College Students With Intellectual and Developmental Disabilities' Experiences, Conception, and Development of Emotional Wellness.

This study aimed to understand the ways in which college students with intellectual and developmental disabilities (IDD) experience and develop their understanding of emotions and emotional wellness. Semi-structured interviews with college students with IDD were conducted. The research team utilized consensual qualitative research (CQR) to analyze interviews and came to consensus in generating domains, core ideas, and a cross-analysis to answer the research question, "What are the experiences of college students with IDD in developing an understanding of emotions and emotional wellness?" Findings suggest college students with IDD have experience developing and maintaining their emotional wellness, though they may experience barriers prior to and during college enrollment. Limitations and implications for future research are discussed.

Imaging in Pediatric Lung Disease: Current Practice and Future Directions.

Pediatric diseases present differently from adult diseases and imaging forms a cornerstone of modern pediatric care through differential diagnosis, disease monitoring, and measuring response to therapy. Imaging is especially well suited to providing novel insights into the underlying mechanisms driving disease through structural and functional imaging. In this review, we describe key imaging findings in standard-of-care and state-of-the-art techniques in pediatric and adult diseases with origins in childhood. We examine applications in small airways disease, large airway disease, diseases of maturity, interstitial lung disease, neuromuscular disease, congenital disease, and pulmonary infection.

Evaluating the Impact of Low-Pathogenicity Avian Influenza H6N1 Outbreaks in United Kingdom and Republic of Ireland Poultry Farms during 2020.

In January 2020, increased mortality was reported in a small broiler breeder flock in County Fermanagh, Northern Ireland. Gross pathological findings included coelomitis, oophoritis, salpingitis, visceral gout, splenomegaly, and renomegaly. Clinical presentation included inappetence, pronounced diarrhoea, and increased egg deformation. These signs, in combination with increased mortality, triggered a notifiable avian disease investigation. High pathogenicity avian influenza virus (HPAIV) was not suspected, as mortality levels and clinical signs were not consistent with HPAIV. Laboratory investigation demonstrated the causative agent to be a low-pathogenicity avian influenza virus (LPAIV), subtype H6N1, resulting in an outbreak that affected 15 premises in Northern Ireland. The H6N1 virus was also associated with infection on 13 premises in the Republic of Ireland and six in Great Britain. The close genetic relationship between the viruses in Ireland and Northern Ireland suggested a direct causal link whereas those in Great Britain were associated with exposure to a common ancestral virus. Overall, this rapidly spreading outbreak required the culling of over 2 million birds across the United Kingdom and the Republic of Ireland to stamp out the incursion. This report demonstrates the importance of investigating LPAIV outbreaks promptly, given their substantial economic impacts.

Factors Affecting Specialty Training Preference Among UK Medical Students (FAST): Protocol for a National Cross-Sectional Survey.

BACKGROUND: The UK medical education system faces a complex landscape of specialty training choices and heightened competition. The Factors Affecting Specialty Training Preference Among UK Medical Students (FAST) study addresses the need to understand the factors influencing UK medical students' specialty choices, against a backdrop of increasing challenges in health care workforce planning. OBJECTIVE: The primary objectives of the FAST study are to explore UK medical students' preferred specialties and the factors that influence these choices. Secondary objectives are to evaluate students' confidence in securing their chosen specialty, to understand how demographic and academic backgrounds affect their decisions, and to examine how specialty preferences and confidence levels vary across different UK medical schools. METHODS: A cross-sectional survey design will be used to collect data from UK medical students. The survey, comprising 17 questions, uses Likert scales, multiple-choice formats, and free-text entry to capture nuanced insights into specialty choice factors. The methodology, adapted from the Ascertaining the Career Intentions of UK Medical Students (AIMS) study, incorporates adjustments based on literature review, clinical staff feedback, and pilot group insights. This approach ensures comprehensive and nondirective questioning. Data analysis will include descriptive statistics to establish basic patterns, ANOVA for group comparisons, logistic regression for outcome modeling, and discrete choice models for specialty preference analysis. RESULTS: The study was launched nationally on December 4, 2023. Data collection is anticipated to end on March 1, 2024, with data analysis beginning thereafter. The results are expected to be available later in 2024. CONCLUSIONS: The FAST study represents an important step in understanding the factors influencing UK medical students' career pathways. By integrating diverse student perspectives across year groups and medical schools, this study seeks to provide critical insights into the dynamics of specialty, or residency, selection. The findings are anticipated to inform both policy and educational strategies, aiming to align training opportunities with the evolving needs and aspirations of the future medical workforce. Ultimately, the insights gained may guide initiatives to balance specialty distribution, improve career guidance, and improve overall student satisfaction within the National Health Service, contributing to a more stable and effective health care system. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55155.

Modification of χ_{c1}(3872) and ψ(2S) Production in pPb Collisions at sqrt[s_{NN}]=8.16 TeV.

The LHCb Collaboration measures production of the exotic hadron χ_{c1}(3872) in proton-nucleus collisions for the first time. Comparison with the charmonium state ψ(2S) suggests that the exotic χ_{c1}(3872) experiences different dynamics in the nuclear medium than conventional hadrons, and comparison with data from proton-proton collisions indicates that the presence of the nucleus may modify χ_{c1}(3872) production rates. This is the first measurement of the nuclear modification factor of an exotic hadron.

Overfeeding copper during rearing affects the liver function and fertility of replacement dairy heifers.

BACKGROUND: Oversupply of dietary copper (Cu) is common among UK dairy herds, but studies on the long-term outcomes of this oversupply are scarce. METHODS: A longitudinal study was undertaken to determine the long-term implications when 80 Holstein‒Friesian heifers with a mean (±standard error) age of 4.1 ± 0.1 months and a mean liveweight of 137 ± 2.4 kg were fed a recommended (R; 16 mg/kg dry matter [DM]) or high (H; 32 mg/kg DM) dietary Cu concentration until 6 weeks prior to calving. RESULTS: Hepatic Cu concentrations in both treatment groups were elevated into the ranges used to diagnose chronic Cu toxicity in cattle at 6.9 months of age (798 ± 46.4 mg/kg DM for H vs. 643 ± 35.4 mg/kg DM for R), with associated evidence of liver damage. Hepatic Cu concentrations then returned to normality but remained higher (p < 0.001) for heifers fed H than for those fed R and were associated with a reduced (p = 0.044) conception rate to first and second services (73.7 ± 8.05% for H vs. 91.2 ± 7.68% for R). LIMITATION: This retrospective analysis identified pre-study liver damage, which may have affected results. CONCLUSIONS: Supplying Cu in excess of requirements resulted in liver damage and reduced conception rates.

Synthesis and evaluation of sulfonamide derivatives of quinoxaline 1,4-dioxides as carbonic anhydrase inhibitors.

A series of sulfonamide-derived quinoxaline 1,4-dioxides were synthesized and evaluated as inhibitors of carbonic anhydrases (CA) with antiproliferative potency. Overall, the synthesized compounds demonstrated good inhibitory activity against four CA isoforms. Compound 7g exhibited favorable potency in inhibiting a CA IX isozyme with a K i value of 42.2 nM compared to the reference AAZ (K i = 25.7 nM). Nevertheless, most of the synthesized compounds have their highest activity against CA I and CA II isoforms over CA IX and CA XII. A molecular modeling study was used for an estimation of the binding mode of the selected ligand 7g in the active site of CA IX. The most active compounds (7b, 7f, 7h, and 18) exhibited significant antiproliferative activity against MCF-7, Capan-1, DND-41, HL60, and Z138 cell lines, with IC50 values in low micromolar concentrations. Moreover, derivatives 7a, 7e, and 8g showed similar hypoxic cytotoxic activity and selectivity compared to tirapazamine (TPZ) against adenocarcinoma cells MCF-7. The structure-activity relationships analysis revealed that the presence of a halogen atom or a sulfonamide group as substituents in the phenyl ring of quinoxaline-2-carbonitrile 1,4-dioxides was favorable for overall cytotoxicity against most of the tested cancer cell lines. Additionally, the presence of a carbonitrile fragment in position 2 of the heterocycle also had a positive effect on the antitumor properties of such derivatives against the majority of cell lines. The most potent derivative, 3-trifluoromethylquinoxaline 1,4-dioxide 7h, demonstrated higher or close antiproliferative activity compared to the reference agents, such as doxorubicin, and etoposide, with an IC50 range of 1.3-2.1 µM. Analysis of the obtained results revealed important patterns in the structure-activity relationship. Moreover, these findings highlight the potential of selected lead sulfonamides on the quinoxaline 1,4-dioxide scaffold for further in-depth evaluation and development of chemotherapeutic agents targeting carbonic anhydrases.

Multiplexed Shortwave Infrared Imaging Highlights Anatomical Structures in Mice.

Multiplexed fluorescence in vivo imaging remains challenging due to the attenuation and scattering of visible and traditional near infrared (NIR-I, 650 - 950 nm) wavelengths. Fluorescence imaging using short-wave infrared (SWIR, 1000 - 1700 nm, a.k.a. NIR-II) light enables deeper tissue penetration due to reduced tissue scattering as well as minimal background autofluorescence. SWIR-emitting semiconductor quantum dots (QDs) with tunable emission peaks and optical stability are powerful contrast agents, yet few imaging demonstrations exclusively use SWIR emission beyond two-color imaging schemes. In this study, we engineered three high quality lead sulfide/cadmium sulfide (PbS/CdS) core/shell QDs with distinct SWIR emission ranging from 1100 - 1550 nm for simultaneous three-color imaging in mice. We first use the exceptional photostability of QDs to non-invasively track lymphatic drainage with longitudinal imaging, highlighting the detailed networks of lymphatic vessels with widefield imaging over a 2 hr period. We then perform multiplexed imaging with all three QDs to distinctly visualize the lymphatic system and spatially overlapping vasculature networks, including clearly distinguishing the liver and spleen. This work establishes optimized SWIR QDs for next-generation multiplexed and longitudinal preclinical imaging, unlocking numerous opportunities for preclinical studies of disease progression, drug biodistribution, and cell trafficking dynamics in living organisms.

Feeding nanoparticles of copper oxide coated with lysine with or without added antagonists affects the copper status but not performance of Holstein dairy cows.

The apparent absorption of copper (Cu) in ruminants is low, with between 0.01 and 0.07 g/g absorbed from sources such as copper oxide (CuO) under typical feeding conditions, resulting in high levels of excretion. Improving the bioavailability of Cu could reduce the supplemental amount required to maintain Cu status and reduce excretion, particularly in the presence of dietary antagonists such as sulfur (S) and molybdenum (Mo). The objective of our study was to determine the Cu status of cows when fed nanoparticle CuO coated with Lys compared with conventional CuO when fed without or in combination with antagonists to Cu absorption (S and Mo) in the diet of dairy cows. Fifty-six multiparous Holstein-Friesian cows that were 48 d ± 17.4 (mean ± SD) post calving and yielding 40.6 ± 6.9 kg milk/d were used in a 2 × 2 factorial design. The 4 treatment groups were; CuO (O-), CuO with added antagonists (O+), nano CuO with a lysine coating (N-), and nano CuO with a Lys coating with added antagonists (N+), fed for 16 wks. We formulated the diets to contain approximately 17 mg Cu/kg dry matter (DM) and diets with antagonists contained an additional 1 g S/kg DM and 6 mg Mo/kg DM, with Lys added to O- and O+ to provide the same daily supply as N- and N+. Blood samples were collected at wk 0, 2, 4, 6, 10 and 16, and liver biopsy samples at wk 0 and 16. We found no effect of dietary treatment on DM intake, milk yield, live weight or body condition score, with mean values of 23.3 kg/d, 40.1 kg/d, 646 kg and 2.68, but milk SCC was higher in cows fed conventional compared with non CuO, or with added antagonist. We also found no effect of treatment on blood activity of gamma glutamyl transferase, superoxide dismutase or ceruloplasmin, hematology profile, or plasma Cu and iron concentration. We found that plasma Mo concentration was increased from 0.36 µmol/L in cows fed O- or N- to 0.80 µmol/L in those receiving O+ or N+. Additional dietary antagonists also decreased the concentration of Cu in the liver of cows fed conventional CuO (C+) over the study period by 1.3 mg/kg DM/d, but in cows fed dietary antagonists and nano CuO coated with Lys (N+), liver Cu concentration was increased by 1.1 mg/kg DM/d. Our study is the first to demonstrate that reducing the particle size of CuO into the nano scale with a lysine coating improves the bioavailability of CuO in the presence of dietary antagonists in dairy cattle, and we did not observe any negative effects on performance or health.

Diabetic Ketoacidosis and Adverse Outcomes Among Pregnant Individuals With Pregestational Diabetes in the United States, 2010-2020.

OBJECTIVE: To assess the frequency of, risk factors for, and adverse outcomes associated with diabetic ketoacidosis (DKA) at delivery hospitalization among individuals with pregestational diabetes (type 1 and 2 diabetes mellitus) and secondarily to evaluate the frequency of and risk factors for antepartum and postpartum hospitalizations for DKA. METHODS: We conducted a serial, cross-sectional study using the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project Nationwide Readmissions Database from 2010 to 2020 of pregnant individuals with pregestational diabetes hospitalized for delivery. The exposures were 1) sociodemographic and clinical risk factors for DKA and 2) DKA. The outcomes were DKA at delivery hospitalization, maternal morbidity (nontransfusion severe maternal morbidity (SMM), critical care procedures, cardiac complications, acute renal failure, and transfusion), and adverse pregnancy outcomes (preterm birth, hypertensive disorders of pregnancy, and cesarean delivery) and secondarily DKA at antepartum and postpartum hospitalizations. RESULTS: Of 392,796 deliveries in individuals with pregestational diabetes (27.2% type 1 diabetes, 72.8% type 2 diabetes), there were 4,778 cases of DKA at delivery hospitalization (89.1% type 1 diabetes, 10.9% type 2 diabetes). The frequency of DKA at delivery hospitalization was 1.2% (4.0% with type 1 diabetes, 0.2% with type 2 diabetes), and the mean annual percentage change was 10.8% (95% CI, 8.2-13.2%). Diabetic ketoacidosis at delivery hospitalization was significantly more likely among those who had type 1 diabetes compared with those with type 2 diabetes, who were younger in age, who delivered at larger and metropolitan hospitals, and who had Medicaid insurance, lower income, multiple gestations, and prior psychiatric illness. Diabetic ketoacidosis during the delivery hospitalization was associated with an increased risk of nontransfusion SMM (20.8% vs 2.4%, adjusted odds ratio [aOR] 8.18, 95% CI, 7.20-9.29), critical care procedures (7.3% vs 0.4%, aOR 15.83, 95% CI, 12.59-19.90), cardiac complications (7.8% vs 0.8%, aOR 8.87, 95% CI, 7.32-10.76), acute renal failure (12.3% vs 0.7%, aOR 9.78, 95% CI, 8.16-11.72), and transfusion (6.2% vs 2.2%, aOR 2.27, 95% CI, 1.87-2.75), as well as preterm birth (31.9% vs 13.5%, aOR 2.41, 95% CI, 2.17-2.69) and hypertensive disorders of pregnancy (37.4% vs 28.1%, aOR 1.11, 95% CI, 1.00-1.23). In secondary analyses, the overall frequency of antepartum DKA was 3.1%, and the mean annual percentage change was 4.1% (95% CI, 0.3-8.6%); the overall frequency of postpartum DKA was 0.4%, and the mean annual percentage change was 3.5% (95% CI, -1.6% to 9.6%). Of 3,092 antepartum hospitalizations among individuals with DKA, 15.7% (n=485) had a recurrent case of DKA at delivery hospitalization. Of 1,419 postpartum hospitalizations among individuals with DKA, 20.0% (n=285) previously had DKA at delivery hospitalization. The above risk factors for DKA at delivery hospitalization were similar for DKA at antepartum and postpartum hospitalizations. CONCLUSION: The frequency of DKA at delivery hospitalization and antepartum hospitalizations for DKA increased between 2010 and 2020 among deliveries in individuals with pregestational diabetes in the United States. Diabetic ketoacidosis is associated with an increased risk of maternal morbidity and adverse pregnancy outcomes. Risk factors for DKA at delivery were similar to those for DKA during the antepartum and postpartum periods.

Cross polarization stability in multidimensional NMR spectroscopy of biological solids.

Magic-angle spinning (MAS) solid-state nuclear magnetic resonance (SSNMR) spectroscopy is a powerful and versatile technique for probing structure and dynamics in large, insoluble biological systems at atomic resolution. With many recent advances in instrumentation and polarization methods, technology development in SSNMR remains an active area of research and presents opportunities to further improve data collection, processing, and analysis of samples with low sensitivity and complex tertiary and quaternary structures. SSNMR spectra are often collected as multidimensional data, requiring stable experimental conditions to minimize signal fluctuations (t1 noise). In this work, we examine the factors adversely affecting signal stability as well as strategies used to mitigate them, considering laboratory environmental requirements, configuration of amplifiers, and pulse sequence parameter selection. We show that Thermopad® temperature variable attenuators (TVAs) can partially compensate for the changes in amplifier output power as a function of temperature and thereby ameliorate one significant source of instability for some spectrometers and pulse sequences. We also consider the selection of tangent ramped cross polarization (CP) waveform shapes, to balance the requirements of sensitivity and instrumental stability. These findings collectively enable improved stability and overall performance for CP-based multidimensional spectra of microcrystalline, membrane, and fibrous proteins performed at multiple magnetic field strengths.

A Rocky Road: Bladder Stones in the Augmented Exstrophy-Epispadias Complex Patient.

OBJECTIVES: To determine the rate of stone formation amongst patients of the exstrophy-epispadias complex with augmentation cystoplasty. We hypothesize that bowel segment choice influences the rate of stone formation after bladder augmentation and the rate of complications from bladder stone surgery. METHODS: An IRB approved institutional database of 1512 exstrophy-epispadias patients was reviewed retrospectively. Patients that had a history of bladder augmentation and were seen at our institution between 2003 and 2023 were included. RESULTS: Out of 259 patients, bladder stones developed in 21.6% (56), of which the bowel segment used was colon in 147 patients and ileum in 100. Stones formed in 19% of colon augments compared to 29% ileal augments, however this was not statistically significant (p=0.07). The most common primary stone component was dahllite, followed by struvite for all augments. The median time to stone treatment after augmentation was 4.14 years (0.75-31). 74% of patients had a recurrence that required a second surgery. The median time from first to second surgery and second to third surgery was 1.4 years and 2.22 years, respectively. Bladder stone surgery complications occurred in 14% of patients, vesicocutaneous fistula being the most common, and complications did not differ by augment type. Median follow up after first stone intervention was 6.07 years (0-19.5). CONCLUSION: The treatment of bladder stones in the exstrophy-epispadias complex remains challenging. Interventions to prevent recurrence are crucial as the majority of patients will require two or more stone surgeries in their lifetime.

Puncture Cube Patient-Mounted Navigation System versus Freehand Method for CT-Guided Needle Placement: Study on a Neoprene Covered Elliptical Cylinder Gelatin Phantom.

PURPOSE: The study aims to show how the "Puncture Cube" (PC) (Medical Templates, Egg, Switzerland) compares to the freehand method (FHM) for CT-guided punctures. METHODS: The PC is a patient-mounted disassemblable cube consisting of an upper and lower template with multiple holes each to predefine puncture trajectory. A total of 80 punctures (FHM in-plane, FHM off-plane, PC in-plane, PC off-plane) was performed by 4 radiologists on a target 9.1 cm below surface level of a neoprene covered elliptical cylinder gelatin phantom. The PC was never disassembled. Evaluated parameters were procedure time, number of CT-scans, euclidean distance (ED) and normal distance (ND). Respective parameters of FHM and PC were compared using the Wilcoxon signed-rank test and Levene test with significance levels of 5%. RESULTS: PC achieved smaller ED and ND values after initial needle insertion without corrections for both in-plane and off-plane punctures (P > 0.05). Variance of initial NDs was off-plane significantly larger for FHM. Final ED after needle path corrections was smaller for FHM both in- and off-plane (P < 0.05). Final off-plane ND was significantly lower for FHM with no significant difference in final in-plane ND. FHM off-plane punctures were significantly faster. There was no significant difference in CT-scans between both methods. CONCLUSION: Utilizing the PC may improve initial needle positioning and safety especially off-plane. However, better final needle positioning after correction with the greater freedom of movement method may suggest need for disassembly of the cube.

Design, in silico Evaluation, and Determination of Antitumor Activity of Potential Inhibitors Against Protein Kinases: Application to BCR-ABL Tyrosine Kinase.

Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is still an unmet need for effective and safe agents to treat patients with resistance and intolerance to the drugs used in clinic. In this work, we designed 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid, assessed in silico their inhibitory potential against Bcr-Abl tyrosine kinase, and determined their antitumor activity in K562 (CML), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) cells. Based on the analysis of computational and experimental data, three compounds with the antitumor activity against K562 and HL-60 cells were identified. The lead compound efficiently suppressed the growth of these cells, as evidenced by the low IC50 values of 2.8 ± 0.8 µM (K562) and 3.5 ± 0.2 µM (HL-60). The obtained compounds represent promising basic structures for the design of novel, effective, and safe anticancer drugs able to inhibit the catalytic activity of Bcr-Abl kinase by blocking the ATP-binding site of the enzyme.

--Redox Transformations of the OX063 Radical in Biological Media: Oxidative Decay of Initial Trityl with Further Formation of Structurally-Modified TAM.

Being a low-toxic and hydrophilic representative of TAM, OX063 has shown its suitability for in-vivo and in-cell EPR experiments and design of spin labels. Using 13C labeling, we investigated the course of oxidative degradation of OX063 into quinone-methide (QM) under the influence of superoxide as well as further thiol-promoted reduction of QM into TAM radical, which formally corresponds to substitution of a carboxyl function by a hydroxyl group. We found these transformations being quantitative in model reactions mimicking specific features of biological media and confirmed the presence of these reactions in the blood and liver homogenate of mice in vitro. The emergence of the trityl with the hydroxyl group can be masked by an initial TAM in EPR spectra and may introduce distortions into EPR-derived oximetry data if they have been obtained for objects under hypoxia. 13C labeling allows one to detect its presence, considering its different hyperfine splitting constant on 13C1 (2.04 mT) as compared to OX063 (2.30 mT). The potential involvement of these reactions should be considered when using TAM in spin-labeling of biopolymers intended for subsequent EPR experiments, as well as in the successful application of TAM in experiments in vivo and in cell.

A Pd-catalyzed route to carborane-fused boron heterocycles.

Due to the expanding applications of icosahedral carboranes in medicinal and materials chemistry research, their functionalizations have become one of the central themes in boron-rich cluster chemistry. Although several strategies for incorporating nitrogen-containing nucleophiles on a single boron vertex of the icosahedral carboranes (C2B10H12) have been developed, methods for preparing clusters with vicinal B-N moieties are still lacking. The steric bulk of icosahedral carboranes and disparate electronic and steric nature of the N-containing groups have rendered the vicinal diamination challenging. In this article, we show how a developed Pd-catalyzed process is used to incorporate an array of NH-heterocycles, anilines, and heteroanilines with various electronic and steric profiles onto the vicinal boron vertices of a meta-carborane cluster via sequential or one-pot fashion. Importantly, oxidative cyclizations of the cross-coupling products with indoles and pyrroles appended to boron vertices generate a previously unknown class of all-boron-vertex bound carborane-fused six- and seven-membered ring heterocycles. Photophysical studies of the meta-carborane-fused heterocycles show that these structures can exhibit luminescence with high quantum yields and are amenable to further manipulations.

Cell wall integrity modulates HOOKLESS1 and PHYTOCHROME INTERACTING FACTOR4 expression controlling apical hook formation.

Formation of the apical hook in etiolated dicot seedlings results from differential growth in the hypocotyl apex and is tightly controlled by environmental cues and hormones, among which auxin and gibberellins (GAs) play an important role. Cell expansion is tightly regulated by the cell wall, but whether and how feedback from this structure contributes to hook development is still unclear. Here, we show that etiolated seedlings of the Arabidopsis (Arabidopsis thaliana) quasimodo2-1 (qua2) mutant, defective in pectin biosynthesis, display severe defects in apical hook formation and maintenance, accompanied by loss of asymmetric auxin maxima and of differential cell expansion. Moreover, qua2 seedlings show reduced expression of HOOKLESS 1 (HLS1) and PHYTOCHROME INTERACTING FACTOR 4 (PIF4), which are positive regulators of hook formation. Treatment of wild-type seedlings with the cellulose inhibitor isoxaben (isx) also prevents hook development and represses HLS1 and PIF4 expression. Exogenous GAs, loss of DELLA proteins or HLS1 overexpression partially restore hook development in qua2 and isx-treated seedlings. Interestingly, increased agar concentration in the medium restores, both in qua2 and isx-treated seedlings, hook formation, asymmetric auxin maxima and PIF4 and HLS1 expression. Analysis of plants expressing a FRET-based GA sensor indicate that isx reduces accumulation of GAs in the apical hook region in a turgor-dependent manner. Lack of the cell wall integrity sensor THESEUS 1, which modulates turgor loss point, restores hook formation in qua2 and isx-treated seedlings. We propose that turgor-dependent signals link changes in cell wall integrity to the PIF4-HLS1 signalling module to control differential cell elongation during hook formation.

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.

Monocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs' survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.

Single cell view of tumor microenvironment gradients in pleural mesothelioma.

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.

Aspects of acceptance: building a shared conceptual understanding.

Many contemplatives, scientists, and clinicians have pointed to the value of responding to life's difficulties by accepting experiences as they are. A growing body of research also suggests that acceptance contributes to effective coping with adversity, reduced stress, and improved emotional well-being. Yet within the scientific literature, there is little consensus on what acceptance means or how it should be measured. This makes it nearly impossible to synthesize empirical work on acceptance into a cohesive scientific understanding. Our goal in this paper is to clarify four facets of acceptance that are commonly referenced in research: acknowledging, allowing, non-judging, and non-attachment. We do not propose a specific definition of acceptance or even a set of privileged facets that must be included in future frameworks. We instead offer a vocabulary to facilitate productive communication among researchers that will, in turn, enable a more definitive scientific understanding of this important construct to emerge. After defining and explaining these aspects of acceptance, we further clarify these constructs in two ways. First, we illustrate how the four aspects are dissociable from one another. Second, we analyze their correspondence to related constructs from Acceptance and Commitment Therapy (ACT). Finally, we provide a concept worksheet that scholars can utilize to precisely operationalize acceptance in their own work.