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Planktic foraminifera are key producers of pelagic carbonate, and their shell weight is suggested to have been influenced by the environment in which they calcify. However, there is debate about the use of size-normalised weight (SNW) as a proxy, as some authors invoke a carbonate system control on calcification (and by extension SNW as a pCO2 proxy), while others suggest that species optimum conditions, nutrient concentration, or temperature drive shell weight. To better understand this proxy, we investigate what drives SNW and whether discrepancies in the proposed control on weight are due to differing data collection methodologies and/or regionally different drivers. We integrate new and published SNW data with environmental hindcast data from the CMIP6 modelling suite. Using Bayesian regression modelling, we find that the environment alone does not explain the variability in SNW across species. Although physiology likely modulates the response to the environment, we find little evidence of a unifying driver at the ecogroup level. Instead, we identify species-specific responses associated with drivers including (but not limited to) the carbonate system, which are likely different between ocean basins. We hypothesise that this is partly influenced by cryptic species and regional phenotypic plasticity in changes to shell weight that are not well understood, such as the thickness of calcite deposited during some species' reproductive phases. Consequently, which species to use as a pCO2 proxy or whether multiple species should be used in parallel to reduce uncertainty should be carefully considered. We strongly encourage the regional testing and calibration of pCO2–SNW relationships.

A concern in weed biological control research is the potential for candidate biocontrol agents to impact not only the target weed but also native or economically important flora. The degree of evolutionary relatedness between the target weed species and a non-target species is a key predictor of the susceptibility of the non-target to the biocontrol agent. To manage this risk, biocontrol practitioners need to understand the phylogenetic position of the host weed relative to non-target plant species. However, comprehensively sampled phylogenetic trees are often unavailable, with incomplete information scattered across multiple publications. Further, older published phylogenies based on Sanger sequence data often lack branch resolution and support, which increases uncertainty in biocontrol decision making. Decreasing sequencing cost and technological advances have led to phylogenomic approaches being more widely used to understand evolutionary relationships between species. For example, target capture sequencing methods using bait kits such as Angiosperms353 enable cost-effective and timely phylogenomic-level analysis of flowering plant groups at different scales. Here, we introduce a workflow to embed a comprehensive understanding of evolutionary relationships into the efficient development of host test lists in weed biological control. We demonstrate the effectiveness of the workflow through a case study on the major crop weed flaxleaf fleabane (Erigeron bonariensis). Phylogenomic analysis was conducted on 280 species of the tribe Astereae (family Asteraceae) occurring in Australia and New Zealand, clarifying relationships between the target species and related clades of native and non-native Astereae. We consider the phylogenetic tree in the context of a previously proposed host test list and discuss taxonomic implications, highlighting avenues of future molecular-based work to uncover the origin of Australian fleabanes. This study provides a workflow and demonstrates the practical application of target sequence capture for phylogenomic inference to support risk analysis and decision making in classical weed biological control.

Two adult women with cystic fibrosis (CF) who developed colonic carcinoma, both at age 31, are described. In both patients the carcinoma occurred in the midtransverse colon. The diagnosis had not been suspected, partly because of the patients’ relatively young age. In case 1, the symptoms also mimicked the distal intestinal obstruction syndrome. At diagnosis she was shown to have metastases to the regional lymph nodes. In case 2, despite a long history of chronic pulmonary and sinus disorders, CF was not diagnosed until the patient was 36 years old. The incidence of gastrointestinal malignancies has been shown to be significantly increased in patients with CF. As the life expectancy of the CF population increases, vigilance for gastrointestinal cancers in CF patients is important, as illustrated by these two cases.

Abstract A growing number of studies have investigated the feasibility of utilizing hemp by-products as livestock feedstuffs; however, their impact on livestock microbiomes remains unexplored. Here, we evaluated the effects of feeding hempseed cake on the gastrointestinal, respiratory, and reproductive microbiota in beef heifers. Angus-crossbred heifers (19-months old, initial body weight = 494 ± 10 kg [SE]) were fed a corn-based finishing diet containing 20% hempseed cake as a substitute for 20% corn dried distillers’ grains with solubles (DM basis; Control; n = 16/group) for 111 days until slaughter. Ruminal fluid and deep nasopharyngeal swabs (days 0, 7, 42, 70 and 98), and vaginal and uterine swabs (at slaughter) were collected, and the microbiota assessed using 16S rRNA gene sequencing. Diet affected the community structure of the ruminal (d 7−98; 0.06 ≤ R2 ≤ 0.12; P

Periodic meltwater pulses from the Laurentide-Greenland Ice Sheets during the last deglaciation drove abrupt changes in sea surface temperature and sea ice extent, according to sediment core biomarker proxy records from the Eirik Drift, eastern Labrador Sea

Planktic foraminifera are major marine calcifiers in the modern ocean, regulating the marine inorganic carbon pump, and generating marine fossil archives of past climate change. The foraminifera contain ecogroups with and without spines and algal symbionts, creating functional trait diversity which expands their ecological niches. Here, we incorporate symbiosis and spine traits into the symbiont-barren non-spinose foraminifer functional type in EcoGEnIE to represent all the extant foraminifera species. We calibrated the modelled new traits using Latin hypercube sampling (LHS) and identified the optimal model parameters from an ensemble of 1200 runs compared with global observations from core-top sediment samples, sediment traps, and plankton nets. The model successfully describes the global distribution and seasonal abundance variation of the four major foraminiferal functional groups. The model reproduces the dominance of the symbiont-obligate group in subtropical gyres and of the symbiont-barren types in the productive subpolar oceans. Global annual mean biomass and foraminifer-derived carbon export rate are correctly predicted compared to data, with biomass ranging from 0.001 to 0.010 mmol C m−3 and organic carbon export 0.002–0.031 mmol C m−2 d−1. The model captures the seasonal peak time of biomass and organic carbon export but struggles to reproduce the amplitude of both in productive areas. The sparseness and uneven distribution of observations and the model's limitation in upwelling regions likely contribute to this discrepancy. Our model overcomes the lack of major groups in the previous ForamEcoGEnIE 1.0 version and offers the potential to explore foraminiferal ecology dynamics and its impact on biogeochemistry in modern, future, and paleogeographic environments.

When testing the virucidal activity of biocides, the non-inactivated residual virus is titrated on cell cultures by the end point dilution method on 96-well tissue culture plates. However, residues of the biocide to be tested also come into contact with the cell cultures in varying concentrations and thus can lead to cytotoxic effects even at high levels of dilution. In the European standards for testing biocides, in particular disinfectants, methods such as Large-Volume-Plating (LVP) method and, in some guidelines, gel filtration procedures are described for reducing cytotoxic effects in the case of highly cytotoxic products, if the classical dilution method proves to be impractical.In order to enable the testing of highly cytotoxic biocides for their activity against viruses, an alternative method for reducing cytotoxicity is introduced, which is based on a procedure of isolating infectious viruses from cytotoxic patients’ materials such as stool and can be applied when the other methods fail.

Abstract Background A lack of undergraduate medical curricula on providing healthcare to transgender and gender diverse (TGD) patients has contributed to significant health disparities for TGD communities. To address this gap, we designed and evaluated a novel curriculum to train Obstetrics and Gynecology (OB/GYN) clerkship students in caring for TGD patients. Methods Following Kern’s 6-step method for curriculum development, we created a two-part curriculum on TGD healthcare topics – an online module on gender-affirming care, followed by a series of interactive cases on TGD-specific health topics. Undergraduate medical students completing their core OB/GYN clerkships at a university academic medical center (January-December 2021) were invited to complete this curriculum. Participants completed pre/post assessment surveys to assess their experience caring for TGD patients, as well as a scored knowledge assessment before and after completing the curriculum. Results Sixty-five students participated in this curricular assessment. Prior to completing the module, 45% agreed that they had received adequate TGD health training. Following module completion, students reported increased comfort in caring for transgender patients (49.2% vs. 81.5%; p

Abstract Premise The HybPiper pipeline has become one of the most widely used tools for the assembly of target capture data for phylogenomic analysis. After the production of locus sequences and before phylogenetic analysis, the identification of paralogs is a critical step for ensuring the accurate inference of evolutionary relationships. Algorithmic approaches using gene tree topologies for the inference of ortholog groups are computationally efficient and broadly applicable to non‐model organisms, especially in the absence of a known species tree. Methods and Results We containerized and expanded the functionality of both HybPiper and a pipeline for the inference of ortholog groups, providing novel options for the treatment of target capture sequence data, and allowing seamless use of the outputs of the former as inputs for the latter. The Singularity container presented here includes all dependencies, and the corresponding pipelines (hybpiper‐nf and paragone‐nf, respectively) are implemented via two Nextflow scripts for easier deployment and to vastly reduce the number of commands required for their use. Conclusions The hybpiper‐nf and paragone‐nf pipelines are easily installed and provide a user‐friendly experience and robust results to the phylogenetic community. They are used by the Australian Angiosperm Tree of Life project. The pipelines are available at https://github.com/chrisjackson-pellicle/hybpiper-nf and https://github.com/chrisjackson-pellicle/paragone-nf.

Early life microbial colonization and factors affecting colonization patterns are gaining interest due to recent developments suggesting that early life microbiome may play a role in Developmental Origins of Health and Disease. In cattle, limited information exists on the early microbial colonization of anatomical sites involved in bovine health beyond the gastrointestinal tract. Here, we investigated 1) the initial microbial colonization of seven different anatomical locations in newborn calves and 2) whether these early life microbial communities and 3) serum cytokine profiles are influenced by prenatal vitamin and mineral (VTM) supplementation. Samples were collected from the hoof, liver, lung, nasal cavity, eye, rumen (tissue and fluid), and vagina of beef calves that were born from dams that either received or did not receive VTM supplementation throughout gestation (n = 7/group). Calves were separated from dams immediately after birth and fed commercial colostrum and milk replacer until euthanasia at 30 h post-initial colostrum feeding. The microbiota of all samples was assessed using 16S rRNA gene sequencing and qPCR. Calf serum was subjected to multiplex quantification of 15 bovine cytokines and chemokines. Our results indicated that the hoof, eye, liver, lung, nasal cavity, and vagina of newborn calves were colonized by site-specific microbiota, whose community structure differed from the ruminal-associated communities (0.64 ≥ R2 ≥ 0.12, p ≤ 0.003). The ruminal fluid microbial community was the only one that differed by treatment (p < 0.01). However, differences (p < 0.05) by treatment were detected in microbial richness (vagina); diversity (ruminal tissue, fluid, and eye); composition at the phylum and genus level (ruminal tissue, fluid, and vagina); and in total bacterial abundance (eye and vagina). From serum cytokines evaluated, concentration of chemokine IP-10 was greater (p = 0.02) in VTM calves compared to control calves. Overall, our results suggest that upon birth, the whole-body of newborn calves are colonized by relatively rich, diverse, and site-specific bacterial communities. Noticeable differences were observed in ruminal, vaginal, and ocular microbiota of newborn calves in response to prenatal VTM supplementation. These findings can derive future hypotheses regarding the initial microbial colonization of different body sites, and on maternal micronutrient consumption as a factor that may influence early life microbial colonization.

Abstract A passive‐adaptive slat concept was designed to avoid separation in the root region of a horizontal‐axis wind turbine blade. This concept incorporates an autonomously moveable slat device only driven by the aerodynamic forces acting on it without the need for mechanical or electrical actuation. It opens at high local angles of attack to delay the stall angle and closes for small angles of attack to increase the lift to drag ratio of the blade segment. This article describes the development of a passive‐adaptive slat for a DU‐91‐W2‐250 airfoil, which is a segment of the reference rotor blade in the project SmartBlades 2.0. In the course of the passive‐adaptive slat design, the optimization of the slat and its extended position is presented. This is followed by the development of two passive‐adaptive slat kinematics, which are opening and closing the slat passively at different angles of attack. With the designed passive‐adaptive slat the stall of the airfoil is delayed by 20° in incidence and the maximum lift of the airfoil is increased by about 130% at the same time in comparison to the original airfoil. Furthermore, the DU‐91‐W2‐250 airfoil with moveable passive‐adaptive slat has in most conditions a higher climb index and therefore a better aerodynamic performance than the same airfoil with a fixed integrated slat.

Abstract Background Gangliosides are glycosphingolipids highly enriched in the brain, with important roles in cell signaling, cell-to-cell communication, and immunomodulation. Genetic defects in the ganglioside biosynthetic pathway result in severe neurodegenerative diseases, while a partial decrease in the levels of specific gangliosides was reported in Parkinson’s disease and Huntington’s disease. In models of both diseases and other conditions, administration of GM1—one of the most abundant gangliosides in the brain—provides neuroprotection. Most studies have focused on the direct neuroprotective effects of gangliosides on neurons, but their role in other brain cells, in particular microglia, is not known. In this study we investigated the effects of exogenous ganglioside administration and modulation of endogenous ganglioside levels on the response of microglia to inflammatory stimuli, which often contributes to initiation or exacerbation of neurodegeneration. Methods In vitro studies were performed using BV2 cells, mouse, rat, and human primary microglia cultures. Modulation of microglial ganglioside levels was achieved by administration of exogenous gangliosides, or by treatment with GENZ-123346 and L–t-PDMP, an inhibitor and an activator of glycolipid biosynthesis, respectively. Response of microglia to inflammatory stimuli (LPS, IL-1β, phagocytosis of latex beads) was measured by analysis of gene expression and/or secretion of pro-inflammatory cytokines. The effects of GM1 administration on microglia activation were also assessed in vivo in C57Bl/6 mice, following intraperitoneal injection of LPS. Results GM1 decreased inflammatory microglia responses in vitro and in vivo, even when administered after microglia activation. These anti-inflammatory effects depended on the presence of the sialic acid residue in the GM1 glycan headgroup and the presence of a lipid tail. Other gangliosides shared similar anti-inflammatory effects in in vitro models, including GD3, GD1a, GD1b, and GT1b. Conversely, GM3 and GQ1b displayed pro-inflammatory activity. The anti-inflammatory effects of GM1 and other gangliosides were partially reproduced by increasing endogenous ganglioside levels with L–t-PDMP, whereas inhibition of glycolipid biosynthesis exacerbated microglial activation in response to LPS stimulation. Conclusions Our data suggest that gangliosides are important modulators of microglia inflammatory responses and reveal that administration of GM1 and other complex gangliosides exerts anti-inflammatory effects on microglia that could be exploited therapeutically.

Background: Women experiencing homelessness with substance use disorders face unique and intersecting barriers to realizing their reproductive goals. Objective: This study explored the reproductive aspirations of this population, as well as the barriers to accessing reproductive services from the perspectives of affected individuals, and the healthcare providers who serve them. Design: This mixed-methods study included surveys and interviews with women experiencing homelessness with substance use disorders and healthcare providers. Methods: We conducted surveys and semi-structured interviews with women recruited from opiate treatment programs and homeless encampments in San Francisco, California in 2018. We also conducted interviews and focus groups with healthcare providers in reproductive health and substance use treatment settings. Interviews were recorded, transcribed, and coded. Descriptive statistics of survey results were performed. Results: Twenty-eight women completed surveys, 96% of whom reported current substance use. Ten women participated in interviews. One-third (9/28) reported desiring pregnancy in the next year; over half (16/28) reported they would be somewhat or very happy to learn they were pregnant. A majority used no contraception at last intercourse (14/28). Twenty-six healthcare providers participated in interviews (n = 15) and focus groups (n = 2). Patients and providers identified similar barriers to care access, including discrimination, logistical and financial challenges, and delayed pregnancy awareness. While providers proposed solutions focused on overcoming logistical challenges, patients emphasized the importance of transforming the healthcare environment to treat patients affected by substance use and homelessness with dignity and respect. Conclusion: Women experiencing homelessness with substance use disorders face intersecting and compounding barriers to accessing reproductive health services. For patients, the impact of stigma and bias on treatment experiences are particularly salient, in contrast to logistical barriers emphasized by providers. Improving access will require structural and individual-level solutions to address stigma and create person-centered, trauma-informed, and respectful care environments.

Climate change is impacting marine seascapes against a backdrop of multiple anthropogenic stressors. These current impacts are projected to increase in the future with increasing warming, acidification, oxygen loss, and sea level rise. Marine Protected Areas (MPAs) have been established to protect features in the ocean, traditionally with a focus to reduce fishing pressures and infrastructure placements. These MPAs are static in nature and are rarely considering climate change; therefore, their potential adaptation effectiveness as local adaptation measures for conservation in response to climate change are not clear. Here we discuss the challenges to Marine Protected Areas as conservation tools and for adaptation to climate change threats. We use two case studies from the UK to ask how climate change resilience could be included in MPA management to future-proof these conservation measures. We conclude that the resilience of MPAs to climate change would be better supported when adaptive management measures and an ecosystem-based approaches are adopted. We emphasise the need to increase the recognition in the primary legislation of MPAs and the monitoring of sites to better understand climate change as it becomes more pronounced, and impacts emerge.

Abstract We build random forests models to predict elastic properties and mechanical hardness of a compound, using only its chemical formula as input. The model training uses over 10,000 target compounds and 60 features based on stoichiometric attributes, elemental properties, orbital occupations, and ionic bonding levels. Using the models, we construct triangular graphs for B-C-N compounds to map out their bulk and shear moduli, as well as hardness values. The graphs indicate that a 1:1 B-N ratio can lead to various superhard compositions. We also validate the machine learning results by evolutionary structure prediction and density functional theory. Our study shows that BC10N, B4C5N3, and B2C3N exhibit dynamically stable phases with hardness values >40 GPa, which are superhard materials that potentially could be synthesized by low-temperature plasma methods.

Latent Profile Analysis (LPA) is a method to extract homogeneous clusters characterized by a common response profile. Previous works employing LPA to human value segmentation tend to select a small number of moderately homogeneous clusters based on model selection criteria such as Akaike information criterion, Bayesian information criterion and Entropy. The question is whether a small number of clusters is all that can be gleaned from the data. While some studies have carefully compared different statistical model selection criteria, there is currently no established criteria to assess if an increased number of clusters generates meaningful theoretical insights. This article examines the content and meaningfulness of the clusters extracted using two algorithms: Variational Bayesian LPA and Maximum Likelihood LPA. For both methods, our results point towards eight as the optimal number of clusters for characterizing distinctive Schwartz value typologies that generate meaningful insights and predict several external variables.

MAPM (Mapping Air Pollution eMissions) is a project whose goal is to develop a method to infer airborne particulate matter (PM) emissions maps from in situ PM concentration measurements. In support of MAPM, a winter field campaign was conducted in New Zealand in 2019 (June to September) to obtain the measurements required to test and validate the MAPM methodology. Two different types of instruments measuring PM were deployed: ES-642 remote dust monitors (17 instruments) and Outdoor Dust Information Nodes (ODINs; 50 instruments). The measurement campaign was bracketed by two intercomparisons where all instruments were co-located, with a permanently installed tapered element oscillating membrane (TEOM) instrument, to determine any instrument biases. Changes in biases between the pre- and post-campaign intercomparisons were used to determine instrument drift over the campaign period. Once deployed, each ES-642 was co-located with an ODIN. In addition to the PM measurements, meteorological variables (temperature, pressure, wind speed, and wind direction) were measured at three automatic weather station (AWS) sites established as part of the campaign, with additional data being sourced from 27 further AWSs operated by other agencies. Vertical profile measurements were made with 12 radiosondes during two 24 h periods and complimented measurements made with a mini micropulse lidar and ceilometer. Here we present the data collected during the campaign and discuss the correction of the measurements made by various PM instruments. We find that when compared to measurements made with a simple linear correction, a correction based on environmental conditions improves the quality of measurements retrieved from ODINs but results in over-fitting and increases the uncertainties when applied to the more sophisticated ES-642 instruments. We also compare PM2.5 and PM10 measured by ODINs which, in some cases, allows us to identify PM from natural and anthropogenic sources. The PM data collected during the campaign are publicly available from https://doi.org/10.5281/zenodo.4542559 (Dale et al., 2020b), and the data from other instruments are available from https://doi.org/10.5281/zenodo.4536640 (Dale et al., 2020a).

Abstract The southern Great Plains of the USA has great potential to produce biofuel feedstock while minimizing the dual stresses of woody plant encroachment and climate change. Switchgrass (Panicum virgatum) cultivation, woody biomass captured during removal of the encroaching eastern redcedar (Juniperus virginiana) to restore grasslands and thinning of the native oak forest can provide an integrated source of feedstock and improve ecosystem services. In north‐central Oklahoma, we quantified productivity and ecosystem water use of switchgrass stands and degraded ecosystems encroached by eastern redcedar and compared these to native oak forest and tallgrass prairie ecosystems. We measured aboveground net primary productivity (ANPP) using allometric equations (trees) and clip plots (herbaceous), and evapotranspiration (ET) using a water balance approach from gauged watersheds, and calculated water use efficiency (WUE = ANPP/ET) from 2016 to 2019. Among vegetation cover types, ANPP averaged 5.1, 5.4, 6.0, and 7.8 Mg ha−1 year−1 for the prairie, oak, eastern redcedar, and switchgrass watersheds and was significantly greater for switchgrass in 2018 and 2019 (2 and 3 years post establishment) when it reached 8.6 Mg ha−1 year−1. Averaged across 2017–2019, ET was significantly greater in the forested watersheds than the grassland watersheds (1022 mm year−1 for eastern redcedar, 1025 mm year−1 for oak, 874 mm year−1 for prairie, and 828 mm year−1 for switchgrass). The mean WUE was significantly greater (9.47 kg ha−1 mm−1) for switchgrass than for the prairie, eastern redcedar, and oak cover types (6.03, 6.02, and 5.31 kg ha−1 mm−1). Switchgrass offered benefits of greater ANPP, less ET, and greater WUE. Our findings indicate that an integrated biofuel feedstock system that includes converting eastern redcedar encroached areas to switchgrass and thinning the oak forest can increase productivity, increase runoff to streams, and improve ecosystem services.

Climate change is impacting organisms in every region of the world ocean by acting though on individuals in response to their local environments. Given projected future risks derived from these changes, it is becoming increasingly important to understand regional signals of how organisms respond to facilitate their governance and protection. Benthic organisms structure ecological compositions and ecosystem dynamics, therefore not only providing insights into their own response to climate change but also how ecosystems might respond to future conditions. European seas are transitional areas including boreal, warm-temperate, and subarctic waters with organisms frequently at limits of their distributions. Here, we use a meta-analytical approach to assess how calcification, growth, metabolism, photosynthesis, reproduction, and survival in European benthic organisms respond to ocean acidification and warming. Using meta-regression, we examine how study design factors influence effect-size outcomes. Longer experimental periods generally amplified the effects of climate change on taxonomic groupings and related physiological traits and against expectation do not result in acclimation. In agreement with global studies, we find that impacts vary considerably on different taxonomic groupings and their physiological traits. We found calcifying organisms are an at-risk taxon in European waters, with climate stressors decreasing growth rates, reproduction, and survival rates. Fleshy algal species demonstrate resilience to climate stressors, suggesting future European benthic ecosystems will undergo restructuring based on current climate emission pathways.

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of immunomodulatory receptors expressed on cells of the hematopoietic lineage. Here the authors demonstrate an approach for the identification of the glycan ligands of Siglecs, which is also applicable to other families of glycan-binding proteins.

Modern diffusion and functional magnetic resonance imaging (dMRI/fMRI) provide non-invasive high-resolution images from which multi-layered networks of whole-brain structural and functional connectivity can be derived. Unfortunately, the lack of observed correspondence between the connectivity profiles of the two modalities challenges the understanding of the relationship between the functional and structural connectome. Rather than focusing on correspondence at the level of connections we presently investigate correspondence in terms of modular organization according to shared canonical processing units. We use a stochastic block-model (SBM) as a data-driven approach for clustering high-resolution multi-layer whole-brain connectivity networks and use prediction to quantify the extent to which a given clustering accounts for the connectome within a modality. The employed SBM assumes a single underlying parcellation exists across modalities whilst permitting each modality to possess an independent connectivity structure between parcels thereby imposing concurrent functional and structural units but different structural and functional connectivity profiles. We contrast the joint processing units to their modality specific counterparts and find that even though data-driven structural and functional parcellations exhibit substantial differences, attributed to modality specific biases, the joint model is able to achieve a consensus representation that well accounts for both the functional and structural connectome providing improved representations of functional connectivity compared to using functional data alone. This implies that a representation persists in the consensus model that is shared by the individual modalities. We find additional support for this viewpoint when the anatomical correspondence between modalities is removed from the joint modeling. The resultant drop in predictive performance is in general substantial, confirming that the anatomical correspondence of processing units is indeed present between the two modalities. Our findings illustrate how multi-modal integration admits consensus representations well-characterizing each individual modality despite their biases and points to the importance of multi-layered connectomes as providing supplementary information regarding the brain's canonical processing units.

Doses of irradiation above 25 ​kGy are known to cause irreversible mechanical decay in bone tissue. However, the impact of irradiation doses absorbed in a clinical setting on the mechanical properties of bone remains unclear. In daily clinical practice and research, patients and specimens are exposed to irradiation due to diagnostic imaging tools, with doses ranging from milligray to Gray. The aim of this study was to investigate the influence of irradiation at these doses ranges on the mechanical performance of bone independent of inter-individual bone quality indices.Therefore, cortical bone specimens (n ​= ​10 per group) from a selected organ donor were irradiated at doses of milligray, Gray and kilogray (graft tissue sterilization) at five different irradiation doses. Three-point bending was performed to assess mechanical properties in the study groups.Our results show a severe reduction in mechanical performance (work to fracture: 50.29 ​± ​11.49 Nmm in control, 14.73 ​± ​1.84 Nmm at 31.2 ​kGy p ​≤ ​0.05) at high irradiation doses of 31.2 ​kGy, which correspond to graft tissue sterilization or synchrotron imaging. In contrast, no reduction in mechanical properties were detected for doses below 30 ​Gy. These findings are further supported by fracture surface texture imaging (i.e. more brittle fracture textures above 31.2 ​kGy).Our findings show that high radiation doses (≥31.2 ​kGy) severely alter the mechanical properties of bone. Thus, irradiation of this order of magnitude should be taken into account when mechanical analyses are planned after irradiation. However, doses of 30 ​Gy and below, which are common for clinical and experimental imaging (e.g., radiation therapy, DVT imaging, CT imaging, HR-pQCT imaging, DXA measurements, etc.), do not alter the mechanical bending-behavior of bone.

Abstract Zinc protoporphyrin (ZnPP), a naturally occurring metalloprotoporphyrin (MPP), is currently under development as a chemotherapeutic agent although its mechanism is unclear. When tested against other MPPs, ZnPP was the most effective DNA synthesis and cellular proliferation inhibitor while promoting apoptosis in telomerase positive but not telomerase negative cells. Concurrently, ZnPP down‐regulated telomerase expression and was the best overall inhibitor of telomerase activity in intact cells and cellular extracts with IC50 and EC50 values of ca 2.5 and 6 µM, respectively. The natural fluorescence properties of ZnPP enabled direct imaging in cellular fractions using non‐denaturing agarose gel electrophoresis, western blots, and confocal fluorescence microscopy. ZnPP localized to large cellular complexes (>600 kD) that contained telomerase and dysskerin as confirmed with immunocomplex mobility shift, immunoprecipitation, and immunoblot analyses. Confocal fluorescence studies showed that ZnPP co‐localized with telomerase reverse transcriptase (TERT) and telomeres in the nucleus of synchronized S‐phase cells. ZnPP also co‐localized with TERT in the perinuclear regions of log phase cells but did not co‐localize with telomeres on the ends of metaphase chromosomes, a site known to be devoid of telomerase complexes. Overall, these results suggest that ZnPP does not bind to telomeric sequences per se, but alternatively, interacts with other structural components of the telomerase complex to inhibit telomerase activity. In conclusion, ZnPP actively interferes with telomerase activity in neoplastic cells, thus promoting pro‐apoptotic and anti‐proliferative properties. These data support further development of natural or synthetic protoporphyrins for use as chemotherapeutic agents to augment current treatment protocols for neoplastic disease.

Many tissue-specific stem cells maintain the ability to produce multiple cell types during long periods of non-division, or quiescence. FOXO transcription factors promote quiescence and stem cell maintenance, but the mechanisms by which FOXO proteins promote multipotency during quiescence are still emerging. The single FOXO ortholog in C. elegans, daf-16, promotes entry into a quiescent and stress-resistant larval stage called dauer in response to adverse environmental cues. During dauer, stem and progenitor cells maintain or re-establish multipotency to allow normal development to resume after dauer. We find that during dauer, daf-16/FOXO prevents epidermal stem cells (seam cells) from prematurely adopting differentiated, adult characteristics. In particular, dauer larvae that lack daf-16 misexpress collagens that are normally adult-enriched. Using col-19p::gfp as an adult cell fate marker, we find that all major daf-16 isoforms contribute to opposing col-19p::gfp expression during dauer. By contrast, daf-16(0) larvae that undergo non-dauer development do not misexpress col-19p::gfp. Adult cell fate and the timing of col-19p::gfp expression are regulated by the heterochronic gene network, including lin-41 and lin-29. lin-41 encodes an RNA-binding protein orthologous to LIN41/TRIM71 in mammals, and lin-29 encodes a conserved zinc finger transcription factor. In non-dauer development, lin-41 opposes adult cell fate by inhibiting the translation of lin-29, which directly activates col-19 transcription and promotes adult cell fate. We find that during dauer, lin-41 blocks col-19p::gfp expression, but surprisingly, lin-29 is not required in this context. Additionally, daf-16 promotes the expression of lin-41 in dauer larvae. The col-19p::gfp misexpression phenotype observed in dauer larvae with reduced daf-16 requires the downregulation of lin-41, but does not require lin-29. Taken together, this work demonstrates a novel role for daf-16/FOXO as a heterochronic gene that promotes expression of lin-41/TRIM71 to contribute to multipotent cell fate in a quiescent stem cell model.