Cosmic Ray Processes in Galactic Ecosystems

Galaxy evolution is an important topic, and our physical understanding must be complete to establish a correct picture. This includes a thorough treatment of feedback. The effects of thermal–mechanical and radiative feedback have been widely considered; however, cosmic rays (CRs) are also powerful energy carriers in galactic ecosystems. Resolving the capability of CRs to operate as a feedback agent is therefore essential to advance our understanding of the processes regulating galaxies. The effects of CRs are yet to be fully understood, and their complex multi-channel feedback mechanisms operating across the hierarchy of galaxy structures pose a significant technical challenge. This review examines the role of CRs in galaxies, from the scale of molecular clouds to the circumgalactic medium. An overview of their interaction processes, their implications for galaxy evolution, and their observable signatures is provided and their capability to modify the thermal and hydrodynamic configuration of galactic ecosystems is discussed. We present recent advancements in our understanding of CR processes and interpretation of their signatures, and highlight where technical challenges and unresolved questions persist. We discuss how these may be addressed with upcoming opportunities

Black bone MRI with 3D reconstruction for the detection of skull fractures in children with suspected abusive head trauma.

PURPOSE: The purpose of this study was to determine the accuracy of "black bone" (BB) MRI for the detection of skull fractures in children with potential abusive head trauma. METHODS: A total of 34 pediatric patients were evaluated for potential abusive head trauma. All patients had both a non-contrast head CT (HCT) with multiplanar reformatted images and 3D volumetric reformatted images where available (gold standard) for fracture diagnosis and BB of the head with multiplanar reformatted images and 3D volumetric images. BB was performed using an ultrashort TE pointwise encoding time reduction with radial acquisition (PETRA) sequence at 1.5 T or 3 T. BB datasets were post-processed and 3D images created using Fovia's High Definition Volume Rendering® software. Two board-certified pediatric neuroradiologists independently reviewed the HCT and BB imaging, blinded to the findings from the other modality. RESULTS: Median patient age was 4 months (range 1.2-30 months). A total of 20 skull fractures in six patients (18% incidence of skull fractures) were detected on HCT. BB demonstrated 83% sensitivity (95%[CI] 36-99%), 100% specificity (95%[CI] 88-100%), 100% PPV (95%[CI] 46-100%), 97% NPV (95%[CI] 82-99%), and 97% accuracy (95%[CI] 85-99%) for diagnosis of a skull fracture. BB detected 95% (19/20) of the skull fractures detected by CT. CONCLUSION: A black bone MRI sequence may provide high sensitivity and specificity for detection of skull fractures in pediatric patients with abusive head trauma

Parentage Influence On Gene Expression Under Acidification Revealed Through Single-Embryo Sequencing

The dissolution of anthropogenic carbon dioxide (CO2) in seawater has altered its carbonate chemistry in the process of ocean acidification (OA). OA affects the viability of marine species. In particular, calcifying organisms and their early planktonic larval stages are considered vulnerable. These organisms often utilize energy reserves for metabolism rather than growth and calcification as supported by bulk RNA-sequencing (RNA-seq) experiments. Yet, transcriptomic profiling of a bulk sample reflects the average gene expression of the population, neglecting the variations between individuals, which forms the basis for natural selection. Here, we used single-embryo RNA-seq on larval sea urchin Heliocidaris crassispina, which is a commercially and ecologically valuable species in East Asia, to document gene expression changes to OA at an individual and family level. Three paternal half-sibs groups were fertilized and exposed to 3 pH conditions (ambient pH 8.0, 7.7 and 7.4) for 12 h prior to sequencing and oxygen consumption assay. The resulting transcriptomic profile of all embryos can be distinguished into four clusters, with differences in gene expressions that govern biomineralization, cell differentiation and patterning, as well as metabolism. While these responses were influenced by pH conditions, the male identities also had an effect. Specifically, a regression model and goodness of fit tests indicated a significant interaction between sire and pH on the probability of embryo membership in different clusters of gene expression. The single-embryo RNA-seq approach is promising in climate stressor research because not only does it highlight potential impacts before phenotypic changes were observed, but it also highlights variations between individuals and lineages, thus enabling a better determination of evolutionary potential

Questionnaire study to gain an insight into the manufacturing and fitting process of artificial eyes in children: an ocularist perspective

Purpose To gain an insight into the manufacturing and fitting of artificial eyes in children and potential improvements to the process. Method An online qualitative survey was distributed to 39 ocularists/prosthetists in Europe and Canada. Participants were recruited through purposive sampling, specifically maximum variation sampling from the researcher’s contacts and an online search. Results The findings highlighted the current impression technique as being the most difficult yet most important part of the current process for both the ocularist and child patient. Negatively affecting obtaining a good impression, the child patients distress can be reduced by their parents by providing encouragement, reassurance, practicing the insertion and removal of the artificial eye and being matter of fact. Whilst improvements to the current process provided mixed views, the incorporation of current technology was perceived as not being able to meet the requirements to produce aesthetically pleasing artificial eyes. Conclusion The current artificial eye process can be seen as an interaction with its success being dependent on the child patient’s acceptance and adjustment which is dependent on the factors associated to the process. Investigation into the needs of the patient and whether technology can improve the process are the next steps in its advancement

Novel bisphosphonate-based cathepsin K-triggered compound targets the enthesis without impairing soft tissue-to-bone healing

Background: Osteoadsorptive fluorogenic sentinel 3 (OFS-3) is a recently described compound that contains a bone-targeting bisphosphonate (BP) and cathepsin K (Ctsk)-triggered fluorescence signal. A prior study in a murine Achilles repair model demonstrated its effectiveness at targeting the site of tendon-to-bone repair, but the intrinsic effect of this novel bisphosphonate chaperone on tendon-to-bone healing has not been previously explored. We hypothesized that application of this bisphosphonate-fluorophore cargo conjugate would not affect the biomechanical properties or histologic appearance of tendon-bone repairs.Materials and Methods: Right hindlimb Achilles tendon-to-bone repair was performed on 12-week old male mice. Animals were divided into 2 groups of 18 each: 1) Achilles repair with OFS-3 applied directly to the repair site prior to closure, and 2) Achilles repair with saline applied prior to closure. Repaired hindlimbs from 12 animals per group were harvested at 6 weeks for biomechanical analysis with a custom 3D-printed jig. At 4 and 6 weeks, repaired hindlimbs from the remaining animals were assessed histologically using H&E, immunohistochemistry (IHC) staining for the presence of Ctsk, and second harmonic generation (SHG) imaging to evaluate collagen fibers.Results: At 6 weeks, there was no significant difference in failure load, stiffness, toughness, or displacement to failure between repaired hindlimbs that received OFS-3 versus saline. There was no difference in tissue healing on H&E or Ctsk staining on immunohistochemistry between animals that received OFS-3 versus saline. Finally, second harmonic generation imaging demonstrated no difference in collagen fiber parameters between the two groups.Conclusion: OFS-3 did not significantly affect the biomechanical properties or histologic appearance of murine Achilles tendon-to-bone repairs. This study demonstrates that OFS-3 can target the site of tendon-to-bone repair without causing intrinsic negative effects on healing. Further development of this drug delivery platform to target growth factors to the site of tendon-bone repair is warranted

Racial and ethnic disparities in access to minimally invasive mitral valve surgery

IMPORTANCE: Whether people from racial and ethnic minority groups experience disparities in access to minimally invasive mitral valve surgery (MIMVS) is not known. OBJECTIVE: To investigate racial and ethnic disparities in the utilization of MIMVS. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from the Society of Thoracic Surgeons Database for patients who underwent mitral valve surgery between 2014 and 2019. Statistical analysis was performed from January 24 to August 11, 2022. EXPOSURES: Patients were categorized as non-Hispanic White, non-Hispanic Black, and Hispanic individuals. MAIN OUTCOMES AND MEASURES: The association between MIMVS (vs full sternotomy) and race and ethnicity were evaluated using logistic regression. RESULTS: Among the 103 753 patients undergoing mitral valve surgery (mean [SD] age, 62 [13] years; 47 886 female individuals [46.2%]), 10 404 (10.0%) were non-Hispanic Black individuals, 89 013 (85.8%) were non-Hispanic White individuals, and 4336 (4.2%) were Hispanic individuals. Non-Hispanic Black individuals were more likely to have Medicaid insurance (odds ratio [OR], 2.21; 95% CI, 1.64-2.98; P \u3c .001) and to receive care from a low-volume surgeon (OR, 4.45; 95% CI, 4.01-4.93; P \u3c .001) compared with non-Hispanic White individuals. Non-Hispanic Black individuals were less likely to undergo MIMVS (OR, 0.65; 95% CI, 0.58-0.73; P \u3c .001), whereas Hispanic individuals were not less likely to undergo MIMVS compared with non-Hispanic White individuals (OR, 1.08; 95% CI, 0.67-1.75; P = .74). Patients with commercial insurance had 2.35-fold higher odds of undergoing MIMVS (OR, 2.35; 95% CI, 2.06-2.68; P \u3c .001) than those with Medicaid insurance. Patients operated by very-high volume surgeons (300 or more cases) had 20.7-fold higher odds (OR, 20.70; 95% CI, 12.7-33.9; P \u3c .001) of undergoing MIMVS compared with patients treated by low-volume surgeons (less than 20 cases). After adjusting for patient risk, non-Hispanic Black individuals were still less likely to undergo MIMVS (adjusted OR [aOR], 0.88; 95% CI, 0.78-0.99; P = .04) and were more likely to die or experience a major complication (aOR, 1.25; 95% CI, 1.16-1.35; P \u3c .001) compared with non-Hispanic White individuals. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, non-Hispanic Black patients were less likely to undergo MIMVS and more likely to die or experience a major complication than non-Hispanic White patients. These findings suggest that efforts to reduce inequity in cardiovascular medicine may need to include increasing access to private insurance and high-volume surgeons

Targeting Superficial or Nodular Basal Cell Carcinoma with Topically Formulated Small Molecule Inhibitor of Smoothened

Purpose: Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened. Experimental Design: In preclinical studies, we used a depilatory model to evaluate the ability of topical formulations of CUR61414 to repress Hh responsive cells found at the base of hair follicles in normal skin. We also tested the in vivo effects of topical CUR61414 on murine BCCs developed in $Ptch1^{ +/−}$ K14-CreER2 p53 fl/fl mice. In a phase I clinical study, we evaluated the safety, tolerability, and efficacy of a multidose regimen of CUR61414 (0.09%, 0.35%, 1.1%, and 3.1%) applied topically to human superficial or nodular BCCs for up to 28 days. Results: In mice, topical CUR61414 significantly inhibited skin Hh signaling, blocked the induction of hair follicle anagen, and shrank existing BCCs. However, we observed no clinical activity of this formulation in human superficial or nodular BCCs in a phase I clinical study. Conclusions: Our data highlight some of the challenges of translating preclinical experience into successful human results for a topical anticancer agent.Stem Cell and Regenerative Biolog

Integrating 5-Hydroxymethylcytosine into the Epigenomic Landscape of Human Embryonic Stem Cells

Covalent modification of DNA distinguishes cellular identities and is crucial for regulating the pluripotency and differentiation of embryonic stem (ES) cells. The recent demonstration that 5-methylcytosine (5-mC) may be further modified to 5-hydroxymethylcytosine (5-hmC) in ES cells has revealed a novel regulatory paradigm to modulate the epigenetic landscape of pluripotency. To understand the role of 5-hmC in the epigenomic landscape of pluripotent cells, here we profile the genome-wide 5-hmC distribution and correlate it with the genomic profiles of 11 diverse histone modifications and six transcription factors in human ES cells. By integrating genomic 5-hmC signals with maps of histone enrichment, we link particular pluripotency-associated chromatin contexts with 5-hmC. Intriguingly, through additional correlations with defined chromatin signatures at promoter and enhancer subtypes, we show distinct enrichment of 5-hmC at enhancers marked with H3K4me1 and H3K27ac. These results suggest potential role(s) for 5-hmC in the regulation of specific promoters and enhancers. In addition, our results provide a detailed epigenomic map of 5-hmC from which to pursue future functional studies on the diverse regulatory roles associated with 5-hmC

State Variation in Squamous Cell Carcinoma of the anus incidence and Mortality, and association With Hiv/Aids and Smoking in the United States

PURPOSE: Squamous cell carcinoma of the anus (SCCA) incidence and mortality rates are rising in the United States. Understanding state-level incidence and mortality patterns and associations with smoking and AIDS prevalence (key risk factors) could help unravel disparities and provide etiologic clues. METHODS: Using the US Cancer Statistics and the National Center for Health Statistics data sets, we estimated state-level SCCA incidence and mortality rates. Rate ratios (RRs) were calculated to compare incidence and mortality in 2014-2018 versus 2001-2005. The correlations between SCCA incidence with current smoking (from the Behavioral Risk Factor Surveillance System) and AIDS (from the HIV Surveillance system) prevalence were evaluated using Spearman\u27s rank correlation coefficient. RESULTS: Nationally, SCCA incidence and mortality rates (per 100,000) increased among men (incidence, 2.29-3.36, mortality, 0.46-0.74) and women (incidence, 3.88-6.30, mortality, 0.65-1.02) age ≥ 50 years, but decreased among men age \u3c 50 years and were stable among similar-aged women. In state-level analysis, a marked increase in incidence (≥ 1.5-fold for men and ≥ two-fold for women) and mortality (≥ two-fold) for persons age ≥ 50 years was largely concentrated in the Midwestern and Southeastern states. State-level SCCA incidence rates in recent years (2014-2018) among men were correlated ( CONCLUSION: During 2001-2005 to 2014-2018, SCCA incidence and mortality nearly doubled among men and women age ≥ 50 years living in Midwest and Southeast. State variation in AIDS and smoking patterns may explain variation in SCCA incidence. Improved and targeted prevention is needed to combat the rise in SCCA incidence and mitigate magnifying geographic disparities

Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance

Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers