Search

We measured the complex conductivity of single crystals of Eu2CuO4 from 3 to 15 GHz and observed collective transport with a sample-independent spectral weight. An unusual activated temperature dependence for the spectral weight, and anomalous temperature dependence of the Eu Mossbauer line, indicate magnetic effects well above the Néel temperature. The collective transport is similar to that observed in (TMTSF)2PF6 where TMSF denotes tetramethyltetrathiofulvalene and where charged, massive solitons are the suspected source of the transport. © 1988 The American Physical Society.

This study compares the trends in AIDS case reports in Southern states and in other regions and estimates the factors associated with the trends. Data from the HIV/AIDS Surveillance Reports 1999 and 2004 of the Centers for Disease Control and Prevention were used to calculate the proportion of the total cumulative cases (1981-2004) that occurred in the five most recent years (2000-2004). A linear regression model was fitted to estimate the factors associated with the highest recent growth rate for AIDS cases by state. Results revealed that Southern states (including the District of Columbia) are more likely to have a disproportionate proportion of total AIDS cases reported within the past five years (25.5% in 16 states and the District) compared to the rest of the U.S. (mean = 19.3% in 34 states and Puerto Rico and the U.S. Virgin Islands; p < 0.001). Being a southern state (4.3% higher in proportion; 95% CI, 1.3%-7.3%) and higher representation of black race (0.1%, 95% CI, 0.02%-0.2%) were factor independently associated with higher recent growth rate for a state. AIDS case rates suggest recent worrisome trends in the South. Those states and territories that are in the South and that have higher proportions of African-Americans have a higher proportion of recent AIDS case reports than elsewhere, suggesting the need for a special geographic focus to encourage prevention, HIV testing, and access to care. [ABSTRACT FROM AUTHOR]

Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) to predict ligands from virtual libraries yielded first-in-class, drug-like ligands for 7 of the 16 WDR domains screened, thus demonstrating the broader ligandability of WDRs. This study establishes a template for evaluation of protein family wide ligandability and provides an extensive resource of WDR protein biochemical and chemical tools, knowledge, and protocols to discover potential therapeutics for this highly disease-relevant, but underexplored target class.

Purpose: To assess vitamin D, folate, vitamin B 12 , and iron status in Old Order Anabaptist (OOA) pregnant/postpartum women. Methods: Blood was analyzed for plasma 25 hydroxy vitamin D (25(OH)D), red blood cell (RBC) folate, serum vitamin B 12 , and iron status indicators. Dietary intakes (food and supplements) from 3-day estimated records were compared to Dietary Reference Intakes and Canada's Food Guide (2007). Results: Fifty women participated in this descriptive cross-sectional study. Concentrations of 25(OH)D were low (<50 nmol/L for 20% and < 75 nmol/L for 63%); 42% had total vitamin D intakes < estimated average requirement (EAR). All women had RBC folate above the 1360 mmol/L cut-off. Nineteen percent had folate intakes upper limit. One woman had low serum vitamin B 12 (<148 pmol/L); serum vitamin B 12 was high (>652 pmol/L) for 24%. None had vitamin B 12 intakes 12 . These findings provide guidance to ensure appropriate dietary and supplement intakes in this potentially vulnerable and rarely studied population.

Ricin is one of the most toxic substances known and a type B biothreat agent. Shiga toxins (Stxs) produced by E. coli (STEC) and Shigella dysenteriae are foodborne pathogens. There is no effective therapy against ricin or STEC and there is an urgent need for inhibitors. Ricin toxin A subunit (RTA) and A1 subunit of Stx2a (Stx2A1) bind to the C-terminal domain (CTD) of the ribosomal P-stalk proteins to depurinate the sarcin/ricin loop. Modulation of toxin-ribosome interactions has not been explored as a strategy for inhibition. Therefore, development of assays that detect inhibitors targeting toxin-ribosome interactions remains a critical need. Here we describe a fluorescence anisotropy (FA)-based competitive binding assay using a BODIPY-TMR labeled 11-mer peptide (P11) derived from the P-stalk CTD to measure the binding affinity of peptides ranging from 3 to 11 amino acids for the P-stalk pocket of RTA and Stx2A1. Comparison of the affinity with the surface plasmon resonance (SPR) assay indicated that although the rank order was the same by both methods, the FA assay could differentiate better between peptides that show nonspecific interactions by SPR. The FA assay detects only interactions that compete with the labeled P11 and can validate inhibitor specificity and mechanism of action., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Shiga toxins are the main virulence factors of Shiga toxin producing E. coli (STEC) and S. dysenteriae . There is no effective therapy to counter the disease caused by these toxins. The A1 subunits of Shiga toxins bind the C-termini of ribosomal P-stalk proteins to depurinate the sarcin/ricin loop. The ribosome binding site of Shiga toxin 2 has not been targeted by small molecules. We screened a fragment library against the A1 subunit of Shiga toxin 2 (Stx2A1) and identified a fragment, BTB13086 , which bound at the ribosome binding site and mimicked the binding mode of the P-stalk proteins. We synthesized analogs of BTB13086 and identified a series of molecules with similar affinity and inhibitory activity. These are the first compounds that bind at the ribosome binding site of Stx2A1 and inhibit activity. These compounds hold great promise for further inhibitor development against STEC infection.

Genomic screened homeobox 1 (Gsx1 or Gsh1) is a neurogenic transcription factor required for the generation of excitatory and inhibitory interneurons during spinal cord development. In the adult, lentivirus (LV) mediated Gsx1 expression promotes neural regeneration and functional locomotor recovery in a mouse model of lateral hemisection spinal cord injury (SCI). The LV delivery method is clinically unsafe due to insertional mutations to the host DNA. In addition, the most common clinical case of SCI is contusion/compression. In this study, we identify that adeno-associated virus serotype 6 (AAV6) preferentially infects neural stem/progenitor cells (NSPCs) in the injured spinal cord. Using a rat model of contusion SCI, we demonstrate that AAV6 mediated Gsx1 expression promotes neurogenesis, increases the number of neuroblasts/immature neurons, restores excitatory/inhibitory neuron balance and serotonergic neuronal activity through the lesion core, and promotes locomotor functional recovery. Our findings support that AAV6 preferentially targets NSPCs for gene delivery and confirmed Gsx1 efficacy in clinically relevant rat model of contusion SCI., Competing Interests: Declaration of competing interest L.C. is listed as a co-inventor in the patent application related to this work. L.C. is a founder of NeuroNovus Therapeutics Inc. and a member of the scientific advisory board. S.G. was the CEO of NeuroNovus Therapeutics Inc. The remaining authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

There is paucity of data assessing levels of food/beverage waste in long-term care (LTC) facilities, especially in Ontario. Observations in the Veteran's Centre (VC) at Sunnybrook Health Sciences Centre (Sunnybrook) indicated food/beverage waste may be high, potentially impacting sustainability efforts within our institution. Before proceeding with waste reduction efforts, we conducted a comprehensive 3-day waste-audit of food/beverage items provided to VC residents with the goal of understanding the extent of food/beverage waste at VC, items wasted, and any other factors that may inform future changes. Our results indicate that 28% of items served to residents were wasted. Lunch was the meal with greatest waste at 31% and waste of solid items was 12% higher than that of liquids. We observed a large variability in waste between residents and within each resident, with 15% of residents wasting >50% of items provided. This study provides a deeper insight into the magnitude of food/beverage waste in a LTC population and highlights the importance of considering individualized strategies to address waste to avoid negative impact on residents.

Metastatic breast cancer remains a significant source of mortality amongst breast cancer patients and is generally considered incurable in part due to the difficulty in detection of early micro-metastases. The pre-metastatic niche (PMN) is a tissue microenvironment that has undergone changes to support the colonization and growth of circulating tumor cells, a key component of which is the myeloid-derived suppressor cell (MDSC). Therefore, the MDSC has been identified as a potential biomarker for PMN formation, the detection of which would enable clinicians to proactively treat metastases. However, there is currently no technology capable of the in situ detection of MDSCs available in the clinic. Here, we propose the use of shortwave infrared-emitting nanoprobes for the tracking of MDSCs and identification of the PMN. Our rare-earth albumin nanocomposites (ReANCs) are engineered to bind the Gr-1 surface marker of murine MDSCs. When delivered intravenously in murine models of breast cancer with high rates of metastasis, the targeted ReANCs demonstrated an increase in localization to the lungs in comparison to control ReANCs. However, no difference was seen in the model with slower rates of metastasis. This highlights the potential utility of MDSC-targeted nanoprobes to assess PMN development and prognosticate disease progression.

Ricin, a category-B agent for bioterrorism, and Shiga toxins (Stxs), which cause food poisoning bind to the ribosomal P-stalk to depurinate the sarcin/ricin loop. No effective therapy exists for ricin or Stx intoxication. Ribosome binding sites of the toxins have not been targeted by small molecules. We previously identified CC10501, which inhibits toxin activity by binding the P-stalk pocket of ricin toxin A subunit (RTA) remote from the catalytic site. Here, we developed a fluorescence polarization assay and identified a new class of compounds, which bind P-stalk pocket of RTA with higher affinity and inhibit catalytic activity with submicromolar potency. A lead compound, RU-NT-206, bound P-stalk pocket of RTA with similar affinity as a five-fold larger P-stalk peptide and protected cells against ricin and Stx2 holotoxins for the first time. These results validate the P-stalk binding site of RTA as a critical target for allosteric inhibition of the active site., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nilgun Tumer reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Checkpoint immunotherapy has made great strides in the treatment of solid tumors, but many patients do not respond to immune checkpoint inhibitors. Identification of tumor-infiltrating cytotoxic T cells (CTLs) has the potential to stratify patients and monitor immunotherapy responses. In this study, the design of cluster of differentiation (CD8 + ) T cell-targeted nanoprobes that emit shortwave infrared (SWIR) light in the second tissue-transparent window for noninvasive, real-time imaging of CTLs in murine models of breast cancer is presented. SWIR-emitting rare-earth nanoparticles encapsulated in human serum albumin are conjugated with anti-CD8α to target CTLs with high specificity. CTL targeting is validated in vitro through binding of nanoprobes to primary mouse CTLs. The potential for the use of SWIR fluorescence intensity to determine CTL presence is validated in two syngeneic mammary fat pad tumor models, EMT6 and 4T1, which differ in immune infiltration. SWIR imaging using CD8-targeted nanoprobes successfully identifies the presence of CTLs in the more immunogenic EMT6 model, while imaging confirms the lack of substantial immune infiltration in the nonimmunogenic 4T1 model. In this work, the opportunity for SWIR imaging using CD8-targeted nanoprobes to assess CTL infiltration in tumors for the stratification and monitoring of responders to checkpoint immunotherapy is highlighted., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Advanced NanoBiomed Research published by Wiley‐VCH GmbH.)

Social network position in non-human primates has far-reaching fitness consequences. Critically, social networks are both heterogeneous and dynamic, meaning an individual's current network position is likely to change due to both intrinsic and extrinsic factors. However, our understanding of the drivers of changes in social network position is largely confined to opportunistic studies. Experimental research on the consequences of in situ, controlled network perturbations is limited. Here we conducted a food-based experiment in rhesus macaques to assess whether allowing an individual the ability to provide high-quality food to her group changed her social behavioural relationships. We considered both her social network position across five behavioural networks, as well as her dominance and kin interactions. We found that gaining control over a preferential food resource had far-reaching social consequences. There was an increase in both submission and aggression centrality and changes in the socio-demographic characteristics of her agonistic interaction partners. Further, we found that her grooming balance shifted in her favour as she received more grooming than she gave. Together, these results provide a novel, preliminary insight into how in situ , experimental manipulations can modify social network position and point to broader network-level shifts in both social capital and social power., Competing Interests: We declare we have no competing interests., (© 2024 The Authors.)

Background: Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aβ) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (fAβ) burden, microglial modulation, and neuroprotection., Methods: We designed a nanotechnology approach to regulate the SR-mediated intracellular fAβ trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM-NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM-NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines., Results: AM-NPs interrupted Aβ fibrilization, attenuated fAβ microglial internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM-NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ., Conclusions: The AM-NP nanotechnology presents a multifactorial strategy to target pathological Aβ aggregation and arrest the fAβ-mediated pathological progression in microglia and neurons., (© 2024. The Author(s).)

The use of microfluidic devices in biomedicine is growing rapidly in applications such as organs-on-chip and separations. Polydimethylsiloxane (PDMS) is the most popular material for microfluidics due to its ability to replicate features down to the nanoscale, flexibility, gas permeability, and low cost. However, the inherent hydrophobicity of PDMS leads to the adsorption of macromolecules and small molecules on device surfaces. This curtails its use in "organs-on-chip" and other applications. Current technologies to improve PDMS surface hydrophilicity and fouling resistance involve added processing steps or do not create surfaces that remain hydrophilic for long periods. This work describes a novel, simple, fast, and scalable method for improving surface hydrophilicity and preventing the nonspecific adsorption of proteins and small molecules on PDMS through the use of a surface-segregating zwitterionic copolymer as an additive that is blended in during manufacture. These highly branched copolymers spontaneously segregate to surfaces and rearrange in contact with aqueous solutions to resist nonspecific adsorption. We report that mixing a minute amount (0.025 wt%) of the zwitterionic copolymer in PDMS considerably reduces hydrophobicity and nonspecific adsorption of proteins (albumin and lysozyme) and small molecules (vitamin B12 and reactive red). PDMS blended with these zwitterionic copolymers retains its mechanical and physical properties for at least six months. Moreover, this approach is fully compatible with existing PDMS device manufacture protocols without additional processing steps and thus provides a low-cost and user-friendly approach to fabricating reliable biomicrofluidics.

Selectivity with respect to chloride ( K PFAS ∕ C ) was determined for nine drinking water relevant perfluoroalkyl and polyfluoroalkyl substances (PFAS): perfluoro-2-propoxypropanoic acid (GenX), five perfluoroalkyl carboxylic acids (PFCAs), and three perfluoroalkyl sulfonic acids (PFSAs). Three single-use strong base anion exchange gel resins were investigated, targeting drinking water relevant equilibrium PFAS liquid concentrations (≤500 ng/L). Except for the longest carbon chain PFCA (perfluorodecanoic acid) and PFSA (perfluorooctanesulfonic acid) studied, PFAS followed traditional ion exchange theory (law of mass action), including increasing equilibrium PFAS liquid concentrations with increasing equilibrium chloride liquid concentrations. Overall, K PFAS ∕ C values were (i) similar among resins for a given PFAS, (ii) 1-5 orders of magnitude greater than the selectivity of inorganic anions (e.g., nitrate) previously studied, (iii) 2 orders of magnitude greater for the same carbon chain length PFSA versus PFCA, (iv) found to proportionally increase with carbon chain length for both PFSAs and PFCAs, and (v) similar for GenX and perfluorohexanoic acid (six-carbon PFCA). A multisolute competition experiment demonstrated binary isotherm-determined K PFAS ∕ C values could be applied to simulate a multisolute system, extending work previously done with only inorganic anions to PFAS. Ultimately, estimated K PFAS ∕ C values allow future extension and validation of an open-source anion exchange column model to PFAS.

Background: Moral distress (MD) refers to psychological unease when healthcare professionals identify morally correct actions to take but are constrained in their ability to take those actions., Methods: This study evaluated the relationship between out-of-hours decisions and MD among 40 Foundation Year 2 (FY2) doctors. They were asked to choose the 'expected' and the 'right' management options for five out-of-hours scenarios and complete an adapted Measure of Moral Distress for Health Professionals (MMD-HP) questionnaire., Results: 28/40 (70%) reported discordance between 'expected' and 'right' options more frequently than concordance. The mean total MMD-HP score was low: 64.9 ( SD  = 26.9), range 13-143, maximum 288. The association between decision-making discordance and MMD-HP score was weak., Conclusion: Out-of-hours decisions by FY2 doctors were characterised by doing what is 'expected' rather than what is perceived to be 'right'. Providing guidance regarding decision-making in deteriorating patients is needed for patient safety and staff well-being., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Purpose: To examine the level of agreement between a patient-completed food frequency questionnaire (FFQ) and assessment of usual intake by a registered dietitian (RD) to score adherence to a Mediterranean diet (MedD) in patients with inflammatory bowel disease (IBD). Methods: Patients with IBD completed a short FFQ and were subsequently interviewed by an RD. A 12-item MedD score (MDS), adapted from the Mediterranean Diet Adherence Screener (MEDAS), was calculated from the FFQ and RD assessments. To determine agreement between individual items, Cohen's kappa coefficients were calculated. Absolute agreement between assessment methods was quantified using a one-way random intra-class correlation coefficient for a single measure. Results: Forty-six patients with IBD participated. The mean FFQ-MDS was 4.59 (standard deviation [SD] = 1.65), and mean RD-MDS was 4.83 (SD = 1.53). Kappa coefficients for individual MEDAS items ranged from 0.41 to 0.78 ( p  < 0.01) between the FFQ- and RD-MDS. Most items demonstrated moderate to substantial agreement. The intra-class correlation coefficient for absolute agreement between the summed FFQ-MDS and RD-MDS was 0.71 (95% confidence interval: 0.52-0.83, p  < 0.001), indicating moderate reliability. Conclusions: This patient-completed FFQ may be a promising tool in clinical practice and research and would benefit from additional evaluation to validate its use in patients with IBD.

Background: Many perform resistance training (RT) to increase muscle mass and strength. Energy surpluses are advised to support such gains; however, if too large, could cause unnecessary fat gain. We randomized 21 trained lifters performing RT 3 d/wk for eight weeks into maintenance energy (MAIN), moderate (5% [MOD]), and high (15% [HIGH]) energy surplus groups to determine if skinfold thicknesses (ST), squat and bench one-repetition maximum (1-RM), or biceps brachii, triceps brachii, or quadriceps muscle thicknesses (MT) differed by group. COVID-19 reduced our sample, leaving 17 completers. Thus, in addition to Bayesian ANCOVA comparisons, we analyzed changes in body mass (BM) with ST, 1-RM, and MT changes via regression. We reported Bayes factors (BF 10 ) indicating odds ratios of the relative likelihood of hypotheses (e.g., BF 10  = 2 indicates the hypothesis is twice as likely as another) and coefficients of determination (R 2 ) for regressions., Results: ANCOVAs provided no evidence supporting the group model for MT or squat 1-RM. However, moderate (BF 10  = 9.9) and strong evidence (BF 10  = 14.5) indicated HIGH increased bench 1-RM more than MOD and MAIN, respectively. Further, there was moderate evidence (BF 10  = 4.2) HIGH increased ST more than MAIN and weak evidence (BF 10  = 2.4) MOD increased ST more than MAIN. Regression provided strong evidence that BM change predicts ST change (BF 10  = 14.3, R 2  = 0.49) and weak evidence predicting biceps brachii MT change (BF 10  = 1.4, R 2  = 0.24)., Conclusions: While some group-based differences were found, our larger N regression provides the most generalizable evidence. Therefore, we conclude faster rates of BM gain (and by proxy larger surpluses) primarily increase rates of fat gain rather than augmenting 1-RM or MT. However, biceps brachii, the muscle which received the greatest stimulus in this study, may have been positively impacted by greater BM gain, albeit slightly. Our findings are limited to the confines of this study, where a group of lifters with mixed training experience performed moderate volumes 3 d/wk for 8 weeks. Thus, future work is needed to evaluate the relationship between BM gains, increases in ST and RT adaptations in other contexts., (© 2023. The Author(s).)

Plasmepsin X (PMX) has been identified as a multistage antimalarial target. PMX is a malarial aspartyl protease essential for merozoite egress from infected red blood cells and invasion of the host erythrocytes. Previously, we reported the identification of PMX inhibitors by structure-based optimization of a cyclic guanidine core. Preclinical assessment of UCB7362 , which displayed both in vitro and in vivo antimalarial activity, revealed a suboptimal dose paradigm (once daily dosing of 50 mg for 7 days for treatment of uncomplicated malaria) relative to current standard of care (three-dose regime). We report here the efforts toward extending the half-life ( t 1/2 ) by reducing metabolic clearance and increasing volume of distribution ( V ss). Our efforts culminated in the identification of a biaryl series, with an expected longer t 1/2 in human than UCB7362 while maintaining a similar in vitro off-target hit rate., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Hypothesis: The design of biodegradable tyrosine-derived polymeric surfactants (TyPS) through the use of calculated thermodynamic parameters could lead to phospholipid membrane surface modifiers capable of controlling cellular properties such as viability. Delivery of cholesterol by TyPS nanospheres into membrane phospholipid domains could provide further controlled modulation of membrane physical and biological properties., Experiment: Calculated Hansen solubility parameters (∂ T ) and hydrophile:lipophile balances (HLB) were applied to design and synthesize a small family of diblock and triblock TyPS with different hydrophobic blocks and PEG hydrophilic blocks. Self-assembled TyPS/cholesterol nanospheres were prepared in aqueous media via co-precipitation. Cholesterol loading and Langmuir film balance surface pressures of phospholipid monolayers were obtained. TyPS and TyPS/cholesterol nanosphere effects on human dermal cell viability were evaluated by cell culture using poly(ethylene glycol) (PEG) and Poloxamer 188 as controls., Findings: Stable TyPS nanospheres incorporated between 1% and 5% cholesterol. Triblock TyPS formed nanosphere with dimensions significantly smaller than diblock TyPS nanospheres. In accord calculated thermodynamic parameters, cholesterol binding increased with increasing TyPS hydrophobicity. TyPS inserted into phospholipid monolayer films in a manner consistent with their thermodynamic properties and TyPS/cholesterol nanospheres delivered cholesterol into the films. Triblock TyPS/cholesterol nanospheres increased human dermal cell viability, which was indicative of potentially beneficial TyPS effects on cell membrane surface properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A coconut shell (AC1230CX) and a bituminous coal based (F400) granular activated carbon (GAC) were ground with mortar and pestle (MP), a blender, and a bench-scale ball milling unit (BMU). Blender was the most time-efficient for particle size reduction. Four size fractions ranging from 20 × 40 to 200 × 325 were characterized along with the bulk GACs. Compared to bulk GACs, F400 blender and BMU 20 × 40 fractions decreased in specific surface area (SSA, -23% and -31%, respectively) while smaller variations (-14% to 5%) occurred randomly for AC1230CX ground fractions. For F400, the blender and BMU size fraction dependencies were attributed to the combination of (i) radial trends in the F400 particle properties and (ii) importance of shear (outer layer removal) versus shock (particle fracturing) size reduction mechanisms. Compared to bulk GACs, surface oxygen content (At%-O1s) increased up to 34% for the F400 blender and BMU 20 × 40 fractions, whereas all AC1230CX ground fractions, except for the blender 100 × 200 and BMU 60 × 100 and 100 × 200 fractions, showed 25-29% consistent increases. The At%-O1s gain was attributed to (i) radial trends in F400 properties and (ii) oxidization during grinding, both of which supported the shear mechanism of mechanical grinding. Relatively small to insignificant changes in point of zero charge (pH PZC ) and crystalline structure showed similar trends with the changes in SSA and At%-O1s. The study findings provide guidance for informed selection of grinding methods based on GAC type and target particle sizes to improve the representativeness of adsorption studies conducted with ground GAC, such as rapid small-scale column tests. When GACs have radial trends in their properties and when the target size fraction only includes larger particle sizes, manual grinding is recommended., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Organometallic phosphors are an important class of emissive materials used in high-efficiency organic light-emitting devices. However, problems of low photostability arise for blue-emitting phosphors due to chemical and environmental degradation and triplet quenching processes. Various approaches have been developed to improve the photostability of such phosphors, including the design of new organometallic molecules and control of host-dopant composition in thin films. Here, we demonstrate a different approach for improving the photostability of blue organometallic phosphors that uses localized surface plasmon resonances to increase the triplet recombination rate. The increased recombination rate improves the photostability of the phosphor due to the reduction in triplet quenching pathways. We show that the lifetime of phosphorescence is decreased significantly by nanoparticle-based plasmonic surfaces, which improves the photostability of the blue organometallic phosphor by up to a factor of 3.6. Other plasmonic surfaces are also tested and exhibit less significant photostability improvements due to a reduced spectral overlap of the plasmonic modes with the emitter and lower mode confinement. The use of plasmonic surfaces to improve phosphor photostability at blue wavelengths is distinct from other approaches because it involves modification to the local electromagnetic environment of the phosphor rather than modifications to the phosphor molecular structure or the emitting material composition., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Background: Substance misuse teaching within the undergraduate medical curriculum has been underrepresented compared to more traditional medical topics. In response several national curriculum reviews such as the most recent UK department of health initiative (DOH) have identified deficiencies in substance misuse education and have suggested curriculum interventions for local faculties to implement. The student perspective however has largely been muted during this process and this study aims to explore this using a constructivist grounded theory approach., Methods: Eleven final year and intercalating medical students across three separate focus groups participated in this study over a three-month period commencing from March 2018. Time between the audio recorded focus groups allowed for a parallel process of data collection and analysis into more focussed codes and categories to occur, consistent with the grounded theory approach. The qualitative study took place in a single medical school in the UK., Results: Medical students had a common consensus that substance misuse education was an underperforming subject in their curriculum, from limited teaching hours to curriculum design and organisational problems. Students identified an alternative curriculum is required to not only prepare students for their future clinical duties but also their own personal lives. Students highlighted this proximity to a 'dangerous world' where exposure to substance misuse risks were faced daily. This exposure also provided a source of informal learning experiences which students deemed as being potentially unbalanced and even dangerous. Students also identified unique barriers to curriculum change with reference to a lack of openness due to the impacts of disclosure in substance misuse., Conclusion: Large scale curriculum initiatives appear to correspond to the student voice obtained in this study, providing backing for the implementation of a co-ordinated substance misuse curriculum within medical schools. The student voice however provides an alternative lens by outlining how substance misuse pervades into students' lives and how informal learning is a largely underestimated hidden source of learning with more dangers than benefits. This together with the identification of further barriers to curriculum change, provide space for medical faculties to incorporate and work with students to facilitate local level curriculum changes relating to substance misuse education., (© 2023. Crown.)

Utilizing cognitive psychology as a foundation, this paper offers a deeper consideration of contemporary theoretical influences on coaching pedagogy. Countering recent dichotomies suggested between pedagogic approaches, we reintroduce key findings from the cognitive tradition and their implications for practice which coaches may find useful. Using cognitive load, novice and expert differences, desirable difficulty, and fidelity, we suggest that the lines drawn between different "pedagogies" may not be as sharp as suggested. Instead, we suggest that coaches avoid defining themselves as being aligned to a specific pedagogical or paradigmatic stance. We conclude by advocating for research informed practice, absent of strict theoretical boundaries and instead, considering contemporary pedagogy as drawing on the needs of the context, the experience of the coach and the best available evidence., Competing Interests: Authors JT, MA and RC were employed by Grey Matters Performance Ltd. The remaining author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Taylor, Taylor, Ashford and Collins.)

When implementing anion exchange (AEX) for per- and polyfluoroalkyl substances treatment, temporal drinking water quality changes from concurrent inorganic anion (IA) removal can create unintended consequences (e.g., corrosion control impacts). To understand potential effects, four drinking water-relevant IAs (bicarbonate, chloride, sulfate, and nitrate) and three gel-type, strong-base AEX resins were evaluated. Batch binary isotherm experiments provided estimates of IA selectivity with respect to chloride ( K x ∕ C ) for IA/resin combinations where bicarbonate < sulfate ≤ nitrate at studied conditions. A multi-IA batch experiment demonstrated that binary isotherm-determined K x ∕ C values predicted competitive behavior. Subsequent column experiments with and without natural organic matter (NOM) allowed for the validation of a new ion exchange column model (IEX-CM; https://github.com/USEPA/Water&#95;Treatment&#95;Models). IA breakthrough was well-simulated using binary isotherm-determined K x ∕ C values and was minimally impacted by NOM. Initial AEX effluent water quality changes with corrosion implications included increased chloride and decreased sulfate and bicarbonate concentrations, resulting in elevated chloride-to-sulfate mass ratios (CSMRs) and Larson ratios (LRs) and depressed pH until the complete breakthrough of the relevant IA(s). IEX-CM utility was further illustrated by simulating the treatment of low-IA source water and a change in the source water to understand the resulting duration of changes in IAs and water quality parameters.

Water molecules at protein-ligand interfaces are often of significant pharmaceutical interest, owing in part to the entropy which can be released upon the displacement of an ordered water by a therapeutic compound. Protein structures may not, however, completely resolve all critical bound water molecules, or there may be no experimental data available. As such, predicting the location of water molecules in the absence of a crystal structure is important in the context of rational drug design. Grand canonical Monte Carlo (GCMC) is a computational technique that is gaining popularity for the simulation of buried water sites. In this work, we assess the ability of GCMC to accurately predict water binding locations, using a dataset that we have curated, containing 108 unique structures of complexes between proteins and Food and Drug Administration (FDA)-approved small-molecule drugs. We show that GCMC correctly predicts 81.4% of nonbulk crystallographic water sites to within 1.4 Å. However, our analysis demonstrates that the reported performance of water prediction methods is highly sensitive to the way in which the performance is measured. We also find that crystallographic water sites with more protein/ligand hydrogen bonds and stronger electron density are more reliably predicted by GCMC. An analysis of water networks revealed that more than half of the structures contain at least one ligand-contacting water network. In these cases, displacement of a water site by a ligand modification might yield unexpected results if the larger network is destabilized. Cooperative effects between waters should therefore be explicitly considered in structure-based drug design.

Introduction: Among persons with HIV (PWH), homelessness is associated with poorer health. From 2009-2014, national HIV prevention goals included a reduction in homelessness among PWH. We sought to examine social ecological factors associated with homelessness among PWH at a sub-national level during that period., Methods: National data were used to identify Delaware as the only jurisdiction where homelessness among PWH declined from 2009-2014. We analyzed population-level indicators and conducted telephone interviews with 6 key stakeholders to further examine this trend., Results: Overall homelessness, household poverty, and median housing price were associated with homelessness among PWH in Delaware. Key stakeholders indicated that centralized intake processes improved screening, referral, and linkages of clients to housing units., Discussion: In addition to social and economic factors, collaborative program strategies may improve housing outcomes for PWH. Monitoring trends at sub-national levels can help identify successful approaches as well as needed services or policy change.

Predicting the correct pose of a ligand binding to a protein and its associated binding affinity is of great importance in computer-aided drug discovery. A number of approaches have been developed to these ends, ranging from the widely used fast molecular docking to the computationally expensive enhanced sampling molecular simulations. In this context, methods such as coarse-grained metadynamics and binding pose metadynamics (BPMD) use simulations with metadynamics biasing to probe the binding affinity without trying to fully converge the binding free energy landscape in order to decrease the computational cost. In BPMD, the metadynamics bias perturbs the ligand away from the initial pose. The resistance of the ligand to this bias is used to calculate a stability score. The method has been shown to be useful in reranking predicted binding poses from docking. Here, we present OpenBPMD, an open-source Python reimplementation and reinterpretation of BPMD. OpenBPMD is powered by the OpenMM simulation engine and uses a revised scoring function. The algorithm was validated by testing it on a wide range of targets and showing that it matches or exceeds the performance of the original BPMD. We also investigated the role of accurate water positioning on the performance of the algorithm and showed how the combination with a grand-canonical Monte Carlo algorithm improves the accuracy of the predictions.

Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life ( t 1/2 ) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t 1/2 . UCB7362 is estimated to achieve 9 log 10 unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria.

Despite decades of efforts, state-of-the-art synthetic burn dressings to treat partial-thickness burns are still far from ideal. Current dressings adhere to the wound and necessitate debridement. This work describes the first "supramolecular hybrid hydrogel (SHH)" burn dressing that is biocompatible, self-healable, and on-demand dissoluble for easy and trauma-free removal, prepared by a simple, fast, and scalable method. These SHHs leverage the interactions of a custom-designed cationic copolymer via host-guest chemistry with cucurbit[7]uril and electrostatic interactions with clay nanosheets coated with an anionic polymer to achieve enhanced mechanical properties and fast on-demand dissolution. The SHHs show high mechanical strength (>50 kPa), self-heal rapidly in ∼1 min, and dissolve quickly (4-6 min) using an amantadine hydrochloride (AH) solution that breaks the supramolecular interactions in the SHHs. Neither the SHHs nor the AH solution has any adverse effects on human dermal fibroblasts or epidermal keratinocytes in vitro . The SHHs also do not elicit any significant cytokine response in vitro . Furthermore, in vivo murine experiments show no immune or inflammatory cell infiltration in the subcutaneous tissue and no change in circulatory cytokines compared to sham controls. Thus, these SHHs present excellent burn dressing candidates to reduce the time of pain and time associated with dressing changes., Competing Interests: The authors declare no competing financial or nonfinancial interests., (© 2022 The Authors.)

Self-assembled monolayers (SAMs) formed from thiol compounds bound to Ag and Au electrodes have been used as an important strategy in improving the stability and efficiency of optoelectronic devices. Thiol compounds provide only one binding site with the metal electrode which limits their influence. Dithiolane/dithiol compounds can provide multiple binding sites and could be useful in enhancing the performance of the device. In this study, inverted organic semiconducting hole-only devices were fabricated by using Ag back electrodes in conjunction with SAMs formed from disulfide lipoic acid-based compounds and were compared to a long aliphatic chain thiol. The binding and the electronic properties as well as electrical characteristics of the SAMs on silver were studied to look at the influence of their structure on charge injection in the organic semiconductor devices. It was found that the SAMs formed with (±)-α-lipoic acid, isolipoic acid, and (±)-4-phenylbutyl 5-(1,2-dithiolan-3-yl) pentanoate significantly improved the charge injection by either changing the work function of the Ag or altering the physical interaction between the polymer and the metal surface. This study may lead to an understanding of how the nature of the functional groups of the SAM and the number of bonds formed between each SAM molecule and the metal electrode influence the contact resistance and the performance of organic semiconductor devices.

Building on a large volume of recent research in talent identification and development, this paper future directions for research and practice. We suggest that strategic coherence become a greater point of emphasis in both, with the Performance, Outcome and Process framework holding the potential to signal various markers of effectiveness. Secondly, greater recognition of the need to deploy limited resources where they promote movement toward these markers of effectiveness. Finally, we make recommendations for the operationalising of strategy in talent and performance systems by considering the integration of top down and bottom-up strategic processes., Competing Interests: Author JT was employed by Grey Matters Performance Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Taylor, MacNamara and Taylor.)

We present a comprehensive analysis of all ring systems (both heterocyclic and nonheterocyclic) in clinical trial compounds and FDA-approved drugs. We show 67% of small molecules in clinical trials comprise only ring systems found in marketed drugs, which mirrors previously published findings for newly approved drugs. We also show there are approximately 450 000 unique ring systems derived from 2.24 billion molecules currently available in synthesized chemical space, and molecules in clinical trials utilize only 0.1% of this available pool. Moreover, there are fewer ring systems in drugs compared with those in clinical trials, but this is balanced by the drug ring systems being reused more often. Furthermore, systematic changes of up to two atoms on existing drug and clinical trial ring systems give a set of 3902 future clinical trial ring systems, which are predicted to cover approximately 50% of the novel ring systems entering clinical trials.