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Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we applied mass spectrometry technologies. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is co-located on chromatin with GFI1 and LSD1 genome-wide; the strongest HMG20B binding co-locates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing LSD1 on chromatin at GFI1 binding sites. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukemia cell differentiation block.

The activation of P2X7 is a well-known stimulus for the NLRP3-caspase 1 inflammasome and subsequent rapid IL-1β secretion from monocytes and macrophages. Here we show that positive allosteric modulators of P2X7, ginsenosides, can enhance the release of three important cytokines, IL-1β, IL-6 and TNF-α from LPS-primed rodent macrophages using the J774 mouse macrophage cell line and primary rat peritoneal macrophages. We compared the immediate P2X7 responses in un-primed and LPS-primed macrophages and found no difference in calcium response amplitude or kinetics. These results suggest that under inflammatory conditions positive allosteric modulators are capable of increasing cytokine secretion at lower concentrations of ATP, thus boosting the initial pro-inflammatory signal. This may be important in the control of intracellular infections.

An understanding of the molecular features associated with prostate cancer progression (PCa) and resistance to hormonal therapy is crucial for the identification of new targets that can be utilized to treat advanced disease and prolong patient survival. The glycome, which encompasses all sugar polymers (glycans) synthesized by cells, has remained relatively unexplored in the context of advanced PCa despite the fact that glycans have great potential value as biomarkers and therapeutic targets due to their high density on the cell surface. Using imaging mass spectrometry (IMS), we profiled the N-linked glycans in tumor tissue derived from 131 patients representing the major disease states of PCa to identify glycosylation changes associated with loss of tumor cell differentiation, disease remission, therapy resistance and disease recurrence, as well as neuroendocrine (NE) differentiation which is a major mechanism for therapy failure. Our results indicate significant changes to the glycosylation patterns in various stages of PCa, notably a decrease in tri- and tetraantennary glycans correlating with disease remission, a subsequent increase in these structures with the transition to therapy-resistant PCa, and downregulation of complex N-glycans correlating with NE differentiation. Furthermore, both nonglucosylated and monoglucosylated mannose 9 demonstrate aberrant upregulation in therapy-resistant PCa which may be useful therapeutic targets as these structures are not normally presented in healthy tissue. Our findings characterize changes to the tumor glycome that occur with hormonal therapy and the development of castration-resistant PCa (CRPC), identifying several glycan markers and signatures which may be useful for diagnostic or therapeutic purposes.

Advanced and aggressive prostate cancer (PCa) depends on glutamine for survival and proliferation. We have previously shown that inhibition of glutaminase 1, which catalyzes the rate-limiting step of glutamine catabolism, achieves significant therapeutic effect; however, therapy resistance is inevitable. Here we report that while the glutamine carbon is critical to PCa survival, a parallel pathway of glutamine nitrogen catabolism that actively contributes to pyrimidine assembly is equally important for PCa cells. Importantly, we demonstrate a reciprocal feedback mechanism between glutamine carbon and nitrogen pathways which leads to therapy resistance when one of the two pathways is inhibited. Combination treatment to inhibit both pathways simultaneously yields better clinical outcome for advanced PCa patients.

Background Failure of eruption of the maxillary permanent incisor teeth usually presents in the mixed dentition between the ages of 7 and 9 years. Missing and unerupted maxillary incisors can be regarded as unattractive and have a potentially negative impact on facial and dental aesthetics. The presence of a supernumerary tooth (or odontoma) is commonly responsible for failed eruption or impaction of the permanent maxillary incisors. The primary objective of this trial is to investigate the success of eruption associated with maxillary incisor teeth that have failed to erupt because of a supernumerary tooth in the anterior maxilla. Methods This protocol describes an interventional multicentre two-arm randomised clinical trial. Participants meeting the eligibility criteria will be randomised (unrestricted equal participant allocation [1:1]) to either space creation with an orthodontic appliance, removal of the supernumerary tooth and application of direct orthodontic traction or space creation with an orthodontic appliance, removal of the supernumerary tooth and monitoring. The primary outcome of this trial is to determine the prevalence of successfully erupted maxillary central permanent incisors at 6 months following removal of the supernumerary tooth. Secondary outcome measures include (1) the effect of initial tooth position (assessed radiographically) on time taken for the tooth to erupt, (2) time taken to align the unerupted tooth to the correct occlusal position, (3) gingival aesthetics and (4) changes in the self-reported Oral Health Related-Quality of Life (OHRQoL) (pre-and post-treatment). Discussion There is a lack of high-quality robust prospective studies comparing the effectiveness of interventions to manage this condition. Furthermore, the UK national clinical guidelines have highlighted a lack of definitive treatment protocols for the management of children who present with an unerupted maxillary incisor due to the presence of a supernumerary tooth. The results of this trial will inform future treatment guidelines for the management of this condition in young children. Trial registration ISRCTN Registry ISRCTN12709966. Registered on 16 June 2022.

Our understanding of how abdominal organs (like the gut) communicate with the brain, via sensory nerves, has been limited by a lack of techniques to selectively activate or inhibit populations of spinal primary afferent neurons within dorsal root ganglia (DRG), of live animals. We report a survival surgery technique in mice, where select DRG are surgically removed (unilaterally or bilaterally), without interfering with other sensory or motor nerves. Using this approach, pain responses evoked by rectal distension were abolished by bilateral lumbosacral L5-S1 DRG removal, but not thoracolumbar T13-L1 DRG removal. However, animals lacking T13-L1 or L5-S1 DRG both showed reduced pain sensitivity to distal colonic distension. Removal of DRG led to selective loss of peripheral CGRP-expressing spinal afferent axons innervating visceral organs, arising from discrete spinal segments. This method thus allows spinal segment-specific determination of sensory pathway functions in conscious, free-to-move animals, without genetic modification.

ChAdOx1 nCoV-19 (AZD1222) is a replication-deficient simian adenovirus–vectored vaccine encoding the spike (S) protein of SARS-CoV-2, based on the first published full-length sequence (Wuhan-1). AZD1222 has been shown to have 74% vaccine efficacy against symptomatic disease in clinical trials. However, variants of concern (VoCs) have been detected, with substitutions that are associated with a reduction in virus neutralizing antibody titer. Updating vaccines to include S proteins of VoCs may be beneficial, even though current real-world data is suggesting good efficacy following boosting with vaccines encoding the ancestral S protein. Using the Syrian hamster model, we evaluate the effect of a single dose of AZD2816, encoding the S protein of the Beta VoC, and efficacy of AZD1222/AZD2816 as a heterologous primary series against challenge with the Beta or Delta variant. Minimal to no viral sgRNA could be detected in lungs of vaccinated animals obtained at 3- or 5- days post inoculation, in contrast to lungs of control animals. In Omicron-challenged hamsters, a single dose of AZD2816 or AZD1222 reduced virus shedding. Thus, these vaccination regimens are protective against the Beta, Delta, and Omicron VoCs in the hamster model.

Cumulative and synergistic impacts from environmental pressures, particularly in low-lying tropical coastal regions, present challenges for the governance of ecosystems, which provide natural resource-based livelihoods for communities. Here, we seek to understand the relationship between responses to the impacts of El Niño and La Niña events and the vulnerability of mangrove-dependent communities in the Caribbean region of Colombia. Using two case study sites, we show how communities are impacted by, and undertake reactive short-term responses to, El Niño and La Niña events, and how such responses can affect their adaptive capacity to progressive environmental deterioration. We show that certain coping measures to climate variability currently deliver maladaptive outcomes, resulting in circumstances that could contribute to system ‘lock-in’ and engender undesirable ecological states, exacerbating future livelihood vulnerabilities. We highlight the significant role of social barriers on vulnerabilities within the region, including perceptions of state abandonment, mistrust and conflicts with authorities. Opportunities to reduce vulnerability include enhancing the communities’ capacity to adopt more positive and preventative responses based on demonstrable experiential learning capacity. However, these will require close cooperation between formal and informal organisations at different levels, and the development of shared coherent adaptation strategies to manage the complexity of multiple interacting environmental and climatic pressures.

When would an oligopolistic entrant imitate an incumbent’s product (“me-too” entry), rather than horizontally differentiate? We allow an entrant's product choice to vary endogenously with the cost of product differentiation. Such endogenity of product differentiation significantly affects the comparison of Bertrand and Cournot duopoly. We find that if Bertrand entry occurs, products are differentiated, whereas there is a substantial region in which Cournot entry involves a homogenous product. Bertrand prices may be higher than Cournot prices; and, if product differentiation costs are low enough to induce Cournot differentiated entry, then Bertrand industry profit equals or exceeds Cournot industry profit.

PURPOSE: Physical activity is important for healthy cancer survivorship, yet many endometrial cancer survivors do not participate in recommended muscle-strengthening activity. The purpose of this study was to determine the feasibility of home-based muscle strengthening activity in endometrial cancer survivors. METHODS: Forty post-treatment endometrial cancer survivors were enrolled in a randomized trial, of twice-weekly home-based strength exercise versus wait-list control. The intervention included educational materials, exercise equipment (dumbbells, resistance bands), and support/feedback via video coaching sessions. Participants completed the exercises twice per week for 10 weeks, with a 5-week follow-up period. Feasibility was measured by program adherence, as well as safety of and satisfaction with the study. RESULTS: On average, participants were 60.9 years old (SD = 8.7), had a BMI of 39.9 kg/m(2) (SD = 15.2), and were 2.9 years (SD = 1.2) since diagnosis. The majority (83%) had stage I disease at diagnosis. Seventy-five percent adhered to the exercise prescription of twice/week, with 85% of participants missing fewer than 3 of the workouts. Forty percent of participants continued workouts during the 5-week follow-up. Participants were highly satisfied with intervention. No injuries or adverse everts occurred. CONCLUSION: This home-based program was feasible in endometrial cancer survivors. While adherence was measured, future research should focus on long-term maintenance of exercise and should explore progressions and modifications of exercises at a distance for various abilities. IMPLICATIONS FOR CANCER SURVIVORS: Muscle strengthening activities are recommended for all cancer survivors. This study shows that a home-based muscle strengthening exercise is feasible in endometrial cancer survivors.

The evolution of land plants during the Palaeozoic Era transformed Earth’s biosphere 1. Because the Earth's surface and interior are linked by tectonic processes, the linked evolution of the biosphere and sedimentary rocks should be recorded as a near-contemporary shift in the composition of the continental crust. To test this hypothesis, we assessed the isotopic signatures of zircon formed at subduction zones where marine sediments are transported into the mantle 2,3, thereby recording interactions between surface environments and the deep Earth. Using oxygen and lutetium-hafnium isotopes of magmatic zircon that respectively track surface weathering (time-independent) 4 and radiogenic decay (time-dependent) 5, we find a correlation in the composition of continental crust after 430 Myr ago, which is coeval with the onset of enhanced complexity and stability in sedimentary systems related to the evolution of vascular plants. The expansion of terrestrial vegetation brought channelled sand-bed and meandering rivers, muddy floodplains, and thicker soils, lengthening the duration of weathering before final marine deposition 6,7. Collectively, our results suggest that the evolution of vascular plants coupled the degree of weathering and timescales of sediment routing to depositional basins where they were subsequently subducted and melted. The late Palaeozoic isotopic shift of zircon indicates that the greening of the continents was recorded in the deep Earth.

The Structured Inventory of Malingered Symptomatology (SIMS) is a measure of impression management that covers a range of symptomatology through 75 items and five scales, some of which are particularly relevant for cognitive evaluations. The aims of the current projects were to (1) reduce the length of the SIMS to the items most predictive of symptom validity on the Minnesota Multiphasic Inventory-2-RF, (2) explore the factor structure of the remaining items, and (3) test the degree to which the final scale identifies individuals with inadequate performance validity. The sample consisted of 249 veterans referred for outpatient neuropsychological assessment and completed the SIMS, most of whom also completed the MMPI-2-RF and measures of performance validity. Results identified items from the Neurological Injury (11 items) and Amnestic Disorders scales (8 items) that were most strongly related to its theoretically consistent MMPI-2-RF scales and that two distinct factors corresponding to the original scales were identified on factor analysis. The revised subscales correlated at r = 0.55, and each scale had acceptable internal consistency (α = 0.76–0.84), and the Amnestic and Total Revised SIMS were adequately able to identify individuals failing measures of performance validity. The reliability and validity of the SIMS for Neuropsychological Settings (SIMS-NS) and its Amnestic subscale, despite its brevity, were practically psychometrically equivalent to the original SIMS and one prior short form of the test.

There is considerable interest in understanding how contents within the gut wall (including microbiome) can activate sensory nerve endings in the gut that project to the central nervous system. However, we have only recently begun to understand the location and characteristics of extrinsic spinal afferent nerve endings that innervate the lower gastrointestinal (GI) tract. Our aim is to identify the nerve endings in the mouse distal colon that arise from single spinal afferent neurons. C57BL/6 mice were anaesthetised and single dorsal root ganglia (DRG) between lumbosacral L6–S1 were injected with dextran biotin. Mice recovered for 7 days. Animals were then euthanized and whole colons removed, fixed and stained for calcitonin-gene-related-peptide (CGRP). Single spinal afferent nerve axons were identified entering the distal colon that ramified along many rows of myenteric ganglia, often giving rise to varicose nerve endings. These same axons bifurcated in the circular muscle giving rise to 4–5 groups of branching-type intramuscular endings, where each group of endings was separated by ~ 370 μm in the rostro-caudal axis and projected 1.2 mm around the circumference. As spinal afferent axons bifurcated, their axons often showed dramatic reductions in diameter. Here, we identified in the distal colon, the characteristics of nerve endings that arise from single colorectal-projecting axons with cell bodies in DRG. These findings suggest that a population of sensory neurons in DRG can potentially detect sensory stimuli simultaneously via different morphological types of endings that lie in both colonic smooth muscle and myenteric ganglia.

The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS. This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although mucosal serotonin can modulate their characteristics. Chemosensory stimuli applied to the lumen can release subtances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut–brain axis.

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265, Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272, Recent work has suggested that disorganised speech might be a powerful predictor of later psychotic illness in clinical high risk subjects. To that end, several automated measures to quantify disorganisation of transcribed speech have been proposed. However, it remains unclear which measures are most strongly associated with psychosis, how different measures are related to each other and what the best strategies are to collect speech data from participants. Here, we assessed whether twelve automated Natural Language Processing markers could differentiate transcribed speech excerpts from subjects at clinical high risk for psychosis, first episode psychosis patients and healthy control subjects (total N = 54). In-line with previous work, several measures showed significant differences between groups, including semantic coherence, speech graph connectivity and a measure of whether speech was on-topic, the latter of which outperformed the related measure of tangentiality. Most NLP measures examined were only weakly related to each other, suggesting they provide complementary information. Finally, we compared the ability of transcribed speech generated using different tasks to differentiate the groups. Speech generated from picture descriptions of the Thematic Apperception Test and a story re-telling task outperformed free speech, suggesting that choice of speech generation method may be an important consideration. Overall, quantitative speech markers represent a promising direction for future clinical applications., SEM was supported by the Accelerate Programme for Scientific Discovery, funded by Schmidt Futures, a Fellowship from The Alan Turing Institute, London, and a Henslow Fellowship at Lucy Cavendish College, University of Cambridge, funded by the Cambridge Philosophical Society. PEV is supported by a fellowship from MQ: Transforming Mental Health (MQF17_24). This work was supported by The Alan Turing Institute under the EPSRC grant EP/N510129/1, the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), the UK Medical Research Council (MRC) and the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London.

How the Enteric Nervous System (ENS) coordinates propulsion of content along the gastrointestinal (GI)-tract has been a major unresolved issue. We reveal a mechanism that explains how ENS activity underlies propulsion of content along the colon. We used a recently developed high-resolution video imaging approach with concurrent electrophysiological recordings from smooth muscle, during fluid propulsion. Recordings showed pulsatile firing of excitatory and inhibitory neuromuscular inputs not only in proximal colon, but also distal colon, long before the propagating contraction invades the distal region. During propulsion, wavelet analysis revealed increased coherence at ~2 Hz over large distances between the proximal and distal regions. Therefore, during propulsion, synchronous firing of descending inhibitory nerve pathways over long ranges aborally acts to suppress smooth muscle from contracting, counteracting the excitatory nerve pathways over this same region of colon. This delays muscle contraction downstream, ahead of the advancing contraction. The mechanism identified is more complex than expected and vastly different from fluid propulsion along other hollow smooth muscle organs; like lymphatic vessels, portal vein, or ureters, that evolved without intrinsic neurons., Nick Spencer et al. made simultaneous multi-site electrophysiological recordings with video imaging of colonic wall movements from ex vivo mouse colon, in order to correlate propulsion of content with underlying electrical signals from the smooth muscle. Their results demonstrate that excitatory and inhibitory junction potentials are synchronized in both the proximal and distal colon, suggesting that the enteric nervous system network communicates over a longer range than previously expected.

Artemin is a neurotrophic factor that plays a crucial role in the regulation of neural development and regeneration and has also been implicated in the pathogenesis of inflammatory pain. The receptor for artemin, GFRα3, is expressed by sympathetic and nociceptive sensory neurons, including some that innervate the bone marrow, but it is unclear if it is also expressed in other cell types in the bone marrow. Our goal in the present study was to characterise the expression of GFRα3 in nonneuronal cells in the bone marrow. Immunohistochemical studies revealed that GFRα3-expressing cells in the bone marrow are spatially associated with blood vessels and are in intimate contact with nerve fibres. We used various combinations of markers to distinguish different cell types and found that the GFRα3-expressing cells expressed markers of nonmyelinating Schwann cells (e.g. GFAP, p75NTR, nestin). Analysis of bone marrow sections of Wnt1-reporter mice also demonstrated that they originate from the neural crest. Further characterisation using flow cytometry revealed that GFRα3 is expressed in a population of CD51+Sca1-PDGFRα- cells, reinforcing the notion that they are neural crest-derived, nonmyelinating Schwann cells. In conclusion, there is a close association between peripheral nerve terminals and a population of nonneuronal cells that express GFRα3 in the bone marrow. The nonneuronal cells have characteristics consistent with a neural crest-derived, nonmyelinating Schwann cell phenotype. Our findings provide a better understanding of the expression pattern of GFRα3 in the bone marrow microenvironment.

This review will address the current literature available regarding complications after intravesical Bacillus Calmette-Guerin (BCG) therapy for bladder cancer. Topics include intravesical BCG therapy–related complications, role of BCG therapy in immunosuppression, and future directions in the context of BCG-related complications. There are several new reviews and case reports discussing unique complications following intravesical BCG therapy that should raise awareness of possible short-term and long-term effects after using this common treatment modality in bladder cancer patients. Since intravesical BCG is a common treatment option for non-muscle invasive bladder cancer and can cause a variety of complications, it is important to recognize this aspect of the patient’s history when evaluating patients who present with symptoms similar to the ones discussed in this review. This will allow for prompt delivery of treatment as well as preventing unnecessary morbidity and mortality.

Vaccines against SARS-CoV-2 are urgently required, but early development of vaccines against SARS-CoV-1 resulted in enhanced disease after vaccination. Careful assessment of this phenomena is warranted for vaccine development against SARS CoV-2. Here we report detailed immune profiling after ChAdOx1 nCoV-19 (AZD1222) and subsequent high dose challenge in two animal models of SARS-CoV-2 mediated disease. We demonstrate in rhesus macaques the lung pathology caused by SARS-CoV-2 mediated pneumonia is reduced by prior vaccination with ChAdOx1 nCoV-19 which induced neutralising antibody responses after a single intramuscular administration. In a second animal model, ferrets, ChAdOx1 nCoV-19 reduced both virus shedding and lung pathology. Antibody titre were boosted by a second dose. Data from these challenge models on the absence of enhanced disease and the detailed immune profiling, support the continued clinical evaluation of ChAdOx1 nCoV-19., Lambe, Spencer, Thomas, Gilbert and colleagues report on the detailed immune profile of rhesus macaques and ferrets vaccinated against SARS-CoV-2 under high dose challenge. Their findings indicate that the ChAdOx1 nCoV-19 (AZD1222) the vaccine induces immune responses and reduces disease symptoms in both models, including SARS-CoV-2 mediated pneumonia and virus shedding.

Streptococcus pyogenes (Spy) Cas9 has potential as a component of gene therapeutics for incurable diseases. One of its limitations is its large size, which impedes its formulation and delivery in therapeutic applications. Smaller Cas9s are an alternative, but lack robust activity or specificity and frequently recognize longer PAMs. Here, we investigated four uncharacterized, smaller Cas9s and found three employing a “GG” dinucleotide PAM similar to SpyCas9. Protein engineering generated synthetic RNA-guided nucleases (sRGNs) with editing efficiencies and specificities exceeding even SpyCas9 in vitro and in human cell lines on disease-relevant targets. sRGN mRNA lipid nanoparticles displayed manufacturing advantages and high in vivo editing efficiency in the mouse liver. Finally, sRGNs, but not SpyCas9, could be packaged into all-in-one AAV particles with a gRNA and effected robust in vivo editing of non-human primate (NHP) retina photoreceptors. Human gene therapy efforts are expected to benefit from these improved alternatives to existing CRISPR nucleases., Small CRISPR Cas9 proteins have potential in gene therapies but generally have poor editing efficiency or specificity and often recognize sub-optimal PAM sequences. Here the authors characterise four small nucleases and use protein engineering to create effective in vivo editors.

Adenoviral vectors are being developed as vaccines against infectious agents and tumour-associated antigens, because of their ability to induce cellular immunity. However, the protection afforded in animal models has not easily translated into primates and clinical trials, underlying the need for improving adenoviral vaccines-induced immunogenicity. A Toll-like receptor signalling molecule, TRAM, was assessed for its ability to modify the immune responses induced by an adenovirus-based vaccine. Different adenovirus vectors either expressing TRAM alone or co-expressing TRAM along with a model antigen were constructed. The modification of T-cell and antibody responses induced by TRAM was assessed in vivo in mice and in primates. Co-expression of TRAM and an antigen from adenoviruses increased the transgene-specific CD8+ T cell responses in mice. Similar effects were seen when a TRAM expressing virus was co-administered with the antigen-expressing adenovirus. However, in primate studies, co-administration of a TRAM expressing adenovirus with a vaccine expressing the ME-TRAP malaria antigen had no significant effect on the immune responses. While these results support the idea that modification of innate immune signalling by genetic vectors modifies immunogenicity, they also emphasise the difficulty in generalising results from rodents into primates, where the regulatory pathway may be different to that in mice.

Gold nanoparticles (Au NPs) are promising radiosensitizers for cancer therapy. While the radiosensitizing effects of Au NPs have been shown in many epithelial cancers, there are no documented cases of their use in cells of hematopoietic origin, which constitute ~ 10% of all cancer cases and are frequently treated using radiation therapy. In this work, we measure the uptake of polyethylene glycol-coated (PEGylated) Au NPs (5 nm core diameter) in HL-60 II and Jurkat D1.1 cells using flow cytometry and ICP-AES. Electronic cell counting, metabolic activity assays, and DNA synthesis assays reveal cell line–specific radiosensitization that is independent of the number of internalized nanoparticles. The high SER value for the HL-60 II cell line (1.33 at 5 Gy) points to a dominant biological mechanism.

Although research has suggested a net negative influence of sexual media on sexual quality, enough researchers have found results suggesting that sexual media has no effect or a positive influence that the matter warrants further investigation. We present an organizational framework utilizing primarily the acquisition, activation, application model (3AM), and the Antecedents-Context-Effects model (ACE) to reconcile these apparently contradictory claims. By synthesizing these theories, we suggest that to truly understand the impact of sexual media on sexual quality, four factors must be taken into account: (1) the content of the sexual media being viewed, (2) the difference between short-term and long-term sexual quality, (3) the influence of exclusivity, formativeness, resonance, and reinforcement in moderating the extent to which the portrayed sexual script is applied (influences attitudes and behavior), and (4) the couple context for congruency of use, script application, and moral paradigms. While acknowledging the many nuances that should be considered, we ultimately argue that when considering these factors simultaneously, the overall scripts presented in sexual media are congruent with pursuing factors for short-term sexual quality and incongruent with pursuing factors for long-term sexual quality.

Millennials are struggling to meet current financial challenges. As we strive to improve financial capability in future generations, it is important that we look to the primary source of financial education: parents. This qualitative, multigenerational study explored what Millennials and their parents and grandparents (N = 153) wish they had been taught about finances by their parents, as well as what parents and grandparents wish they had taught their children. Thematic content coding of the interviews revealed three core “I Wish” themes: “Practical Knowledge,” “Financial Stewardship,” and “Open Communication.” These findings can assist researchers, family life educators, financial educators, parents, and future parents to enhance the financial education provided by parents in the home.

Aflatoxin is a mycotoxin produced by the fungus Aspergillus flavus (Link:Fr), an opportunistic ear-rot pathogen of maize (Zea mays L. ssp. mays). Pre-harvest contamination of maize grain with aflatoxin is a chronic problem worldwide and particularly in the Southeastern US. Quantitative trait loci (QTL) were mapped by multiple interval mapping (MIM) in a population consisting of 250 F2:3 lines derived from the cross Mp715 × Va35. Mp715 is resistant to the accumulation of aflatoxin and Va35 is susceptible. The population was genotyped with 1200 single-nucleotide polymorphism (SNP) and simple sequence repeat (SSR) molecular markers and phenotyped for the accumulation of total aflatoxins under artificial inoculation in four environments. Both parents contributed resistance alleles. Two QTL in bins 6.06 and 7.03 were the most promising for the marker-assisted introgression of the resistance present in Mp715. They were the most consistent across individual environments and together were responsible for nearly 30% of the phenotypic variance when data was combined across all four environments. In addition to those two QTL, Mp715 was also the source of the beneficial aflatoxin-reducing allele for several smaller effect QTL. Once their effect is validated in further experiments, the identification of these relatively large effect QTL should facilitate the utilization of this aflatoxin accumulation-resistant germplasm in applied maize breeding programs.

Alarmins S100A8 and S100A9 are endogenous molecules released in response to environmental triggers and cellular damage. They are constitutively expressed in immune cells such as monocytes and neutrophils and their expression is upregulated under inflammatory conditions. The molecular mechanisms that regulate inflammatory pathways in tendinopathy are largely unknown therefore identifying early immune effectors is essential to understanding the pathology. Based on our previous investigations highlighting tendinopathy as an alarmin mediated pathology we sought evidence of S100A8 & A9 expression in a human model of tendinopathy and thereafter, to explore mechanisms whereby S100 proteins may regulate release of inflammatory mediators and matrix synthesis in human tenocytes. Immunohistochemistry and quantitative RT-PCR showed S100A8 & A9 expression was significantly upregulated in tendinopathic tissue compared with control. Furthermore, treating primary human tenocytes with exogenous S100A8 & A9 significantly increased protein release of IL-6, IL-8, CCL2, CCL20 and CXCL10; however, no alterations in genes associated with matrix remodelling were observed at a transcript level. We propose S100A8 & A9 participate in early pathology by modulating the stromal microenvironment and influencing the inflammatory profile observed in tendinopathy. S100A8 and S100A9 may participate in a positive feedback mechanism involving enhanced leukocyte recruitment and release of pro-inflammatory cytokines from tenocytes that perpetuates the inflammatory response within the tendon in the early stages of disease.

The post-emission total kinetic energy release (TKE) in the neutron-induced fission of 232Th was measured (using white spectrum neutrons from LANSCE) for neutron energies from $ E_{n} = 3$ to 91MeV. In this energy range the average post-neutron total kinetic energy release decreases from $ 162.3 \pm 0.3$ at $ E_n = 3$ MeV to $ 154.9 \pm 0.3$ MeV at $ E_n = 91$ MeV. Analysis of the fission mass distributions indicates that the decrease in TKE with increasing neutron energy is a combination of increasing yields of symmetric fission (which has a lower associated TKE) and a decrease in the TKE release in asymmetric fission.

Parent–progeny isotope relationships provide critical signatures in forensic efforts designed to determine the history of interdicted nuclear materials. Unfortunately, there is substantial need for new standards and QC strategies yielding confidence in such chronometric measurements. Here, we investigate the initial isolation of progeny uranium in certified reference material-126a for use as a precision comparator in a thermal ionization mass spectrometry-based QC strategy seeking to provide improved uncertainties in isotopic and chronometric measurements for nuclear materials containing elevated U-236, such as plutonium. Application to real-world Pu either preserved or improved upon uncertainties associated with key parent–daughter ratios and further constrained associated chronometric windows.

In the education of deaf learners, from primary school to postsecondary settings, it frequently is suggested that deaf students are visual learners. That assumption appears to be based on the visual nature of signed languages-used by some but not all deaf individuals-and the fact that with greater hearing losses, deaf students will rely relatively more on vision than audition. However, the questions of whether individuals with hearing loss are more likely to be visual learners than verbal learners or more likely than hearing peers to be visual learners have not been empirically explored. Several recent studies, in fact, have indicated that hearing learners typically perform as well or better than deaf learners on a variety of visual-spatial tasks. The present study used two standardized instruments to examine learning styles among college deaf students who primarily rely on sign language or spoken language and their hearing peers. The visual-verbal dimension was of particular interest. Consistent with recent indirect findings, results indicated that deaf students are no more likely than hearing students to be visual learners and are no stronger in their visual skills and habits than their verbal skills and habits, nor are deaf students' visual orientations associated with sign language skills. The results clearly have specific implications for the educating of deaf learners.

In the aftermath of COP21, potential post-2030 emission trajectories and their consistency with the 2 °C target are a core concern for the ocean scientific community in light of the end-century risks of impact scenarios.

The management of temporomandibular joint conditions has changed dramatically since the 1970s, as the knowledge of the physiology, pathology, and evidence base has developed for the temporomandibular joint. One of the main barriers for this progression was the lack of consensus for specific definitions of different diagnoses associated with TMD conditions. The most recent DC/TMD guidelines have refined the different diagnoses so that clinicians can apply these criteria during the examination, diagnosis and management of TMD patients. Most early management strategies for articular disc displacements were aimed at surgically repositioning the articular disc or utilizing an oral appliance to advance the mandible to a point where the condyle was repositioned on the articular disc. These early management approaches often failed to produce the reduction of the pain and dysfunction that both the health care provider and the patient desired. Slowly, management strategies have evolved into less invasive, more patient centered, and more multidisciplinary as the multifactorial nature of temporomandibular joint conditions became evident. This article reviews the specific DC/TMD diagnoses and the evidence base for the utilization of different management strategies.

This paper describes a record of air and soil temperature collected from 2001 to 2016 in temperate forests at the Bear Brook Watershed in Maine (BBWM). BBWM is a long-term research site established to study the response of forest ecosystem function to various environmental disturbances, including chronic acidic deposition. Replicate HOBO data loggers were deployed in BBWM’s two forest types (coniferous and deciduous), to record temperatures at four positions: (1) air temperature, 100 cm above the forest floor; (2) surface organic soil, 2 cm below the forest floor surface; (3) mineral soil, 10 cm below the organic–mineral horizon interface; and (4) mineral soil, 25 cm below the organic–mineral horizon interface. Data were recorded every three hours, and these raw data were used to compute daily maximum, daily minimum, daily average, and monthly average values. This fifteen–year record represents one of the few readily–available soil temperature datasets in the region, and provides information on long-term changes in climatology, and seasonal and episodic weather patterns.