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How the relative impacts of anthropogenic pressures on the natural environment vary between different taxonomic groups, habitats, and geographic regions is increasingly well established. By contrast, the times of day at which those pressures are most forcefully exerted or have greatest influence are not well understood. The impact on the nighttime environment bears particular scrutiny, given that for practical reasons (e.g., researchers themselves belong to a diurnal species), most studies on the impacts of anthropogenic pressures are conducted during the daytime on organisms that are predominantly day active or in ways that do not differentiate between daytime and nighttime. In the present article, we synthesize the current state of knowledge of impacts of anthropogenic pressures on the nighttime environment, highlighting key findings and examples. The evidence available suggests that the nighttime environment is under intense stress across increasing areas of the world, especially from nighttime pollution, climate change, and overexploitation of resources.

Purpose Despite intense scholarly interest in social entrepreneurship, opportunity recognition remains a poorly understood facet of the phenomenon. Linkages between the micro- and macro-level forces shaping social entrepreneurship are particularly unclear. The purpose of this paper is to introduce the concept of institutional channeling, the process by which institutions socialize and direct individuals into specific knowledge corridors, as a key mechanism influencing the ability of entrepreneurs to identify and create different types of opportunities. Design/methodology/approach Through a synthesis of institutional theory and the knowledge corridor thesis, this research offers a theory explaining why some individuals are able to recognize opportunities for social entrepreneurship. Findings The authors develop a conceptual model that explains how non-contested institutions channel entrepreneurs into homogeneous knowledge corridors, which support the creation of purely for-profit and non-profit organizations. By contrast, experiences involving institutional plurality activate and enable heterogeneous knowledge corridors, which are associated with the ability to recognize opportunities, like social entrepreneurship, that blend institutions. Originality/value The central contribution of this paper is an explanation of why certain individuals, because of their institutional experiences, are more likely than others to recognize for-profit, non-profit and social opportunities. This article highlights that previous efforts at addressing this issue were predominantly centered at the micro level of analysis and focus on individual entrepreneurs and their identities, personality traits and social networks. Although these studies have shed light on important facets of opportunity recognition, they do not sufficiently explain the influence that institutions can have on the micro processes involved in social entrepreneurship opportunity recognition.

The concept of asymmetric electronic conductance is explored in solid-state batteries and realised by a p–n junction interphase, enabling dynamic dendrite-free operation via slow reductive generation and rapid oxidative elimination.

Accumulating evidence implicates sleep and circadian rhythm disturbance in obsessive-compulsive disorder (OCD). However, a multimethod characterization of sleep and circadian rhythms in OCD, their association with symptom severity, and the functional relationship between these variables is lacking.The present study measured multiple indicators of sleep and circadian rhythms in a sample of adults with OCD, adults without OCD, and healthy controls (n = 74). Participants completed measures of morningness-eveningness, delayed sleep-wake phase disorder (DSWPD), insomnia symptoms, and OCD symptoms, as well as one week of sleep monitoring via a sleep diary and actigraphy.Delayed circadian rhythms (higher eveningness, later mid-sleep timing, and higher rates of DSWPD) and higher insomnia symptoms were observed in those with OCD compared to healthy controls, as well as associations between delayed circadian rhythms and insomnia symptoms and OCD symptom severity across the full sample. Further, insomnia symptoms mediated the relationship between delayed circadian rhythms and OCD symptoms. In contrast, there were no links between total sleep time or sleep quality and OCD.Data collection during COVID-19 pandemic, correlational data, no physiological measure of circadian rhythms.These findings highlight a robust association between delayed circadian rhythms and OCD and suggest insomnia symptoms may be one mechanism in this relationship. Sleep and circadian rhythm disturbance may be novel targets for OCD treatment.

The disruptions induced by the COVID-19 pandemic have forced quick and significant changes to recruitment and admissions practices in colleges of pharmacy. This process has helped to identify barriers and challenges for prospective students. At the University of North Carolina Eshelman School of Pharmacy, some changes were already under consideration prior to the pandemic, such as moving to test-optional admissions and allowing remote interviews, while new considerations included offering the entire recruitment and admissions process remotely.In 2020-2021, the decision was made to move to test-optional admissions. A separate decision was made to conduct interviews remotely. Data from the admission cycle were collected from the Pharmacy College Application Service as part of the standard admissions process and exported for analysis. Descriptive statistics (mean ± SD) were used.Completed applications increased by 59.1% in 2020-2021 from the previous year. Applications increased by 9.8% from underrepresented students, by 6.2% from those with a bachelor's degree, and by 8.4% by out of state students. Other admissions metrics, such as the mean grade point average (3.50) and mean Pharmacy College Admissions Test composite percentile (88%), did not change.The COVID-19 pandemic experience validated our perspective that we must continue to embrace change and seize opportunities to reduce barriers for prospective students to improve access to the profession. The changes that this pandemic has necessitated may help to close the gaps in accessing health professions education.

Additive manufacturing (AM) has emerged as a disruptive technique within healthcare because of its ability to provide personalized devices; however, printed metal parts still present surface and microstructural defects, which may compromise mechanical and biological interactions. This has made physical and/or chemical postprocessing techniques essential for metal AM devices, although limited fundamental knowledge is available on how alterations in physicochemical properties influence AM biological outcomes. For this purpose, herein, powder bed fusion Ti-6Al-4V samples were postprocessed with three industrially relevant techniques: polishing, passivation, and vibratory finishing. These surfaces were thoroughly characterized in terms of roughness, chemistry, wettability, surface free energy, and surface ζ-potential. A significant increase iniStaphylococcus epidermidis/icolonization was observed on both polished and passivated samples, which was linked to high surface free energy donor γsup-/supvalues in the acid-base, γsupAB/supcomponent. Early osteoblast attachment and proliferation (24 h) were not influenced by these properties, although increased mineralization was observed for both these samples. In contrast, osteoblast differentiation on stainless steel was driven by a combination of roughness and chemistry. Collectively, this study highlights that surface free energy is a key driver between AM surfaces and cell interactions. In particular, while low acid-base components resulted in a desired reduction iniS. epidermidis/icolonization, this was followed by reduced mineralization. Thus, while surface free energy can be used as a guide to AM device development, optimization of bacterial and mammalian cell interactions should be attained through a combination of different postprocessing techniques.

Tinnitus impacts between 10–20% of the population. Individuals most troubled by their tinnitus have their attention bound to and are distracted by, their tinnitus percept. While numerous treatments to ameliorate tinnitus have been tried, no therapeutic approach has been clinically accepted. The present study used an established condition-suppression noise-exposure rat model of tinnitus to: (1) examine tinnitus-related changes in nAChR function of layer 5 pyramidal (PNs) and of vasoactive intestinal peptide (VIP) neurons in primary auditory cortex (A1) and (2) examine how the partial desensitizing nAChR agonists, sazetidine-A and varenicline, can act as potential therapeutic agents in the treatment of tinnitus. We posited that tinnitus-related changes in layer 5 nAChR responses may underpin the decline in attentional resources previously observed in this animal model (Brozoski et al., 2019). In vitro whole-cell patch-clamp studies previously revealed a significant tinnitus-related loss in nAChR-evoked excitatory postsynaptic currents from A1 layer 5 PNs. In contrast, VIP neurons from animals with behavioral evidence of tinnitus showed significantly increased nAChR-evoked excitability. Here we hypothesize that sazetidine-A and varenicline have therapeutic benefits for subjects who cannot divert their attention away from the phantom sound in their heads. We found that sazetidine-A or varenicline normalized tinnitus-related reductions in GABAergic input currents onto A1 layer 5 PNs. We then tested sazetidine-A and varenicline for the management of tinnitus using our tinnitus animal model. Subcutaneous injection of sazetidine-A or varenicline, 1 h prior to tinnitus testing, significantly decreased the rat’s behavioral evidence of tinnitus in a dose-dependent manner. Collectively, these results support the need for additional clinical investigations of partial desensitizing nAChR agonists sazetidine-A and varenicline for the treatment of tinnitus.

A dataset to describe exposed bedrock and surficial geology of Antarctica has been constructed by the GeoMAP Action Group of the Scientific Committee on Antarctic Research (SCAR) and GNS Science. Our group captured existing geological map data into a geographic information system (GIS), refined its spatial reliability, harmonised classification, and improved representation of glacial sequences and geomorphology, thereby creating a comprehensive and coherent representation of Antarctic geology. A total of 99,080 polygons were unified for depicting geology at 1:250,000 scale, but locally there are some areas with higher spatial resolution. Geological unit definition is based on a mixed chronostratigraphic- and lithostratigraphic-based classification. Description of rock and moraine polygons employs the international Geoscience Markup Language (GeoSciML) data protocols to provide attribute-rich and queryable information, including bibliographic links to 589 source maps and scientific literature. GeoMAP is the first detailed geological map dataset covering all of Antarctica. It depicts ‘known geology’ of rock exposures rather than ‘interpreted’ sub-ice features and is suitable for continent-wide perspectives and cross-discipline interrogation.

As key components of multi-hazard, cascading slope-to-river systems around the world, landslide dams can have severe consequences. They form when landslides block a watercourse and can result in catastrophic flooding if they fail rapidly. Nonetheless, they are under-researched given the potentially high consequences of sudden dam breach and failure. Their formation, longevity, and breaching behaviour are not well understood, which is important information needed for effective risk management.We present an Aotearoa New Zealand database of landslide dams, spanning pre-historic to historic natural dams compiled from several existing datasets and inventories. The database includes ~1030 landslide dams, as well as information for each dam such as catchment properties, landslide and dam dimensions, dam type, and dam stability where available. Where possible, quantitative attributes have been calculated automatically using arcpy (a Python site package that utilises ArcGIS processing tools), which allows consistency and repeatability in the database. A data quality ranking scheme has also been developed to assess the reliability of each dataset. The database will be available online on the OSF platform in mid-2023.Several case studies, including the Hapuku, Stanton, Leader, Linton, and Conway landslide dams that formed during the 2016 Mw 7.8 Kaikōura earthquake, have been analysed in detail. Multiple field and remote sensing campaigns completed since 2016 – including field mapping, RTK surveying, drone photogrammetry, and LiDAR surveys – show the evolution of the landslide deposits and dams, providing high-resolution spatiotemporal data on their formation and breaching characteristics.The database is currently being analysed to improve our understanding of dam formation potential and longevity, as well as breaching behaviour. These analyses will contribute to improved hazard management and avoidance.

In the past decade, extracellular vesicles (EVs) have emerged as key regulators of bone development, homeostasis and repair. EV-based therapies have the potential to circumnavigate key issues hindering the translation of cell-based therapies including functional tissue engraftment, uncontrolled differentiation and immunogenicity issues. Due to EVs’ innate biocompatibility, low immunogenicity, and high physiochemical stability, these naturally-derived nanoparticles have garnered growing interest as potential acellular nanoscale therapeutics for a variety of diseases. Our increasing knowledge of the roles these cell-derived nanoparticles play, has made them an exciting focus in the development of novel pro-regenerative therapies for bone repair. Although these nano-sized vesicles have shown promise, their clinical translation is hindered due to several challenges in the EV supply chain, ultimately impacting therapeutic efficacy and yield. From the biochemical and biophysical stimulation of parental cells to the transition to scalable manufacture or maximising vesicles therapeutic response in vivo, a multitude of techniques have been employed to improve the clinical efficacy of EVs. This review explores state of the art bioengineering strategies to promote the therapeutic utility of vesicles beyond their native capacity, thus maximising the clinical potential of these pro-regenerative nanoscale therapeutics for bone repair. Graphical Abstract

Background: The EANM Research Ltd. (EARL) guidelines give recommendations for harmonization of [18F]FDG PET-CT image acquisition and reconstruction, aiming to ensure reproducibility of quantitative data between PET scanners. Recent technological advancements in PET-CT imaging resulted in an updated version of the EARL guidelines (EARL2). The aim of this study is to compare quantitative [18F]FDG uptake metrics of the primary tumor and lymph nodes in patients with head and neck squamous cell carcinoma (HNSCC) on EARL2 versus EARL1 reconstructed images and to describe clinical implications for nodal staging and treatment.Methods: Forty-nine consecutive patients with HNSCC were included. For all, both EARL1 and EARL2 images were reconstructed from a singular [18F]FDG PET-CT scan. Primary tumors and non-necrotic lymph nodes ≥ 5mm were delineated on CT-scan. In the quantitative analysis, maximum standardized uptake values (SUVmax) and standardized uptake ratios (SURmax, i.e. SUVmax normalized to cervical spinal cord uptake) were calculated for all lesions on EARL1 and EARL2 reconstructions. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were compared between EARL1 and EARL2 using different segmentation methods (adaptive threshold; SUV2.5/3.5/4.5; SUR2.5/3.5/4.5; MAX40%/50%). In the qualitative analysis, each lymph node was scored independently by two nuclear medicine physicians on both EARL1 and EARL2 images on different occasions using a 4-point scale.Results: There was a significant increase of SUVmax (19%) and SURmax (11%) of primary tumor and lymph nodes on EARL2 versus EARL1 imaging (p max and SURmax between EARL2 and EARL1 decreased with increasing tumor volume (p 3), independent of the segmentation method. Relative differences in MTVs and TLGs were small using the adaptive threshold method and larger using static SUV or SUR thresholds. With visual scoring of lymph nodes 38% (11/29) of nodes with score 2 on EARL1 were upstaged to score 3 on EARL2, which resulted in an alteration of nodal stage in 18% (6/33) of the patients.Conclusions: Using the EARL2 method for PET image reconstruction resulted in higher SUVmax and SURmax compared to EARL1, with nodal upstaging in a significant number of patients.

This is a single pdf file that contains: (1) supplementary methods; (2) supplementary table 1 (microarray glycans), supplementary table 2 (ADCs), and supplementary table 3 (primers); (3) supplementary figure 1 (ch735 Ab expression/purification), supplementary figure 2 (mo735 mAb ELISA), supplementary figure 3 (mo735 glycan microarray profiling), supplementary figure 4 (binding affinity data), supplementary figure 5 (histograms of Ab-stained cell lines), supplementary figure 6 (cell surface binding of cancer cell lines), supplementary figure 7 (CRISPR-Cas knockout cell lines), supplementary figure 8 (internalization of mo735), supplementary figure 9 (colocalization of mo735), and supplementary figure 10 (synthesis of ADC).

The specific targeting of differentially expressed glycans in malignant cells has emerged as an attractive anticancer strategy. One such target is the oncodevelopmental antigen polysialic acid (polySia), a polymer of α2,8-linked sialic acid residues that is largely absent during postnatal development but is re-expressed during progression of several malignant human tumors, including small-cell and non–small cell lung carcinomas, glioma, neuroblastoma, and pancreatic carcinoma. In these cancers, expression of polySia correlates with tumor progression and poor prognosis and appears to modulate cancer cell adhesion, invasiveness, and metastasis. To evaluate the potential of PolySia as a target for anticancer therapy, we developed a chimeric human polySia-specific mAb that retained low nanomolar (nmol/L) target affinity and exhibited exquisite selectivity for polySia structures. The engineered chimeric mAb recognized several polySia-positive tumor cell lines in vitro and induced rapid endocytosis of polySia antigens. To determine whether this internalization could be exploited for delivery of conjugated cytotoxic drugs, we generated an antibody–drug conjugate (ADC) by covalently linking the chimeric human mAb to the tubulin-binding maytansinoid DM1 using a bioorthogonal chemical reaction scheme. The resulting polySia-directed ADC demonstrated potent target-dependent cytotoxicity against polySia-positive tumor cells in vitro. Collectively, these results establish polySia as a valid cell-surface, cancer-specific target for glycan-directed ADC and contribute to a growing body of evidence that the tumor glycocalyx is a promising target for synthetic immunotherapies.Significance:These findings describe a glycan-specific antibody-drug conjugate that establishes polySia as a viable cell surface target within the tumor glycocalyx.

Over the next century, coastal regions are under threat from projected rising sea levels and the potential emergence of groundwater at the land surface (groundwater inundation). The potential economic and social damages of this largely unseen, and often poorly characterised natural hazard are substantial. To support risk-based decision making in response to this emerging hazard, we present a Bayesian modelling framework (or workflow), which maps the spatial distribution of groundwater level uncertainty and inundation under Intergovernmental Panel on Climate Change (IPCC) projections of Sea Level Rise (SLR). Such probabilistic mapping assessments, which explicitly acknowledge the spatial uncertainty of groundwater flow model predictions, and the deep uncertainty of the IPCC-SLR projections themselves, remains challenging for coastal groundwater systems. Our study, therefore, presents a generalisable workflow to support decision makers, that we demonstrate for a case study of a low-lying coastal region in Aotearoa New Zealand. Our results provide posterior predictive distributions of groundwater levels to map susceptibility to the groundwater inundation hazard, according to exceedance of specified model top elevations. We also explore the value of history matching (model calibration) in the context of reducing predictive uncertainty, and the benefits of predicting changes (rather than absolute values) in relation to a decision threshold. The latter may have profound implications for the many at-risk coastal communities and ecosystems, which are typically data poor. We conclude that history matching can indeed increase the spatial confidence of posterior groundwater inundation predictions for the 2030-2050 timeframe.

This paper assesses the state-of-the-art for rubber tire wheel tracking of asphalt mixtures in a laboratory setting with emphasis on differentiating moisture damage from rutting. This assessment made use of a comprehensive literature review and roughly 300 experiments conducted over several years with the second generation of the Purdue Laboratory Wheel Tracker (PURWheel). The literature review revealed that direct separation of rutting from moisture damage with physical measurements taken with a rubber tire under otherwise identical conditions is not common practice. Collective analysis of these roughly 300 experiments revealed that second-generation PURWheel protocols offer two specific contributions to the asphalt mixture testing community: (1) a pneumatic rubber tire is used, which is most representative of vehicle traffic; and (2) the effects of moisture damage can be decoupled from rutting by testing under both wet and dry conditions where all other parameters are constant. The analysis was performed on data collected for other purposes, but the data did provide seven manners to evaluate moisture damage and three manners to evaluate variability in the context of standardizing protocols. These 10 evaluations clearly demonstrated the potential of rubber tire wheel tracking to improve characterization of asphalt mixtures beyond what has occurred to date. This paper works toward standardization of protocols for rubber tire wheel tracking in wet and dry conditions, and some discussion is provided on the status and needed advancements toward this eventual goal.

INTRODUCTION: The effects on offspring craniofacial bone morphology and accretion because of altered maternal exposure to dietary components such as calcium (Ca) and phosphorus (P) are unclear. The objective of this study was to investigate the changes in offspring skull morphology and tissue mineral density (TMD), including sex-specific changes, with exposure to a maternal diet high in Ca-to-P levels during gestation and lactation in mice. METHODS: Time-mated FVB wild-type mice were fed a normal or experimental diet during gestation until weaning. The experimental diet contained a 3-fold increase in Ca and a 3-fold decrease in P (Ca:P molar ratio, 10.5) compared with normal mouse chow (Ca:P molar ratio, 1.5). The heads of 6-week-old control and experimental offspring mice were collected and scanned using microcomputed tomography. Three-dimensional geometric morphometric analysis was performed to analyze changes in craniofacial morphology. TMD measurements were also analyzed. RESULTS: We observed subtle changes and no significant differences between offspring control and experimental skulls when we compared all samples. However, when we separated skulls by sex, we discovered significant differences in craniofacial morphology and TMD. Experimental female offspring possessed skulls that were smaller, narrower transversely, taller vertically, and decreased in TMD. Experimental male offspring possessed skulls that were larger, wider transversely, shorter vertically, and increased in TMD. CONCLUSIONS: Maternal exposure to diet and increased Ca:P molar ratio during gestation and lactation led to significant, sex-specific morphologic and TMD changes in 6-week-old mouse skulls.

Antibody–drug conjugates (ADC) have emerged as one of the pillars of clinical disease management in oncology. The biggest hurdle to widespread development and application of ADCs has been a narrow therapeutic index. Advances in antibody technologies and formats as well as novel linker and payload chemistries have begun to facilitate structural improvements to ADCs. However, the interplay of structural characteristics with physiologic and pharmacologic factors determining therapeutic success has garnered less attention. This review elaborates on the pharmacology of ADCs, the pathophysiology of cancerous tissues, and the reciprocal consequences on ADC properties and functions. While most currently approved ADCs utilize either microtubule inhibition or DNA damage as primary mechanisms of action, we present arguments to expand this repertoire and highlight the need for payload mechanisms that exploit disease-specific vulnerabilities. We promote the idea that the choice of antibody format, targeting antigen, linker properties, and payload of an ADC should be deliberately fit for purpose by taking the pathophysiology of disease and the specific pharmacology of the drug entity into account, thus allowing a higher probability of clinical success.

Corneal transplantation is the current gold standard treatment to restore visual acuity to patients with severe corneal diseases and injuries. Due to severe donor tissue shortage, efforts to develop a corneal equivalent have been made but the challenge remains unmet. Another issue of concern in ocular surgery is the difficult instillation and fast drainage of antibiotic ocular eye drops as bacterial infections can jeopardize implant success by delaying or impairing tissue healing. In this study, we developed antimicrobial silk-based hydrogels that have the potential to be photoactivated in situ, fully adapting to the corneal injury shape. Gentamicin-loaded methacrylated-silk (SilkMA) hydrogels were prepared within minutes using low UV intensity (3 mW/cm

Introduction Aseptic tibial loosening is now considered the most common reason that total knee arthroplasties (TKA) fail long-term. There are unique subsets of patients that fail into varus alignment of the tibial tray with collapse of the medial proximal tibia. In these patients with varus collapse of the tibia, there is a combination of medial tibial bone collapse and tibial implant loosening. However, it is currently unknown if the implant fixation fails first or if the proximal medial tibia collapses first. Therefore, the following study was designed to answer this question. Materials We performed a retrospective analysis of 88 patients that were revised at our institution secondary to aseptic varus collapse of the proximal tibia. Two fellowship trained Arthroplasty surgeons performed a retrospective analysis on a series of precollapse radiographs in each patient to determine which failed first: the implant fixation (implant-cement or cement-bone interface) or the medial proximal tibia. Discussion 36/88 (40.9%) patients had a series of precollapse radiographs that could be reviewed. Reviewer one identified 23 (63.9%) patients with radiographic evidence of failure at the implant-cement interface before varus collapse, two (5.6%) patients had a mixed pattern of failure at the implant-cement and cement-bone interface before varus collapse, and 11 (30.6%) patients had contemporaneous failure at the implant-cement interface and varus collapse of the proximal tibia. Reviewer two identified 22 (61.1%) at the implant-cement interface, two (5.6%) with a mixed pattern, and 12 (33.3%) with contemporaneous failure and varus collapse. Conclusion The most frequent mechanism of failure identified was failure of the implant-cement interface followed by subsequent medial tibial varus collapse. Improving implant fixation may decrease the incidence of this unique failure mechanism. We advocate the use of supplemental stem fixation in high-risk patients and optimal cement techniques for all patients as methods of potentially avoiding tibial varus collapse, and subsequent bone loss.

This study investigates the relationship between societal temporal orientation and level of innovation. Previous studies linking culture to innovation have predominantly focused on individualism, uncertainty avoidance, power distance, and masculinity as determinants of innovation – overlooking temporal orientation. Utilizing theory from sociology and psychology, we elucidate temporal orientation as an important aspect of culture that can promote innovation. We hypothesize and find evidence for the effect of temporal orientation on three different stages of the innovation process. Results suggest temporal orientation dimensions of culture have important implications for innovation at the country level. Additionally, we find differences in effect between the temporal orientation conceptualizations of Hofstede and the GLOBE project. Our results provide evidence to strengthen theory regarding temporal orientation phenomena. Such implications are discussed along with future research directions.