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Abstract The investigation of tectonic controls on CH4 and CO2 emissions was conducted by measuring the fluxes of the gases in the different tectonic units along the northwestern margin of the Ordos Block in China, a region renowned for its intricate tectonic configuration. The mean fluxes of CH4 ranged from −1.5 to 1.1 mg m−2 d−1, while CO2 fluxes spanned from 2.0 to 29.2 g m−2 d−1. Notably, the Minqin, Ordos, and Haiyuan blocks primarily exhibited absorption characteristics for CH4. In contrast, within the Hetao and Yinchuan grabens, both degassing and absorption processes coexist. A striking observation was that blocks with high internal deformation exhibited significantly higher CH4 and CO2 fluxes compared to those in the stable blocks. Additionally, regions experiencing extensional deformation demonstrated greater gas emission than those undergoing compressional deformation. The spatial distribution of CH4 and CO2 fluxes at the study points exhibited a similar trend to faults in the Yinchuan Graben. Our findings revealed that CH4 and CO2 are mainly of biogenic origin, accompanied by abiotic emissions from underground. And the gas source, migration pathway, and tectonic stress were the primary factors influencing gas emission, with tectonic stress playing a pivotal role. This stress controlled the formation of tectonic structures, changed the degassing pathway, and served as the driving force for gas migration. The results of this study offer valuable insights into the mechanisms governing CH4 and CO2 emission in faulted regions. Furthermore, our results may contribute to future assessments aimed at quantifying the contribution of geological sources to greenhouse gas emissions.

Summary: Probiotic bacteria could be administrated to broilers using the in ovo injection technique during 17.50 and 19.20 d of incubation to accelerate microbial maturation in the intestinal tract. The effects of Lactobacillus rhamnosus (LR) injected in-ovo on intestinal morphology, mRNA expressions of intestinal health-related genes, and selected intestinal microbial of yellow broilers with or without Eimeria challenge were studied. A total of 360 yellow broiler hatching eggs were randomly assigned into 6 treatments with 60 replicate eggs per treatment. Six treatments were arranged in a 3 (LR dosage at 0, 10⁶, and 10⁸ CFU/egg at 18.5 d of incubation) × 2 (Eimeria oocyst challenge vs. PBS challenge at 10 d of age) factorial design. Tissues and cecal contents were sampled on d 19 posthatch. Our results indicated that the coccidial infection increased duodenum, jejunum, and liver relative weights to body weight, duodenal crypt depth, and HSP90 expression, and reduced goblet cell density and Occludin expression. In ovo injection of LR at 106 CFU/egg downregulated the Occludin expression and increased the Clostridium perfringens level in Eimeria-challenged broilers. When the LR dosage increased to 10⁸ CFU/egg, relative weights of duodenum, jejunum, ileum, and liver increased, villus length of lower small intestine and cecal Lactobacillus abundance in challenged broilers were reduced, and the Escherichia coli and Clostridium perfringens abundances in unchallenged broilers were increased. In summary, in ovo injection of LR at a dosage equal to or higher than 106 CFU per egg exacerbated coccidial infection in the intestinal tract and resulted in cecal bacterial imbalance. The probiotic dosage must be considered for in ovo administration in broiler production.

Abstract Colorectal cancers (CRCs) are prevalent worldwide, yet current treatments remain inadequate. Using chemical genetic screens, we identify that co-inhibition of topoisomerase I (TOP1) and NEDD8 is synergistically cytotoxic in human CRC cells. Combination of the TOP1 inhibitor irinotecan or its bioactive metabolite SN38 with the NEDD8-activating enzyme inhibitor pevonedistat exhibits synergy in CRC patient-derived organoids and xenografts. Mechanistically, we show that pevonedistat blocks the ubiquitin/proteasome-dependent repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) induced by TOP1 inhibitors and that the CUL4-RBX1 complex (CRL4) is a prominent ubiquitin ligase acting on TOP1-DPCs for proteasomal degradation upon auto-NEDD8 modification during replication. We identify DCAF13, a DDB1 and Cullin Associated Factor, as the receptor of TOP1-DPCs for CRL4. Our study not only uncovers a replication-coupled ubiquitin-proteasome pathway for the repair of TOP1-DPCs but also provides molecular and translational rationale for combining TOP1 inhibitors and pevonedistat for CRC and other types of cancers.

Abstract Kagome lattice materials are an important platform for highly frustrated magnetism as well as for a plethora of phenomena resulting from flat bands, Dirac cones and van Hove singularities in their electronic structures. We study the little known metallic magnet CrRhAs, which belongs to a vast family of materials that includes 3d, 4f, and 5f magnetic elements, as well as numerous nonmagnetic metals and insulators. Using noncollinear spin density functional calculations (mostly spin spirals), we extract a model magnetic Hamiltonian for CrRhAs. While it is dominated by an antiferromagnetic second nearest neighbor coupling in the kagome plane, the metallic nature of the compound leads to numerous nonzero longer range couplings and to important ring exchange terms. We analyze this Hamiltonian and find unusual ground states which are dominated by nearly isolated antiferromagnetic triangles that adopt 120∘ order either with positive or with negative vector chirality. We discuss the connection to the few known experimental facts about CrRhAs. Finally, we give a brief survey of other interesting magnetic members of this family of kagome compounds.

Snow cornices growing on the leeward side of mountain ridges are common in alpine and polar regions during snow seasons. These structures may crack and fall, leading to an increase in avalanche danger. Although cornice formation has been observed in wind tunnel tests and the field, knowledge gaps still exist regarding the formation mechanism. This is particularly true with respect to wind conditions which favor cornice formation. To characterize the wind effects as the main factor for cornice growth, we carried out ring wind tunnel (RWT) experiments in a cold laboratory under various wind conditions. We quantitatively investigated the growth rate of the cornice in the horizontal and vertical direction as well as the airborne particle concentration. The results show that cornices only appear under a moderate wind speed range (1–2 times the threshold wind speed). The cornice growth rates in length and thickness are mainly determined by the combined effects of mass accumulation and erosion. The lower-limit wind speed for cornice growth is approximately equal to the threshold wind speed for snow transport. The upper limit of wind speed is when the erosion rate is higher than the deposition rate. The length growth rate of the cornices reaches a maximum for wind speeds approximately 40 % higher than the threshold wind speed. Moreover, a conceptual model for interpreting the cornice accretion mechanism is proposed based on the mass conservation and the results of the RWT experiments. The estimated suitable wind condition for cornice growth and formation are in good agreement with field observations in Gruvefjellet, Svalbard. Based on the physics of drifting snow, our results provide new insights into snow cornice formation and improve understanding of cornice processes that can influence avalanche activity. The experimental results and the conceptual model can be used in future snow cornice simulation and prediction work for cornice-induced avalanches.

We forecast constraints on cosmological parameters enabled by three surveys conducted with SPT-3G, the third-generation camera on the South Pole Telescope. The surveys cover separate regions of 1500, 2650, and 6000 deg ^2 to different depths, in total observing 25% of the sky. These regions will be measured to white noise levels of roughly 2.5, 9, and $12\ \mu {\rm{K}}$ -armin, respectively, in cosmic microwave background (CMB) temperature units at 150 GHz by the end of 2024. The survey also includes measurements at 95 and 220 GHz, which have noise levels a factor of ∼1.2 and 3.5 times higher than 150 GHz, respectively, with each band having a polarization noise level $\sim \sqrt{2}$ times higher than the temperature noise. We use a novel approach to obtain the covariance matrices for jointly and optimally estimated gravitational lensing potential band powers and unlensed CMB temperature and polarization band powers. We demonstrate the ability to test the ΛCDM model via the consistency of cosmological parameters constrained independently from SPT-3G and Planck data, and consider the improvement in constraints on ΛCDM extension parameters from a joint analysis of SPT-3G and Planck data. The ΛCDM cosmological parameters are typically constrained with uncertainties up to ∼2 times smaller with SPT-3G data, compared to Planck, with the two data sets measuring significantly different angular scales and polarization levels, providing additional tests of the standard cosmological model.

We present a flare star catalog from 4 yr of nontargeted millimeter-wave survey data from the South Pole Telescope (SPT). The data were taken with the SPT-3G camera and cover a 1500 deg ^2 region of the sky from 20 ^h 40 ^m 0 ^s to 3 ^h 20 ^m 0 ^s in right ascension and from −42° to −70° in declination. This region was observed on a nearly daily cadence from 2019 to 2022 and chosen to avoid the plane of the galaxy. A short-duration transient search of this survey yields 111 flaring events from 66 stars, increasing the number of both flaring events and detected flare stars by an order of magnitude from the previous SPT-3G data release. We provide cross-matching to Gaia DR3, as well as matches to X-ray point sources found in the second ROSAT all-sky survey. We have detected flaring stars across the main sequence, from early-type A stars to M dwarfs, as well as a large population of evolved stars. These stars are mostly nearby, spanning 10–1000 pc in distance. Most of the flare spectral indices are constant or gently rising as a function of frequency at 95/150/220 GHz. The timescale of these events can range from minutes to hours, and the peak ν L _ν luminosities range from 10 ^27 to 10 ^31 erg s ^−1 in the SPT-3G frequency bands.

We hypothesize that large eddies play a major role in the entrainment of aeolian particles. To test this, wind-tunnel experiments are carried out to measure the particle entrainment rate for various sizes and flow conditions. Wind-tunnel flows are usually neutrally stratified with no large eddies, which are typically seen in convective atmospheric boundary layers. Here, a novel technique is applied, by deploying a piece of randomly fluttering cloth, to generate large eddies similar to convective eddies, here referred to as quasi-convective turbulence. The characteristics of quasi-convective turbulence are analyzed with respect to neutral turbulence in the Monin–Obukhov similarity framework, and the probability distributions of surface shear stress are examined. We show that for a given mean flow speed and in comparison with neutral flow conditions, quasi-convective turbulence increases the surface shear stress and alters its probability distribution and hence substantially enhances the entrainment of sand and dust particles. Our hypothesis is thus confirmed by the wind-tunnel experiments. We also explain why large eddies are important to aeolian entrainment and transport.

Abstract Adult mammalian cardiomyocytes are unable to proliferate to regenerate lost tissue after heart injury. Du et al., reporting in Cell Stem Cell, employ a FUCCI- and MADM-based system to screen for small molecules combinations that produced a collaborative effect on cardiomyocyte cycling and cytokinesis. The authors generate a cocktail of five small molecules that increase cardiomyocyte proliferation and regeneration in vitro and in vivo with high efficiency, and explore its potential in cardiac regenerative repair after myocardial infarction through a new potential pathway for cardiomyocyte cell-cycle re-entry.

It is increasingly recognized that atmospheric-boundary-layer stability (ABLS) plays an important role in eolian processes. While the effects of ABLS on particle emission have attracted much attention and been investigated in several studies, those on particle deposition have so far been less well studied. By means of large-eddy simulation, we investigate how ABLS influences the probability distribution of surface shear stress and hence particle deposition. Statistical analysis of the model results reveals that the shear stress can be well approximated using a Weibull distribution, and the ABLS influences on particle deposition can be estimated by considering the shear stress fluctuations. The model-simulated particle depositions are compared with the predictions of a particle-deposition scheme and measurements, and the findings are then used to improve the particle-deposition scheme. This research represents a further step towards developing deposition schemes that account for the stochastic nature of particle processes.

Including millimeter-wave data in multiwavelength studies of the variability of active galactic nuclei (AGN) can provide insights into AGN physics that are not easily accessible at other wavelengths. We demonstrate in this work the potential of cosmic microwave background (CMB) telescopes to provide long-term, high-cadence millimeter-wave AGN monitoring over large fractions of sky. We report on a pilot study using data from the SPTpol instrument on the South Pole Telescope (SPT), which was designed to observe the CMB at arcminute and larger angular scales. Between 2013 and 2016, SPTpol was used primarily to observe a single 500 deg ^2 field, covering the entire field several times per day with detectors sensitive to radiation in bands centered at 95 and 150 GHz. We use SPT 150 GHz observations to create AGN light curves, and we compare these millimeter-wave light curves to those at other wavelengths, in particular γ -ray and optical. In this Letter, we focus on a single source, PKS 2326-502, which has extensive, day-timescale monitoring data in gamma-ray, optical, and now millimeter-wave between 2013 and 2016. We find PKS 2326-502 to be in a flaring state in the first 2 yr of this monitoring, and we present a search for evidence of correlated variability between millimeter-wave, optical R- band, and γ -ray observations. This pilot study is paving the way for AGN monitoring with current and upcoming CMB experiments such as SPT-3G, Simons Observatory, and CMB-S4, including multiwavelength studies with facilities such as Vera C. Rubin Observatories Large Synoptic Survey Telescope.

Abstract The discovery of the Cystic fibrosis (CF) gene in 1989 has paved the way for incredible progress in treating the disease such that the mean survival age of individuals living with CF is now ~58 years in Canada. Recent developments in gene targeting tools and new cell and animal models have re-ignited the search for a permanent genetic cure for all CF. In this review, we highlight some of the more recent gene therapy approaches as well as new models that will provide insight into personalized therapies for CF.

I.v. administration of a high-affinity carbon monoxide–binding (CO-binding) molecule, recombinant neuroglobin, can improve survival in CO poisoning mouse models. The current study aims to discover how biochemical variables of the scavenger determine the CO removal from the RBCs by evaluating 3 readily available hemoproteins, 2,3-diphosphoglycerate stripped human hemoglobin (StHb); N-ethylmaleimide modified hemoglobin (NEMHb); and equine myoglobin (Mb). These molecules efficiently sequester CO from hemoglobin in erythrocytes in vitro. A kinetic model was developed to predict the CO binding efficacy for hemoproteins, based on their measured in vitro oxygen and CO binding affinities, suggesting that the therapeutic efficacy of hemoproteins for CO poisoning relates to a high M value, which is the binding affinity for CO relative to oxygen (KA,CO/KA,O2). In a lethal CO poisoning mouse model, StHb, NEMHb, and Mb improved survival by 100%, 100%, and 60%, respectively, compared with saline controls and were well tolerated in 48-hour toxicology assessments. In conclusion, both StHb and NEMHb have high CO binding affinities and M values, and they scavenge CO efficiently in vitro and in vivo, highlighting their therapeutic potential for point-of-care antidotal therapy of CO poisoning.

TOP1 resolves DNA supercoils by forming cleavage complexes (TOP1cc) that are trapped by TOP1 inhibitors. Here the authors provide insights into the mechanistic understanding of TOP1cc PARylation, showing that inhibition of PARG results in stabilization of TOP1cc PARylation that blocks the proteasomal degradation of TOP1cc.

Abstract Cardiac regeneration is an ancestral trait in vertebrates that is lost both as more recent vertebrate lineages evolved to adapt to new environments and selective pressures, and as members of certain species developmentally progress towards their adult forms. While higher vertebrates like humans and rodents resolve cardiac injury with permanent fibrosis and loss of cardiac output as adults, neonates of these same species can fully regenerate heart structure and function after injury – as can adult lower vertebrates like many teleost fish and urodele amphibians. Recent research has elucidated several broad factors hypothesized to contribute to this loss of cardiac regenerative potential both evolutionarily and developmentally: an oxygen-rich environment, vertebrate thermogenesis, a complex adaptive immune system, and cancer risk trade-offs. In this review, we discuss the evidence for these hypotheses as well as the cellular participators and molecular regulators by which they act to govern heart regeneration in vertebrates.

Understanding the molecular basis of leukaemia predisposition is essential for intervention. The authors here investigate germline genetic leukaemia predisposition by studying Shwachman-Diamond syndrome and report compensatory inactivating mutations in EIF6 and transforming biallelic TP53 alterations.

Particle size distribution of dust at emission (dust PSD) is an essential quantity to estimate in dust studies. It has been recognized in earlier research that dust PSD is dependent on soil properties (e.g. whether soil is sand or clay) and friction velocity, u∗, which is a surrogate for surface shear stress and a descriptor for saltation-bombardment intensity. This recognition has been challenged in some recent papers, causing a debate on whether dust PSD is “invariant” and the search for its justification. In this paper, we analyse the dust PSD measured in the Japan Australian Dust Experiment and show that dust PSD is dependent on u∗ and on atmospheric boundary-layer (ABL) stability. By simple theoretical and numerical analysis, we explain the two reasons for the latter dependency, which are both related to enhanced saltation bombardment in convective turbulent flows. First, u∗ is stochastic and its probability distribution profoundly influences the magnitude of the mean saltation flux due to the non-linear relationship between saltation flux and u∗. Second, in unstable conditions, turbulence is usually stronger, which leads to higher saltation-bombardment intensity. This study confirms that dust PSD depends on u∗ and, more precisely, on the probability distribution of u∗, which in turn is dependent on ABL stability; consequently, dust PSD is also dependent on ABL. We also show that the dependency of dust PSD on u∗ and ABL stability is made complicated by soil surface conditions. In general, our analysis reinforces the basic conceptual understanding that dust PSD depends on saltation bombardment and inter-particle cohesion.

In the present work, a new strategy for preparing authentic two-way shape memory polymer was proposed by using a conventional crosslinked polyurethane (PU) containing crystalline poly(ε-caprolactone) (PCL) as the proof-ofconcept material. Lauroyl peroxide (LPO) was added as a chemical crosslinker for inducing secondary crosslinking during the programming. Having been stretched and heat treated without additional ingredients and chemicals, the trained PU showed the desired two-way shape memory effect. The crosslinking network created by LPO was successfully converted into internal stress supplier, which represents the core progress of this research. As the temperature changed, the reversible melting/re-crystallization of the crystalline phases elaborately cooperated with the compressed crosslinking network, leading to the implementation of two-way shape memory effect. Through the optimization of the LPO quality, an average reversible strain of up to ~21% in the direction of stretching was measured. In principle, all semi-crystalline polymers can be imparted with two-way shape memory effect following the above-proposed method. Given the great convenience of material selection, preparation, programming and application, the current research may have opened a new way for the production and usage of the smart materials in practice.

Muscle fatigue, as a common physiological phenomenon, has attracted much attention in the fields of rehabilitation and athletic training. A wearable technology for monitoring the muscle fatigue anytime and anywhere is urgently needed. In this paper we apply Electrical impedance myography (EIM) technique, usually used for non-invasive detection of neuromuscular diseases with the four-electrode array, for evaluation of the local muscle fatigue status via the variation of electrical impedance. An equivalent multilayer inhomogeneous 3D finite element model of human arm was built in order to optimize the four-electrode configuration to improve EIM detection sensitivity. Current density in muscle layer and differential potential of induction electrodes were selected as the evaluation indexes for optimization. Then the in vivo experiments of dynamic contraction with different maximal voluntary contractions (MVC) were performed on the biceps brachii muscle of eight healthy volunteers. The results showed that muscle resistance (R) decreased almost 8 Ω from the completely relaxed muscle to exhaustion, which is the same trend as for the median frequency (MF) of measured surface electromyography (sEMG) signals. The model and experiments in this paper indicate the feasibility and efficiency of EIM for detection of muscle fatigue using wearable devices.

Abstract Background The Human Cell Atlas is a large international collaborative effort to map all cell types of the human body. Single-cell RNA sequencing can generate high-quality data for the delivery of such an atlas. However, delays between fresh sample collection and processing may lead to poor data and difficulties in experimental design. Results This study assesses the effect of cold storage on fresh healthy spleen, esophagus, and lung from ≥ 5 donors over 72 h. We collect 240,000 high-quality single-cell transcriptomes with detailed cell type annotations and whole genome sequences of donors, enabling future eQTL studies. Our data provide a valuable resource for the study of these 3 organs and will allow cross-organ comparison of cell types. We see little effect of cold ischemic time on cell yield, total number of reads per cell, and other quality control metrics in any of the tissues within the first 24 h. However, we observe a decrease in the proportions of lung T cells at 72 h, higher percentage of mitochondrial reads, and increased contamination by background ambient RNA reads in the 72-h samples in the spleen, which is cell type specific. Conclusions In conclusion, we present robust protocols for tissue preservation for up to 24 h prior to scRNA-seq analysis. This greatly facilitates the logistics of sample collection for Human Cell Atlas or clinical studies since it increases the time frames for sample processing.

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein is a cAMP-activated anion channel that is critical for regulating fluid and ion transport across the epithelium. This process is disrupted in CF epithelia, and patients harbouring CF-causing mutations experience reduced lung function as a result, associated with the increased rate of mortality. Much progress has been made in CF research leading to treatments that improve CFTR function, including small molecule modulators. However, clinical outcomes are not necessarily mutation-specific as individuals harboring the same genetic mutation may present with varying disease manifestations and responses to therapy. This suggests that the CFTR protein may have alternative functions that remain under-appreciated and yet can impact disease. In this mini review, we highlight some notable research implicating an important role of CFTR protein during early lung development and how mutant CFTR proteins may impact CF airway disease pathogenesis. We also discuss recent novel cell and animal models that can now be used to identify a developmental cause of CF lung disease.

Currently, Coronavirus Disease 2019 (COVID-19)—a respiratory contagion spreading through expiratory droplets—has evolved into a global pandemic, severely impacting the public health. Importantly, the emerging of immune evasion SARS-CoV-2 variants and the limited effect of current antivirals against SARS-CoV-2 in clinical trials suggested that alternative strategies in addition to the conventional vaccines and antivirals are required to successfully control the COVID-19 pandemic. Here, we propose to use liquid-repellent coatings to prevent the spread of the disease in the absence of effective vaccines, antimicrobial agents, or therapeutics, wherein the deposition and penetration of pathogen droplets are prohibited. We use SARS-CoV-2 as a model pathogen and find that SARS-CoV-2 remnants are reduced by seven orders of magnitude on coated surfaces, yielding a repelling efficacy far outperforming the inactivation rate of disinfectants. The SARS-CoV-2 remnant scales exponentially with the liquid/solid adhesion, uncovering the mechanism and effective means for minimizing pathogen attachment. The antipathogen coating that both repels and inactivates pathogens is demonstrated by incorporating the super-liquid-repellent coating with antipathogen additives. Together with its versatility over a wide range of substrates and pathogens, the novel antipathogen coating is of considerable value for infection control in everyday life as well as during pandemics.

The precious rare edible fungus Morchella conica is popular worldwide for its rich nutrition, savory flavor, and varieties of bioactive components. Due to its high commercial, nutritional, and medicinal value, it has always been a hot spot. However, the molecular mechanism and endophytic bacterial communities in M. conica were poorly understood. In this study, we sequenced, assembled, and analyzed the genome of M. conica SH. Transcriptome analysis reveals significant differences between the mycelia and fruiting body. As shown in this study, 1,329 and 2,796 genes were specifically expressed in the mycelia and fruiting body, respectively. The Gene Ontology (GO) enrichment showed that RNA polymerase II transcription activity-related genes were enriched in the mycelium-specific gene cluster, and nucleotide binding-related genes were enriched in the fruiting body-specific gene cluster. Further analysis of differentially expressed genes in different development stages resulted in finding two groups with distinct expression patterns. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment displays that glycan degradation and ABC transporters were enriched in the group 1 with low expressed level in the mycelia, while taurine and hypotaurine metabolismand tyrosine metabolism-related genes were significantly enriched in the group 2 with high expressed level in mycelia. Moreover, a dynamic shift of bacterial communities in the developing fruiting body was detected by 16S rRNA sequencing, and co-expression analysis suggested that bacterial communities might play an important role in regulating gene expression. Taken together, our study provided a better understanding of the molecular biology of M. conica SH and direction for future research on artificial cultivation.

Abstract Background Coagadex is a high‐purity plasma‐derived factor X concentrate (pdFX) developed to treat hereditary factor X deficiency (FXD). Objective Evaluate the efficacy and safety of pdFX administered to patients with hereditary FXD. Methods This was an open‐label, multicenter, retrospective analysis of patients receiving pdFX for compassionate use. Efficacy end points included treatments administered, the number and treatment of bleeds, and investigator assessments. Adverse drug reactions (ADRs) were monitored. Results Fifteen patients were included: seven received routine prophylaxis, seven received on‐demand treatment, and one alternated. Most were aged ≥12 years (n = 13) and had severe hereditary FXD (n = 12). The median follow‐up time was 19.2 months (range, 3.5‐48.8). The number of infusions per patient per month was higher for the routine prophylaxis group (median [range], 5.4 [1.4‐10.1]) than for the on‐demand group (0.8 [0.1‐2.3]), as was the dose per infusion (27.9 [21.9‐53.6] IU/kg vs 20.0 [13.6‐27.7] IU/kg). Patients experienced 88 bleeds (34 minor, 7 major, 47 unclassified). The monthly bleed rate per patient was 0.04 in the routine prophylaxis group (based on 17 bleeds in four patients) and 0.8 in the on‐demand group (based on 71 bleeds in eight patients). pdFX was used to treat 79 bleeds and was rated effective in all instances. In an overall assessment, investigators rated pdFX as excellent for 14 patients (93.3%) and good for 1 patient (6.3%). No ADRs or safety concerns were reported. Conclusions This analysis supports the use of pdFX as a safe, effective treatment for hereditary FXD. Routine prophylaxis with pdFX may reduce bleed frequency.

Abstract Regeneration is widespread across the animal kingdom but varies vastly across phylogeny and even ontogeny. Adult mammalian regeneration in most organs and appendages is limited, while vertebrates such as zebrafish and salamanders are able to regenerate various organs and body parts. Here, we focus on the regeneration of appendages, spinal cord, and heart—organs and body parts that are highly regenerative among fish and amphibian species but limited in adult mammals. We then describe potential genetic, epigenetic, and post‐transcriptional similarities among these different forms of regeneration across vertebrates and discuss several theories for diminished regenerative capacity throughout evolution.

TOP1MT is a topoisomerase that is localised to mitochondria. Here, the authors show that TOP1MT has a tumor promoting role in hepatocellular carcinoma by supporting mitochondrial translation and that its deficiency limits tumorigenicity.

Research conducted across phylogeny on cardiac regenerative responses following heart injury implicates endocrine signaling as a pivotal regulator of both cardiomyocyte proliferation and heart regeneration. Three prominently studied endocrine factors are thyroid hormone, vitamin D, and glucocorticoids, which canonically regulate gene expression through their respective nuclear receptors thyroid hormone receptor, vitamin D receptor, and glucocorticoid receptor. The main animal model systems of interest include humans, mice, and zebrafish, which vary in cardiac regenerative responses possibly due to the differential onsets and intensities of endocrine signalin g levels throughout their embryonic to postnatal organismal development. Zebrafish and low er vertebrates tend to retain robust cardiac regenerative capacity into adulthood while mice and other higher vertebrates experience greatly diminished cardiac regenerative potential in their initial postnatal period that is sustained throughout adulthood. Here, we review recent progress in understanding how these three endocrine signaling pathways regulate cardiomyocyte proliferation and heart regeneration with a particular focus on the controversial findings that may arise from different assays, cellular-context, age, and species. Further investigating the role of each endocrine nuclear receptor in cardiac regeneration from an evolutionary perspective enables comparative studies between species in hopes of extrapolating the findings to novel therapies for human cardiova scular disease.

Somatic KRAS mutations are highly prevalent in many cancers. In addition, a distinct spectrum of germline KRAS mutations causes developmental disorders called RASopathies. The mutant proteins encoded by these germline KRAS mutations are less biochemically and functionally activated than those in cancer. We generated mice harboring conditional KrasLSL-P34Rand KrasLSL-T58I knock-in alleles and characterized the consequences of each mutation in vivo. Embryonic expression of KrasT58I resulted in craniofacial abnormalities reminiscent of those seen in RASopathy disorders, and these mice exhibited hyperplastic growth of multiple organs, modest alterations in cardiac valvulogenesis, myocardial hypertrophy, and myeloproliferation. By contrast, embryonic KrasP34R expression resulted in early perinatal lethality from respiratory failure due to defective lung sacculation, which was associated with aberrant ERK activity in lung epithelial cells. Somatic Mx1-Cre–mediated activation in the hematopoietic compartment showed that KrasP34R and KrasT58I expression had distinct signaling effects, despite causing a similar spectrum of hematologic diseases. These potentially novel strains are robust models for investigating the consequences of expressing endogenous levels of hyperactive K-Ras in different developing and adult tissues, for comparing how oncogenic and germline K-Ras proteins perturb signaling networks and cell fate decisions, and for performing preclinical therapeutic trials.

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.

This paper focuses on removal niobium from Nb-bearing hot metal by bottom blown-CO2 gas at flow rate of 1,0×103 Nm3/h, 1,5×10-3 Nm3/h at 1350 °C and 1 450 °C in a medium induction furnace. The results show that Nb and P are oxidized and the ratio of Nb to P in Nb-bearing slag at blowing termination reaches to 46,66 at 1350 °C and CO2 flow rate of 1,5m3/h, which is more than that in the other condition; it improves to remove more Nb from hot metal with bottom-blown CO2 at 1 350 °C than at 1450 °C; Nb starts to oxidize by CO2 to form slag when Si content in molten iron decreases to low 0,1 wt. %.

Sublimation of blowing snow is an important parameter not only for the study of polar ice sheets and glaciers, but also for maintaining the ecology of arid and semi-arid lands. However, sublimation of near-surface blowing snow has often been ignored in previous studies. To study sublimation of near-surface blowing snow, we established a sublimation of blowing snow model containing both a vertical moisture diffusion equation and a heat balance equation. The results showed that although sublimation of near-surface blowing snow was strongly reduced by a negative feedback effect, due to vertical moisture diffusion, the relative humidity near the surface does not reach 100 %. Therefore, the sublimation of near-surface blowing snow does not stop. In addition, the sublimation rate near the surface is 3–4 orders of magnitude higher than that at 10 m above the surface and the mass of snow sublimation near the surface accounts for more than half of the total snow sublimation when the friction wind velocity is less than about 0.55 m s−1. Therefore, the sublimation of near-surface blowing snow should not be neglected.

Background: Autoimmune cytopenias (AICs) are potentially life-threatening complications following hematopoietic cell transplantation (HCT), yet little is understood about the mechanism by which they develop. We hypothesized that discordant B cell and T cell recovery is associated with AICs in transplant patients, and that this might differ based on transplant indication.Methods: In this case control study of children who underwent HCT at our institution, we evaluated the clinical and transplant characteristics of subjects who developed AICs compared to a control group matched by transplant indication and donor type. In cases, we analyzed the state of immune reconstitution, including B cell recovery, T cell recovery, and chimerism, immediately prior to AIC onset. Subjects were stratified by primary indication for transplant as malignancy (n = 7), primary immune deficiency (PID, n = 9) or other non-malignant disease (n = 4). We then described the treatment and outcomes for 20 subjects who developed AICs.Results: In our cohort, cases were older than controls, were more likely to receive a myeloablative conditioning regimen and had a significantly lower prevalence of chronic GVHD. There were distinct differences in the state of immune recovery based on transplant indication. None of the patients (0/7) transplanted for primary malignancy had T cell recovery at AIC onset compared to 71% (5/7) of patients with PID and 33% (1/3) of patients with non-malignant disease. The subset of patients with PID and non-malignant disease who achieved T cell reconstitution (6/6) prior to AIC onset, all demonstrated mixed or split chimerism. Subjects with AIHA or multi-lineage cytopenias had particularly refractory courses with poor treatment response to IVIG, steroids, and rituximab.Conclusions: These results highlight the heterogeneity of AICs in this population and suggest that multiple mechanisms may contribute to the development of post-transplant AICs. Patients with full donor chimerism may have early B cell recovery without proper T cell regulation, while patients with mixed or split donor chimerism may have residual host B or plasma cells making antibodies against donor blood cells. A prospective, multi-center trial is needed to develop personalized treatment approaches that target the immune dysregulation present and improve outcomes in patients with post-transplant AICs.