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In this study, the influence of an amino silane (3-(2-aminoethylamino)-propyldimethoxymethylsilane, AEAPS) on the interfacial structure and adhesion of butyl acrylate/methyl methacrylate copolymers (BAMMAs) to silica was investigated by sum frequency generation vibrational spectroscopy (SFG). Small amounts of methacrylic acid, MAA, were included in the BAMMA polymerizations to assess the impact of carboxylic acid functionality on the glass interface. SFG was used to probe the O-H and C═O groups of incorporated MAA, ester C═O groups of BAMMA, and CH groups from all species at the silica interfaces. The addition of AEAPS resulted in a significant change in the molecular structure of the polymer at the buried interface with silica due to specific interactions between the BAMMA polymers and silane. SFG results were consistent with the formation of ionic bonds between the primary and secondary amines of the AEAPS tail group and the MAA component of the polymer, as evidenced by the loss of the MAA O-H and C═O signals at the interface. It is extensively reported in the literature that methoxy head groups of an amino silane chemically bind to the silanols of glass, leaving the amine groups available to react with various chemical functionalities. Our results are consistent with this scenario and support an adhesion promotion mechanism of amino silane with various aspects: (1) the ionic bond formation between the tail amine group and acid functionality on BAMMA, (2) the chemical coupling between the silane head group and glass, (3) migration of more ester C═O groups to the interface with order, and (4) disordering or reduced levels of CH groups at the interface. These results are important for better understanding of the mechanisms and effect of amino silanes on the adhesion between acrylate polymers and glass substrates in a variety of applications.

Importance: Traditional approaches to practice guidelines frequently result in dissociation between strength of recommendation and quality of evidence.Objective: To construct a clinical guideline for pyogenic osteomyelitis management, with a new standard of evidence to resolve the gap between strength of recommendation and quality of evidence, through the use of a novel open access approach utilizing social media tools.Evidence Review: This consensus statement and systematic review study used a novel approach from the WikiGuidelines Group, an open access collaborative research project, to construct clinical guidelines for pyogenic osteomyelitis. In June 2021 and February 2022, authors recruited via social media conducted multiple PubMed literature searches, including all years and languages, regarding osteomyelitis management; criteria for article quality and inclusion were specified in the group's charter. The GRADE system for evaluating evidence was not used based on previously published concerns regarding the potential dissociation between strength of recommendation and quality of evidence. Instead, the charter required that clear recommendations be made only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were drafted to discuss pros and cons of care choices. Both clear recommendations and clinical reviews were planned with the intention to be regularly updated as new data become available.Findings: Sixty-three participants with diverse expertise from 8 countries developed the group's charter and its first guideline on pyogenic osteomyelitis. These participants included both nonacademic and academic physicians and pharmacists specializing in general internal medicine or hospital medicine, infectious diseases, orthopedic surgery, pharmacology, and medical microbiology. Of the 7 questions addressed in the guideline, 2 clear recommendations were offered for the use of oral antibiotic therapy and the duration of therapy. In addition, 5 clinical reviews were authored addressing diagnosis, approaches to osteomyelitis underlying a pressure ulcer, timing for the administration of empirical therapy, specific antimicrobial options (including empirical regimens, use of antimicrobials targeting resistant pathogens, the role of bone penetration, and the use of rifampin as adjunctive therapy), and the role of biomarkers and imaging to assess responses to therapy.Conclusions and Relevance: The WikiGuidelines approach offers a novel methodology for clinical guideline development that precludes recommendations based on low-quality data or opinion. The primary limitation is the need for more rigorous clinical investigations, enabling additional clear recommendations for clinical questions currently unresolved by high-quality data.

‘We have kicked the can down the road once again – but we are running out of road.’ – Rachel Kyte, Dean of Fletcher School at Tufts University. We, in our capacities as scientists, economists, governance and policy specialists, are shifting from warnings to guidance for action before there is no more ‘road.’ The science is clear and irrefutable; humanity is in advanced ecological overshoot. Our overexploitation of resources exceeds ecosystems’ capacity to provide them or to absorb our waste. Society has failed to meet clearly stated goals of the UN Framework Convention on Climate Change. Civilization faces an epochal crossroads, but with potentially much better, wiser outcomes if we act now. What are the concrete and transformative actions by which we can turn away from the abyss? In this paper we forcefully recommend priority actions and resource allocation to avert the worst of the climate and nature emergencies, two of the most pressing symptoms of overshoot, and lead society into a future of greater wellbeing and wisdom. Humanity has begun the social, economic, political and technological initiatives needed for this transformation. Now, massive upscaling and acceleration of these actions and collaborations are essential before irreversible tipping points are crossed in the coming decade. We still can overcome significant societal, political and economic barriers of our own making. Previously, we identified six core areas for urgent global action – energy, pollutants, nature, food systems, population stabilization and economic goals. Here we identify an indicative, systemic and time-limited framework for priority actions for policy, planning and management at multiple scales from household to global. We broadly follow the ‘Reduce-Remove-Repair’ approach to rapid action. To guide decision makers, planners, managers, and budgeters, we cite some of the many experiments, mechanisms and resources in order to facilitate rapid global adoption of effective solutions. Our biggest challenges are not technical, but social, economic, political and behavioral. To have hope of success, we must accelerate collaborative actions across scales, in different cultures and governance systems, while maintaining adequate social, economic and political stability. Effective and timely actions are still achievable on many, though not all fronts. Such change will mean the difference for billions of children and adults, hundreds of thousands of species, health of many ecosystems, and will determine our common future.

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The mining industry, which provides input to almost every product and service in the world, is a critical component of sustainable growth in mineral-rich countries and the economy at large. This report is intended to deliver an account of mining technologies, processes, and strategies that seek to incorporate environmental sustainability considerations and have the potential for local value creation and green growth. The analysis focuses on three areas--renewable energy, water management, and automation and transportation--that are considered to have the broadest impact on environmental sustainability and in-country value creation through economic linkages. A reference case study is presented for each of the four benchmark minerals: gold mining in Burkina Faso, iron ore in Australia, copper in Peru, and cement in India. The report is part of a series of background reports that inform the research on Building Resilience: A Green Growth Framework for Mobilizing Mining Investment.

The need for mining firms to rethink and retool their local value creation efforts, along with the growing complexity of climate policies, presents an opportunity for forward-thinking mining firms to seize a competitive advantage. As this report argues, firms that systematically tackle their climate responsibilities and adapt to climate realities through technical solutions that offer scalable economic value to host nations are best placed to contribute to sustainable growth in their countries of operation.

The mining industry, which provides input to almost every product and service in the world, is a critical element toward sustainable growth in mineral-rich countries and the economy at large. This report is intended to deliver an account of mining technologies, processes, and strategies that seek to incorporate environmental sustainability considerations and have the potential for local value creation and green growth. The analysis focuses on three areas--renewable energy, water management, and automation and transportation--that are considered to have the broadest impact on environmental sustainability and in-country value creation through economic linkages. A reference case study is presented for each of the four benchmark minerals: gold mining in Burkina Faso, iron ore in Australia, copper in Peru, and cement in India. The report is part of a series of background reports that inform the research on Building Resilience: A Green Growth Framework for Mobilizing Mining Investment.

Candida albicans is a diploid fungus and a predominant opportunistic human pathogen. Notably, C. albicans employs reversible chromosomal aneuploidies as a means of survival in adverse environments. We previously characterized transcription on the monosomic chromosome 5 (Ch5) that arises with adaptation to growth on the toxic sugar sorbose in the mutant Sor125(55). We now extend this analysis to the trisomic hybrid Ch4/7 within Sor125(55) and a diverse group of three mutants harboring a single Ch5. We find a similar pattern of transcriptional changes on either type of aneuploid chromosome within these mutants wherein expression of many genes follows chromosome ploidy, consistent with a direct mechanism to regulate genes important for adaptation to growth. In contrast, a significant number of genes are expressed at the disomic level, implying distinct mechanisms compensating for gene dose on monosomic or trisomic chromosomes consistent with maintaining cell homeostasis. Finally, we find evidence for an additional mechanism that elevates expression of genes on normal disomic Ch4 and Ch7 in mutants to levels commensurate with that found on the trisomic Ch4/7b in Sor125(55). Several of these genes are similarly differentially regulated among mutants, suggesting they play key functions in either maintaining aneuploidy or adaptation to growth conditions.

Background The major human fungal pathogen Candida albicans possesses a diploid genome, but responds to growth in challenging environments by employing chromosome aneuploidy as an adaptation mechanism. For example, we have shown that C. albicans adapts to growth on the toxic sugar l-sorbose by transitioning to a state in which one chromosome (chromosome 5, Ch5) becomes monosomic. Moreover, analysis showed that while expression of many genes on the monosomic Ch5 is altered in accordance with the chromosome ploidy, expression of a large fraction of genes is increased to the normal diploid level, presumably compensating for gene dose. Results In order to understand the mechanism of the apparent dosage compensation, we now report genome-wide ChIP-microarray assays for a sorbose-resistant strain harboring a monosomic Ch5. These data show a significant chromosome-wide elevation in histone H4 acetylation on the mCh5, but not on any other chromosome. Importantly, strains lacking subunits of the NuA4 H4 histone acetyltransferase complex, orthologous to a complex previously shown in Drosophila to be associated with a similar gene dosage compensation mechanism, did not show an increase in H4 acetylation. Moreover, loss of NuA4 subunits severely compromised the adaptation to growth on sorbose. Conclusions Our results are consistent with a model wherein chromosome-wide elevation of H4 acetylation mediated by the NuA4 complex plays a role in increasing gene expression in compensation for gene dose and adaption to growth in a toxic environment.

Background Identifying patients who may progress to a poor clinical outcome will encourage earlier appropriate therapeutic interventions. Brain edema may contribute to secondary injury in traumatic brain injury (TBI) and thus, may be a useful prognostic indicator. Objective We determined whether the presence of brain edema on the initial computed tomography (CT) scan of TBI patients would predict poor in-hospital outcome. Methods We performed a retrospective review of all trauma patients with nonpenetrating head trauma at a Level I Trauma Center. International Classification of Diseases, Ninth Revision codes indicated the presence of brain edema and we evaluated the validity of this pragmatic assessment quantitatively in a random subset of patients. In-hospital mortality was the primary outcome variable. Univariate analysis and logistic regression identified predictors of mortality in all TBI patients and those with mild TBI. Results Over 7200 patients were included in the study, including 6225 with mild TBI. Measurements of gray and white matter CT density verified radiological assessments of brain edema. Patients with documented brain edema had a mortality rate over 10 times that of the entire study population. With logistic regression accounting for Injury Severity Score, Glasgow Coma Scale score, other CT findings, and clinical variables, brain edema predicted an eightfold greater mortality rate in all patients (odds ratio 8.0, 95% confidence interval 4.6–14.0) and fivefold greater mortality rate for mild TBI patients (odds ratio 4.9, 95% confidence interval 2.0–11.7). Conclusions Brain edema is an independent prognostic variable across all categories of TBI severity. By alerting emergency physicians to patients with poor predicted clinical outcomes, this finding will drive better resource allocation, earlier intervention, and reduced patient mortality.

On Tuesday 27 April 1880, the Boston Evening Transcript published a lengthy obituary of John Pond Ordway, “a prominent citizen of Boston” who had been “identified in many important enterprises” in ...

Does inferential justification require the subject to be aware that her premises support her conclusion? Externalists tend to answer “no” and internalists tend to answer “yes”. In fact, internalists often hold the strong higher-level requirement that an argument justifies its conclusion only if the subject justifiably believes that her premises support her conclusion. I argue for a middle ground. Against most externalists, I argue that inferential justification requires that one be aware that her premises support her conclusion. Against many internalists, I argue that this higher-level awareness needn’t be doxastic or justified. I also argue that the required higher-level awareness needn’t be caused in some appropriate way, e.g. by a reliable or properly functioning faculty. I suspect that this weaker higher-level requirement is overlooked because, at first glance, it seems absurd to allow nondoxastic, unjustified, and unreliably-caused higher-level awareness to contribute to inferential justification. One of the central goals of this paper is to explain how such weak awareness can make an essential contribution to inferential justification.

The Neo-Moorean Deduction (I have a hand, so I am not a brain-in-a-vat) and the Zebra Deduction (the creature is a zebra, so it isn't a cleverly disguised mule) are notorious. Crispin Wright, Martin Davies, Fred Dretske, and Brian McLaughlin, among others, argue that these deductions are instances of transmission failure. That is, they argue that these deductions cannot transmit justification to their conclusions. This essay contends, however, that the notoriety of these deductions is undeserved. Its strategy is to clarify, attack, defend, and apply. The essay clarifies what transmission and transmission failure really are, thereby exposing two questionable but quotidian assumptions. It attacks existing views of transmission failure, especially those of Crispin Wright. It defends a permissive view of transmission failure, one holding that deductions of a certain kind fail to transmit only because of premise circularity. Finally, it applies this account to the Neo-Moorean and Zebra Deductions and shows that, given the essay's permissive view, these deductions transmit in an intuitively acceptable way—at least if either a certain type of circularity is benign or a certain view of perceptual justification is false.

During the last five years there has been considerable doubt over the age of the continental uppermost Permian Russian stages, the Kazanian and Tatarian. Traditionally they have been regarded as Late Permian but were re-dated as Middle Permian in the 2004 international time scale, despite fossil evidence that the Tatarian, at least, is Late Permian. These debated ages are tested by magnetostratigraphic study of five sections spanning the Permian Triassic Boundary (PTB) of the SE Urals in the Orenburg region of Russia. The Upper Permian and Lower Triassic of this region have a well documented vertebrate fauna whose evolution has a significant bearing on our understanding of the PTB mass extinction event. If the Tatarian is viewed as Mid Permian, then the Late Permian in Russia is marked by a 9–10 Ma stratigraphic gap. The palaeomagnetic data yield a distinct series of polarity zones that provide clear local and regional correlation and are readily tied to a recently compiled global magnetostratigraphic record. On the basis of this correlation the sampled sections span the upper Guadalupian to Induan stages without any obvious break, so confirming the traditional view that the Tatarian is Late Permian in age. Anomalies in the magnetic inclination are consistent with sediment compaction (inclination shallowing, a common phenomenon of red beds) but declination anomalies between these sites and elsewhere in Russia may suggest localised vertical axis rotation.

This chapter focuses on the criteria for designing amorphous solid dispersions (ASDs) with combinations of various surfactant-type molecules and polymers for stabilization of the supersaturated or high-energy form, and to improve the bioavailability of poorly soluble drugs. The successful formulation of an ASD requires the generation of basic physical properties of both the drug substance and the carrier agent. In the case of the polymer or surfactant utilized as the carrier for the ASD, physical properties to be considered include molecular weight, glass transition temperature (Tg), solubility in organic solvents, thermal stability, melt viscosity, and the ability to process the polymer by various methods. The ability to utilize these important active pharmaceutical ingredient (API) and polymer properties combined with the critical parameters for the process used for creating the amorphous solid dispersion can guide a formulator to create a stable ASD. Keywords: active pharmaceutical ingredient (API); amorphous solid dispersions (ASDs); drug substance; polymers; surfactants

We investigated the effects of dietary nitrate (NO3−) supplementation on the concentration of plasma nitrite ([NO2−]), oxygen uptake (V̇o2) kinetics, and exercise tolerance in normoxia (N) and hypoxia (H). In a double-blind, crossover study, 12 healthy subjects completed cycle exercise tests, twice in N (20.9% O2) and twice in H (13.1% O2). Subjects ingested either 140 ml/day of NO3−-rich beetroot juice (8.4 mmol NO3; BR) or NO3−-depleted beetroot juice (PL) for 3 days prior to moderate-intensity and severe-intensity exercise tests in H and N. Preexercise plasma [NO2−] was significantly elevated in H-BR and N-BR compared with H-PL ( P < 0.01) and N-PL ( P < 0.01). The rate of decline in plasma [NO2−] was greater during severe-intensity exercise in H-BR [−30 ± 22 nM/min, 95% confidence interval (CI); −44, −16] compared with H-PL (−7 ± 10 nM/min, 95% CI; −13, −1; P < 0.01) and in N-BR (−26 ± 19 nM/min, 95% CI; −38, −14) compared with N-PL (−1 ± 6 nM/min, 95% CI; −5, 2; P < 0.01). During moderate-intensity exercise, steady-state pulmonary V̇o2 was lower in H-BR (1.91 ± 0.28 l/min, 95% CI; 1.77, 2.13) compared with H-PL (2.05 ± 0.25 l/min, 95% CI; 1.93, 2.26; P = 0.02), and V̇o2 kinetics was faster in H-BR (τ: 24 ± 13 s, 95% CI; 15, 32) compared with H-PL (31 ± 11 s, 95% CI; 23, 38; P = 0.04). NO3− supplementation had no significant effect on V̇o2 kinetics during severe-intensity exercise in hypoxia, or during moderate-intensity or severe-intensity exercise in normoxia. Tolerance to severe-intensity exercise was improved by NO3− in hypoxia (H-PL: 197 ± 28; 95% CI; 173, 220 vs. H-BR: 214 ± 43 s, 95% CI; 177, 249; P = 0.04) but not normoxia. The metabolism of NO2− during exercise is altered by NO3− supplementation, exercise, and to a lesser extent, hypoxia. In hypoxia, NO3− supplementation enhances V̇o2 kinetics during moderate-intensity exercise and improves severe-intensity exercise tolerance. These findings may have important implications for individuals exercising at altitude.

The American research university system is largely thought of by policymakers in terms of its contribution to basic research. The direct contribution of universities to technical advance in industry has largely been overlooked. The policy implications of this misguided perspective have been profound: universities have undermined efforts to support applied research initiatives and at the same time their funding quests have led to a rich mix of applied research despite the system. Also industry has bemoaned the university community's lack of interest in industrially useful R&D. The opportunity cost of not recognizing that the American research university community is a key element of America's de facto technology policy has been huge. Copyright , Beech Tree Publishing.

The Kamchia Depression is the easternmost onshore part of the Balkan Foredeep in Bulgaria (Figure 1). It has a long history of petroleum exploration and production numerous wells drilled, often before seismic. There has been limited gas production to date, but there have been numerous shows of gas and gas condensate from a range of late Mesozoic to Oligocene reservoirs, in some cases with high recorded flow rates. Exploration plays exist in the (i) allochthonous and para-autochthonus Balkan Thrust belt; (ii) autochthonous Mesozoic and early Palaeogene normal fault block highs in the foreland (analogous to the offshore Galata Field, Currie et al., (2010)), and (iii) the syn- to early postorogenic fore-Balkan trough (the Kamchia Basin) The focus of this study are thick (up to 1100m) Palaeogene turbidites deposited prior to, during and after the emplacement of the Balkan thrust sheets. Legacy well data shows numerous thick and porous sandstone units, many of which flowed gas but were not developed or were drilled prior to seismic acquisition and were not drilled in optimal positions. The distribution of reservoir sands has been enigmatic, with rapid changes in facies and thickness presenting a major risk in ongoing exploration. The key exploration challenges in this region have been understanding and predicting (i) the rapid changes in facies, sand presence and reservoir quality and (ii) charge and seal effectiveness for individual sands intervals.

Background Hippocampal slices swell and release taurine during oxidative stress. The influence of cellular signalling pathways on this process is unclear. Glutamate signalling can facilitate volume regulation in other CNS preparations. Therefore, we hypothesize activation of taurine release by oxidative stress results from tissue swelling and is coupled to activation of glutamate receptors. Methods Rat hippocampi were incubated at room temperature for 2 hr in artificial cerebrospinal fluid (aCSF) equilibrated with 95% O2 plus 5% CO2. For some slices, 1 mM taurine was added to the aCSF to maintain normal tissue taurine content. Slices then were perfused with aCSF at 35° C and baseline data recorded before 2 mM H2O2 was added. For some studies, mannitol or inhibitors of glutamate receptors or the volume-regulated anion channel (VRAC) were added before and during H2O2 treatment. The intensity of light transmitted through the slice (the intrinsic optical signal, IOS) was determined at 1-min intervals. Samples of perfusate were collected at 2-min intervals and amino acid contents determined by HPLC. Data were analyzed by repeated measures ANOVA and post hoc Dunnett’s test with significance indicated for p Results IOS of slices prepared without taurine treatment increased significantly by 3.3±1.3% (mean±SEM) during oxidative stress. Little taurine was detected in the perfusate of these slices and the rate of taurine efflux did not change during H2O2 exposure. The α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate antagonist, 25 µM CNQX, but not the N-methyl-D-aspartate (NMDA) receptor antagonist, 10 µM MK-801, inhibited the increase in IOS during H2O2 treatment. Taurine-treated slices exposed to H2O2 showed no change in IOS; however, taurine efflux increased by 335±178%. When these slices were perfused with hypertonic aCSF (350 mOsm) or exposed to the VRAC inhibitor, 20 µM DCPIB, no increase in the taurine efflux rate was observed during H2O2 exposure. Taurine-treated slices perfused with 10 µM MK-801 during H2O2 exposure showed a 4.6±1.9% increase in IOS but no increase in the taurine efflux rate. Conclusions Taurine efflux via VRAC is critical for volume regulation of hippocampal slices exposed to oxidative stress. This increased taurine efflux does not result from direct activation of the taurine release pathway by H2O2. NMDA receptor activation plays an important role in taurine release during oxidative stress.

Bromodeoxyuridine (BrdU) was administered to 128 newly diagnosed patients with standard risk acute myelocytic leukaemia (AML) for cell cycle measurements. Labelling indices (LI) were obtained from both the bone marrow aspirate (BMasp) and biopsies (bx) and durations of S-phase (Ts) and total cell cycle time (Tc) were measured by double-labelling the S-phase cells in vitro with tritiated thymidine. Median LI BMasp was 8% and from BMbx was 25%. The median Ts was 12 h (range 3.1-35 h) and Tc was 48 h (range 11.5-211 h). All patients received induction therapy with a combination of cytosine arabinoside and an anthracycline. Outcome of therapy or FAB type were not related to cell cycle characteristics. Patients with above median LI BMasp, however, had longer remission durations (P = 0.03) as did patients with above median Ts (P = 0.03) and Tc (P = 0.03). Upon longer follow-ups, even some of the patients with slowly cycling myeloblasts have relapsed (log rank P = 0.453 and 0.203 for Ts and Tc respectively). We conclude that patients with rapidly cycling cells tend to relapse faster; however, slowly cycling nature of myeloblasts is not associated with curability.

OX40 agonists have shown to enhance anti-tumor immunity in several mouse tumor models with similar efficacy to PD-1 and CTLA-4 blockade. We wanted to compare these T cell immune enhancing strategies in subcutaneous vaccine models to understand the role that each of these Abs might have in immune priming. We used both the OVA-specific CD4 and CD8 TCR transgenic adoptive transfer models, D011.10 and OT1, to determine the effect these antibodies have upon vaccination with ovalbumin (OVA). Mice were immunized with whole OVA protein in the absence of adjuvant (soluble OVA). The Abs were delivered on the day of immunization and one day later. Peripheral blood and spleens were analyzed at several time points after immunization. We found that the OX40 agonist in both T cell models enhanced the % and numbers of Ag-specific T cells to a greater extent then either CTLA-4 or PD-1 blockade. This was true both early after activation (4 days) as well as survival of T cells 28 days following immunization in both models. Based on this evidence we hypothesize that OX40 agonists may be more important for immune cell priming to tumor Ags and that PD-1 and CTLA-4 blockade may play a role in decreasing T cell tolerance within the tumor microenvironment. Hence these immune activating pathways most likely have non-overlapping pathways to activate T cells and we now have compelling in vivo evidence that combining OX40 agonists with checkpoint inhibitors have synergistic effects in mouse tumor models.