD-scid-IL2Rgnull mice with memory CD4+ T-cells isolated from an ARV-suppressed HIV+ donor. An autologous HIV-specific Cytotoxic T-Lymphocyte (CTL) clone was isolated, and killing potential confirmed. Four weeks post humanization, mice were infected with HIV and received an infusion of unmodified HIV-Specific CTLs, or IL-15SA Deep-Primed HIV-specific CTLs (CTL-DP). T-cell numbers and plasma viral loads were quantified weekly by flow cytometry and qRT-PCR. RESULTS/ANTICIPATED RESULTS: Mice receiving unmodified CTLs trended toward reduced viral loads compared to the No Treatment condition, while mice receiving CTL-DP saw significant, 2-Log10 reductions in VL (p < 0.01). At 41 days post-infection 100% (5/5) of the No Treatment, 66.7% (4/6) of the CTL treatment, and 16.7% (1/6) of CTL-DP treatment mice had detectable viremia. IL-15SA Deep-Priming increased CTL expansion and persistence in peripheral blood which correlated with improved CD4+T-cell preservation. DISCUSSION/SIGNIFICANCE OF IMPACT: Here we demonstrate the first in vivo analysis of IL-15SA Deep-Priming of HIV-Specific CTLs. These data suggest that Deep-Priming of patient T-cells can enhance in vivo function and persistence, leading to improved viral suppression; a significant advancement in the field of HIV cure research. CONFLICT OF INTEREST DESCRIPTION: Austin Boesch, Thomas Andresen, and Douglas Jones are employees of Torque. Darrell Irvine is a co-founder of Torque and Chairman of Torque’s Scientific Advisory Board.

Reformatted magnetic resonance imaging scans of 27 normal wrists were examined in incremental degrees of rotation around the central axis of the radial shaft to 30° in both directions from true lateral. A line was superimposed on the outer border of the radial dorsal cortex and continued distally to the carpal region. Measurements were made from the superior pole of the lunate to this line. This distance did not change significantly with rotation. This allows a quick and accurate way of assessing distal radial fracture reduction from poorly taken lateral radiographs. In addition, the relevant landmarks are not obscured by implants or casts. Level of evidence: III, diagnostic study

Glycoside phosphorylases (GPs) with specificity for β‐(1 → 3)‐gluco‐oligosaccharides are potential candidate biocatalysts for oligosaccharide synthesis. GPs with this linkage specificity are found in two families thus far—glycoside hydrolase family 94 (GH94) and the recently discovered glycoside hydrolase family 149 (GH149). Previously, we reported a crystallographic study of a GH94 laminaribiose phosphorylase with specificity for disaccharides, providing insight into the enzyme's ability to recognize its' sugar substrate/product. In contrast to GH94, characterized GH149 enzymes were shown to have more flexible chain length specificity, with preference for substrate/product with higher degree of polymerization. In order to advance understanding of the specificity of GH149 enzymes, we herein solved X‐ray crystallographic structures of GH149 enzyme Pro_7066 in the absence of substrate and in complex with laminarihexaose (G6). The overall domain organization of Pro_7066 is very similar to that of GH94 family enzymes. However, two additional domains flanking its catalytic domain were found only in the GH149 enzyme. Unexpectedly, the G6 complex structure revealed an oligosaccharide surface binding site remote from the catalytic site, which, we suggest, may be associated with substrate targeting. As such, this study reports the first structure of a GH149 phosphorylase enzyme acting on β‐(1 → 3)‐gluco‐oligosaccharides and identifies structural elements that may be involved in defining the specificity of the GH149 enzymes.

The current study examined trajectories of maternal and paternal depression in the year following the birth of an infant sibling, and relations with family risk factors and firstborn children's internalizing and externalizing behavior problems. Latent class growth analysis was conducted on 231 families in a longitudinal investigation (prebirth and 1, 4, 8, and 12 months postbirth) and revealed four classes of families: both mother and father low in depressive symptoms (40.7%); mother high–father low (25.1%); father high–mother low (24.7%), and both mother and father high (9.5%). Families with both mothers and fathers high on depressive symptoms were higher on marital negativity, parenting stress, and children's internalizing and externalizing problems, and lower on marital positivity and parental efficacy than other classes. Children, parents, and marital relationships were more problematic in families with fathers higher on depressive symptoms than in families in which mothers were higher, indicating the significant role of paternal support for firstborn children undergoing the transition to siblinghood. Maternal and paternal depression covaried with an accumulation of family risks over time, no doubt increasing the likelihood of children's problematic adjustment after the birth of their infant sibling.

Specific interactions between proteins and DNA are essential to many biological processes. Yet it remains unclear how the diversification in DNA-binding specificity was brought about, and what were the mutational paths that led to changes in specificity. Using a pair of evolutionarily related DNA-binding proteins, each with a different DNA preference (ParB and Noc: both having roles in bacterial chromosome maintenance), we show that specificity is encoded by a set of four residues at the protein-DNA interface. Combining X-ray crystallography and deep mutational scanning of the interface, we suggest that permissive mutations must be introduced before specificity-switching mutations to reprogram specificity, and that mutational paths to a new specificity do not necessarily involve dual-specificity intermediates. Overall, our results provide insight into the possible evolutionary history of ParB and Noc, and in a broader context, might be useful in understanding the evolution of other classes of DNA-binding proteins.

BACKGROUND Delivery of topical pharmacotherapy to the paranasal sinuses remains integral to the management of chronic rhinosinusitis. The frontal sinus remains a difficult access site for irrigations, often limited by its position relative to the nostril and ethmoid sinus. In view of the previous demonstration of improved frontal sinus irrigation with Draf III vs Draf IIa, in this work we sought to evaluate topical access of Draf IIb relative to Draf IIa and Draf III modification of the frontal sinus outflow tract. METHODS Unfixed human cadaver heads were dissected using Draf IIa, Draf IIb, and Draf III frontal sinusotomies. Draf IIa, Draf IIb, and Draf III frontal sinusotomies were performed in progressive sequence on each cadaver head. Nasal irrigation fluid access to the frontal sinus was tested after each successive frontal sinus intervention. Irrigations were performed using Frankfort horizontal and vertex positioning. Blinded reviewers were then asked to evaluate nasal irrigation access based on an ordinal scale. RESULTS Eight cadaveric specimens (age, 78 ± 12.3 years; 62.5% female) were assessed. The greatest distribution scores were recorded by Draf III, then IIb, and then IIa (90.7% vs 81.3% vs 50.1%; p < 0.001). Similarly, the rate of lavage was greatest with Draf III (50% vs 12.5% vs 12.5%). Vertex positioning and increasing volume trended toward improved distribution but did not reach statistical significance. CONCLUSION Adequate delivery of topical therapy to the paranasal sinuses by nasal irrigation remains critical in the postoperative state. Although increasing the dimensions of the frontal recess improves nasal irrigation delivery, the Draf III procedure provides the optimal delivery of pharmacotherapy in those with frontal sinus disease.

Cycloaddition reactions generate chemical complexity in a single step. Here we report the crystal structures of three homologous plant-derived cyclases involved in the biosynthesis of iboga and aspidosperma alkaloids. These enzymes act on the same substrate, named angryline, to generate three distinct scaffolds. Mutational analysis reveals how these highly similar enzymes control regio- and stereo-selectivity.

The current study explored whether fathers and mothers from 195 two-parent U.S. families engaged in a form of activation parenting (i.e., sensitivity, cognitive stimulation, and moderate intrusiveness) with their secondborn, 12-month-old infants during a 15-min challenging teaching task, and to determine if this type of interaction was more common among fathers. Mean comparisons showed that fathers were lower on sensitivity, positive regard, and stimulation of development, and were more detached than mothers. Latent Profile Analyses revealed similar supportive, disengaged, and activation parenting profiles for fathers and mothers, with more fathers in the activation class. Chi-square analyses found significant associations across mothers and fathers; most infants (30%) had activation fathers and mothers, with 26% having supportive mothers and activation fathers, and 11.4% having two supportive parents. Parenting profiles were unrelated to attachment security. Results need to be replicated with children of different ages, with families from different backgrounds, and beyond the challenging teaching paradigm.

We exploit the nonlinearity arising from the spin-photon interaction in an InAs quantum dot to demonstrate phase shifts of scattered light pulses at the single-photon level. Photon phase shifts of close to 90 degrees are achieved using a charged quantum dot in a micropillar cavity. We also demonstrate a photon phase switch by using a spin-pumping mechanism through Raman transitions in an in-plane magnetic field. The experimental findings are supported by a theoretical model which explores the dynamics of the system. Our results demonstrate the potential of quantum dot-induced nonlinearities for quantum information processing.

Bacterial biofilms are ubiquitous in natural environments and play an important role in many clinical, industrial, and ecological settings. Although much is known about the transcriptional regulatory networks that control biofilm formation in model bacteria such as Bacillus subtilis, very little is known about the role of metabolism in this complex developmental process. To address this important knowledge gap, we performed a time-resolved analysis of the metabolic changes associated with bacterial biofilm development in B. subtilis by combining metabolomic, transcriptomic, and proteomic analyses. Here, we report a widespread and dynamic remodeling of metabolism affecting central carbon metabolism, primary biosynthetic pathways, fermentation pathways, and secondary metabolism. This report serves as a unique hypothesis-generating resource for future studies on bacterial biofilm physiology. Outside the biofilm research area, this work should also prove relevant to any investigators interested in microbial physiology and metabolism., Biofilms are structured communities of tightly associated cells that constitute the predominant state of bacterial growth in natural and human-made environments. Although the core genetic circuitry that controls biofilm formation in model bacteria such as Bacillus subtilis has been well characterized, little is known about the role that metabolism plays in this complex developmental process. Here, we performed a time-resolved analysis of the metabolic changes associated with pellicle biofilm formation and development in B. subtilis by combining metabolomic, transcriptomic, and proteomic analyses. We report surprisingly widespread and dynamic remodeling of metabolism affecting central carbon metabolism, primary biosynthetic pathways, fermentation pathways, and secondary metabolism. Most of these metabolic alterations were hitherto unrecognized as biofilm associated. For example, we observed increased activity of the tricarboxylic acid (TCA) cycle during early biofilm growth, a shift from fatty acid biosynthesis to fatty acid degradation, reorganization of iron metabolism and transport, and a switch from acetate to acetoin fermentation. Close agreement between metabolomic, transcriptomic, and proteomic measurements indicated that remodeling of metabolism during biofilm development was largely controlled at the transcriptional level. Our results also provide insights into the transcription factors and regulatory networks involved in this complex metabolic remodeling. Following upon these results, we demonstrated that acetoin production via acetolactate synthase is essential for robust biofilm growth and has the dual role of conserving redox balance and maintaining extracellular pH. This report represents a comprehensive systems-level investigation of the metabolic remodeling occurring during B. subtilis biofilm development that will serve as a useful road map for future studies on biofilm physiology.

The WHO Global Patient Safety Challenge: Medication Without Harm recognises medication-related harm (MRH) as a global public health issue. Increased life-expectancy coupled with multimorbidity and polypharmacy leads to an increased incidence of MRH, especially in older adults: at a cost of approximately £400 million to the National Health Service (NHS) in England. Harm from medicines has long been recognised by geriatricians, and strategies have been developed to mitigate harm. In general, these have focused on the challenges of polypharmacy and appropriateness of medicines, but impact on the quality of life, clinical and economic outcomes has been variable and often disappointing. The problem of MRH in older adults will continue to grow unless a new approach is adopted. Emerging evidence suggests that we need to take a broader approach as described in our conceptual model, where well-recognised physiological changes are incorporated, as well as other rarely considered psychosocial issues that influences MRH. Parallels may be drawn between this approach and the management of geriatric syndromes. We propose there must be a greater emphasis on MRH, and it, of itself, should be considered as a geriatric syndrome, to bring the spotlight onto the problem and to send a clear signal from geriatric experts that this is an important issue that needs to be addressed using a co-ordinated and tailored approach across health and social care boundaries. This requires a more proactive approach to monitor and review the medicines of older adults in response to their changing need.

Caldicellulosiruptor bescii is an extremely thermophilic, cellulolytic bacterium with a growth optimum at 78 °C and is the most thermophilic cellulose degrader known. It is an attractive target for biotechnological applications, but metabolic engineering will require an in-depth understanding of its primary pathways. A previous analysis of its genome uncovered evidence that C. bescii may have a completely uncharacterized aspect to its redox metabolism, involving a tungsten-containing oxidoreductase of unknown function. Herein, we purified and characterized this new member of the aldehyde ferredoxin oxidoreductase family of tungstoenzymes. We show that it is a heterodimeric glyceraldehyde-3-phosphate (GAP) ferredoxin oxidoreductase (GOR) present not only in all known Caldicellulosiruptor species, but also in 44 mostly anaerobic bacterial genera. GOR is phylogenetically distinct from the monomeric GAP-oxidizing enzyme found previously in several Archaea. We found that its large subunit (GOR-L) contains a single tungstopterin site and one iron-sulfur [4Fe-4S] cluster, that the small subunit (GOR-S) contains four [4Fe-4S] clusters, and that GOR uses ferredoxin as an electron acceptor. Deletion of either subunit resulted in a distinct growth phenotype on both C(5) and C(6) sugars, with an increased lag phase, but higher cell densities. Using metabolomics and kinetic analyses, we show that GOR functions in parallel with the conventional GAP dehydrogenase, providing an alternative ferredoxin-dependent glycolytic pathway. These two pathways likely facilitate the recycling of reduced redox carriers (NADH and ferredoxin) in response to environmental H(2) concentrations. This metabolic flexibility has important implications for the future engineering of this and related species.

Perturbative calculations of factorized physical quantities, such as moments of structure functions, suffer from renormalization- and factorization-scheme dependence. The application of the principle of minimal sensitivity to "optimize" the scheme choices is reconsidered, correcting deficiencies in the earlier literature. The proper scheme variables, RG equations, and invariants are identified. Earlier results of Nakkagawa and Niegawa are recovered, even though their starting point is, at best, unnecessarily complicated. In particular, the optimized coefficients of the coefficient function C are shown to vanish, so that C^opt=1. The resulting simplifications mean that the optimization procedure is as simple as that for purely-perturbative physical quantities., 19 pages, no figures

The Information-Processing Function of Conscious Intentions Richard A. Carlson (racarlson@psu.edu), Lisa M. Stevenson (lms152@psu.edu), Marios N. Avraamides (marios@psu.edu), and Daniel N. Cassenti (dnc112@psu.edu) Department of Psychology, Penn State University 613 Moore Building, University Park, PA 16802 USA We argue that conscious intentions are central to the cognitive control of activity, in contrast to the view that the experience of conscious control is an illusion (Wegner & Wheatley, 1999). We suggest that instantiating a goal to form a conscious intention serves the information-processing function of establishing a procedural frame of reference that organizes mental activity. Information that specifies the origin of this frame of reference simultaneously specifies the conscious agent, the “I” who performs the action. This cospecification hypothesis is part of a more general theory of consciousness (Carlson, 1997). We briefly describe this hypothesis and its theoretical basis, and consider several empirical predictions and results bearing on those predictions. Theory and Hypotheses The cospecification hypothesis suggests that the content of a conscious intention represents the self as achieving an outcome by performing an operation on an object. For example, a conscious intention to add two digits represents the self as performing a calculation on particular tokens of those digits. Activating this representation serves to initiate a procedure to which the digit tokens are assimilated, and to establish a subjective “point of view” from which the digits are considered. The representation of an outcome that satisfies a conscious intention will thus be structurally very similar to the representation of the intention. This description parallels the representation of goals in ACT-R (Anderson & Lebiere, 1998), in which operands and results complete slots in the goal representation. Our research has considered several implications of this hypothesis for the information-processing dynamics of goal- driven cognition. First, goal instantiation must precede effective consideration of objects to be processed (operands). Second, the availability of information specifying goals should constrain the temporal coordination of processes such as managing working memory and picking up information from the environment. Third, failures of coordination (e.g., placekeeping errors) should be reduced by activities or information that increase the spatial and temporal precision with which the acting self is specified. Fourth, the need to update the self’s spatial and temporal location and orientation should constrain the strategies available for organizing sequential activities; for example, activating an intention directed toward appropriate objects may depend on updating one’s perspective on the prior step. Fifth, the construction of explicitly retrievable episodic memories should be associated with goal instantiation because it involves “taking note” of the self as a spatial and temporal marker. Empirical Results We have examined each of these implications, using experimental paradigms that examine skilled performance of mental sequences in which the environmental availability of information is constrained. For example, in a number of studies participants solved cascaded, multiple-step arithmetic or spatial path problems in which the outcome of each step served as a starting point for the next step. These studies provide support for the first and second predictions outlined above. Under temporal constraints, individuals can effectively coordinate information pickup and cognitive processes – a process we call temporal tuning – only when information specifying upcoming goals is available, allowing those goals to be instantiated as intentions. In another series of studies, we examined the use of externalizing strategies such as pointing that serve to support temporal coordination. In these experiments, participants performed simple tasks such as counting under varying temporal and strategy constraints. The results suggest that externalizing strategies can serve both to enhance the individuation of objects to be processed (coordination between steps) and to reduce intention-outcome confusions (coordination within steps). We consider these and other results in relation to the hypotheses sketched above. Conclusions In general, these studies provide support for the predictions derived from the cospecification hypothesis. However, some predictions have been disconfirmed in ways that suggest further hypotheses about the constraints on explicit goal instantiation. For example, neither procedural nor explicit declarative knowledge of operator sequences allows the temporal tuning observed when operators are specified by displayed information. We consider the implications of these successes and failures for the general theory of consciousness described in Carlson (1997). References Anderson, J. R., & Lebiere, C. (1998). The atomic components of thought. Mahwah, NJ: Erlbaum. Carlson, R. A. (1997). Experienced Cognition. Mahwah, NJ: Erlbaum. Wegner, D. M., & Wheatley, T. (1999). Apparent mental causation: Sources of the experience of will. American Psychologist, 54, 480-492.

Depression and coronary artery disease (CAD) are leading causes of death and disability and commonly co-occur. Different antidepressant classes have similar efficacy for depressed patients with CAD, but cardiovascular implications are unclear. Selective serotonin reuptake inhibitors (SSRIs) and mirtazapine are first-line options for depressed patients with CAD. SSRIs, but not mirtazapine, have known antiplatelet effects. Whether this affects risk of bleeding and major adverse cardiac events (MACE) in patients requiring dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is unknown. The aim of this analysis is to examine the impact of SSRI treatment on the co-primary endpoints of composite MACE (death, myocardial infarction, or stroke) and composite bleeding events in patients treated with clopidogrel-based DAPT after PCI. We conducted a retrospective study with co-primary endpoints of bleeding and MACE within 1 year of PCI. Three groups were compared: SSRI patients, mirtazapine patients, and patients on neither agent. Mirtazapine acted as a comparator to control for depression, for which diagnosis coding was inadequate. Time-to-event analyses were performed with Kaplan–Meier estimators and adjusted analyses utilized Cox proportional hazards. There were 6874 (820 SSRI, 55 mirtazapine, 5999 neither) patients included. SSRI patients had lower MACE risk than mirtazapine patients (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.38–0.97, p = 0.036) but higher MACE risk than patients on neither agent (HR 1.21, 95% CI 1.02–1.43, p = 0.030) in adjusted analyses. No significant differences were associated with bleeding risk (SSRI vs. neither adjusted HR 1.07, 95% CI 0.93–1.24, p = 0.36). SSRI use was associated with a significant decrease in MACE rates compared with patients receiving mirtazapine. Bleeding risk was not affected by either antidepressant treatment. SSRIs may have cardioprotective benefits compared with mirtazapine.

This dataset includes 4,582 obsidian artefacts matched to their natural geological source from 45 archaeological sites in New Zealand (Aotearoa). It is a compilation of a number of independent projects conducted in the laboratories of the University of Auckland and University of Otago from 2011 to 2018 [1–13]. It combines previously published studies [3, 5–13], an MA thesis [1], a BA(Hons) dissertation [2], a site report [4], and other previously unpublished primary data. The dataset has high reuse potential for future non-destructive studies of artefacts and social network analyses. Funding statement: This database began as part of a project funded by Royal Society of New Zealand Marsden Grant (UOA1619) and the support of Te Pūnaha Matatini.