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A thick neutron skin emerges from the first determination of root mean square radii of the proton distributions for 17−22N from charge changing cross section measurements around 900A MeV at GSI. Neutron halo effects are signalled for 22N from an increase in the proton and matter radii. The radii suggest an unconventional shell gap at N = 14 arising from the attractive proton–neutron tensor interaction, in good agreement with shell model calculations. Ab initio, in-medium similarity re-normalization group, calculations with a state-of-the-art chiral nucleon–nucleon and three-nucleon interaction reproduce well the data approaching the neutron drip-line isotopes but are challenged in explaining the complete isotopic trend of the radii. Keywords: Proton and matter radii, Neutron skin, Magic number, Shell model, Ab initio theory, Radioactive beams

Isobaric single charge-exchange reactions, changing nuclear charges by one unit but leaving the mass partitions unaffected, have been for the first time investigated by peripheral collisions of 112Sn ions accelerated up to 1A GeV at the GSI facilities. The high-resolving power of the FRS spectrometer allows us to obtain (p,n)-type isobaric charge-exchange cross sections with an uncertainty of 3.5% and to separate quasi-elastic and inelastic components in the missing-energy spectra of the ejectiles. The inelastic component is associated to the excitation of the Δ(1232) isobar resonance and the emission of pions in s-wave both in the target and projectile nucleus, while the quasi-elastic contribution is associated to the nuclear spin-isospin response of nucleon-hole excitations. An apparent shift of the Δ-resonance peak of ∼63 MeV is observed when comparing the missing-energy spectra obtained from the measurements with proton and carbon targets. A detailed analysis, performed with a theoretical model for the reactions, indicates that this observation can be simply interpreted as a change in the relative magnitude between the contribution of the excitation of the resonance in the target and in the projectile.

Desert dust is one of the most abundant ice nucleating particle types in the atmosphere. Traditionally, clay minerals were assumed to determine the ice nucleation ability of desert dust and constituted the focus of ice nucleation studies over several decades. Recently some feldspar species were identified to be ice active at much higher temperatures than clay minerals, redirecting studies to investigate the contribution of feldspar to ice nucleation on desert dust. However, so far no study has shown the atmospheric relevance of this mineral phase.For this study four dust samples were collected after airborne transport in the troposphere from the Sahara to different locations (Crete, the Peloponnese, Canary Islands, and the Sinai Peninsula). Additionally, 11 dust samples were collected from the surface from nine of the biggest deserts worldwide. The samples were used to study the ice nucleation behavior specific to different desert dusts. Furthermore, we investigated how representative surface-collected dust is for the atmosphere by comparing to the ice nucleation activity of the airborne samples. We used the IMCA-ZINC setup to form droplets on single aerosol particles which were subsequently exposed to temperatures between 233 and 250 K. Dust particles were collected in parallel on filters for offline cold-stage ice nucleation experiments at 253–263 K. To help the interpretation of the ice nucleation experiments the mineralogical composition of the dusts was investigated. We find that a higher ice nucleation activity in a given sample at 253 K can be attributed to the K-feldspar content present in this sample, whereas at temperatures between 238 and 245 K it is attributed to the sum of feldspar and quartz content present. A high clay content, in contrast, is associated with lower ice nucleation activity. This confirms the importance of feldspar above 250 K and the role of quartz and feldspars determining the ice nucleation activities at lower temperatures as found by earlier studies for monomineral dusts. The airborne samples show on average a lower ice nucleation activity than the surface-collected ones. Furthermore, we find that under certain conditions milling can lead to a decrease in the ice nucleation ability of polymineral samples due to the different hardness and cleavage of individual mineral phases causing an increase of minerals with low ice nucleation ability in the atmospherically relevant size fraction. Comparison of our data set to an existing desert dust parameterization confirms its applicability for climate models. Our results suggest that for an improved prediction of the ice nucleation ability of desert dust in the atmosphere, the modeling of emission and atmospheric transport of the feldspar and quartz mineral phases would be key, while other minerals are only of minor importance.

Summary: Background: Pulmonary fibrosis is a challenging clinical problem with lung pathology featuring immune cell infiltrates, fibroblast expansion, and matrix deposition. Molecular analysis of diseased lungs and preclinical models have uncovered C–C chemokine receptor type 2 (CCR2)+ monocyte egress from the bone marrow into the lung, where they acquire profibrotic activities. Current drug treatment is focused on fibroblast activity. Alternatively, therapeutic targeting and monitoring CCR2+ cells may be an effective patient management strategy. Methods: Inhibition of CCR2+ cells and, as a benchmark, the clinical antifibrotic agent, nintedanib, were used in mouse lung fibrosis models. Lungs were evaluated directly for CCR2+ cell infiltration and by non-invasive CCR2+ positron emission tomography imaging (CCR2-PET). Findings: Lung CCR2+ cells were significantly elevated in the bleomycin model as determined by tissue evaluation and CCR2-PET imaging. A protective treatment protocol with an oral CCR2 inhibitor was compared to oral nintedanib. While we expected disparate effects on CCR2+ cells, each drug similarly decreased lung CCR2+ cells and fibrosis. Chemotaxis assays showed nintedanib indirectly inhibited C–C motif chemokine 2 (CCL2)-mediated migration of CCR2+ cells. Even delayed therapeutic administration of nintedanib in bleomycin and the silicosis progressive fibrosis models decreased the accumulation of CCR2+ lung cells. In these treatments early CCR2-PET imaging predicted the later development of fibrosis. Interpretation: The inhibition of CCR2+ cell egress is likely a critical controller for stabilising lung fibrosis, as provided by nintedanib. Imaging with CCR2-PET may be useful to monitor nintedanib treatment responses, guide decision-making in the treatment of patients with progressive pulmonary fibrosis, and as a biomarker for drug development. Funding: National Institutes of Health (NIH), R01HL131908 (SLB), R35HL145212 (YL), P41EB025815 (YL), K01DK133670 (DHK); Barnes Jewish Hospital Foundation (SLB).

Vitamin E (α-tocopherol) is the major lipid-soluble antioxidant in many species. Niemann-Pick type C (NPC) disease is a lysosomal storage disorder caused by mutations in the NPC1 or NPC2 gene, which regulates lipid transport through the endocytic pathway. NPC disease is characterized by massive intracellular accumulation of unesterified cholesterol and other lipids in lysosomal vesicles. We examined the roles that NPC1/2 proteins play in the intracellular trafficking of tocopherol. Reduction of NPC1 or NPC2 expression or function in cultured cells caused a marked lysosomal accumulation of vitamin E in cultured cells. In vivo, tocopherol significantly accumulated in murine Npc1-null and Npc2-null livers, Npc2-null cerebella, and Npc1-null cerebral cortices. Plasma tocopherol levels were within the normal range in Npc1-null and Npc2-null mice, and in plasma samples from human NPC patients. The binding affinity of tocopherol to the purified sterol-binding domain of NPC1 and to purified NPC2 was significantly weaker than that of cholesterol (measurements kindly performed by R. Infante, University of Texas Southwestern Medical Center, Dallas, TX). Taken together, our observations indicate that functionality of NPC1/2 proteins is necessary for proper bioavailability of vitamin E and that the NPC pathology might involve tissue-specific perturbations of vitamin E status.

Introduction: The use of the dorsal hamate as a free osteochondral bone graft or vascularized bone flap has become the mainstay for large, comminuted middle phalanx volar lip fractures. To date, few studies have been conducted in the assessment of donor site morbidity for the hemi-hamate graft or flap, and none have discussed modes of repair or reconstruction of this donor site. Methods: A retrospective analysis of 14 hemi-hamate arthroplasty (HHA) procedures, including 6 vascularized and 8 non-vascularized grafts, from two surgeons was performed. Four hamate defect reconstruction techniques were utilized: no formal reconstruction, autologous bone grafting, gel foam, or synthetic bone substitute. The dorsal capsule was repaired with either extensor retinaculum grafting or by direct closure. Wrist range of motion, pain scores, and radiographic alignment were assessed. Results: At 6 months follow-up, all patients achieved full, pain-free wrist motion compared to the uninjured side, with visual analog scale pain scores of 0. Serial radiographs showed maintained carpal alignment without instability or subluxation. No differences based on the hamate defect reconstruction method or capsular repair technique was demonstrated. Conclusion: Safe return to pain free, unrestricted wrist function is achievable after HHA, regardless of hamate donor site management. Adequate dorsal capsular repair appears critical to prevent instability. Further study is needed to compare techniques, but choice may be guided by surgeon preference in the absence of clear evidence.

Abstract Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.

Abstract Background Cognitive impairment associated with schizophrenia (CIAS) represents a distinct, persistent, and core group of schizophrenia symptoms. Cognitive symptoms have been shown to have an impact on quality of life. There are several published CIAS measures, but none based on direct patient self-report. It is important to capture the patient’s perspective to supplement performancebased outcome measures of cognition to provide a complete picture of the patient’s experience. This paper describes additional validation work on the Patient-Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) instrument. Methods Data from two large, international, pharmaceutical clinical trials in medically and psychiatrically stable English-speaking patients with schizophrenia and 88 healthy controls were analyzed. An exploratory factor analysis (EFA) was conducted in one trial (n = 215), using the original 35-item PRECIS. The factor structure suggested by EFA was further evaluated using item response theory (IRT; Samejima’s graded response model), and tested using confirmatory factor analysis (CFA). Both EFA and CFA results were tested in a second trial with similar inclusion/exclusion characteristics (n = 410). Additional statistical properties were evaluated in healthy controls. Results EFA suggested that the best solution after item reduction suggested a factor structure of 6 factors based on 26 items (memory, communication, self-control, executive function, attention, sharpness of thought), supporting a total score, with an additional 2-item bother score (28 items in all). IRT analysis indicated the items were well-ordered within each domain. The CFA demonstrated excellent model fit, accounting for 69% of the variance. The statistical properties of the 28-item version of the PRECIS were confirmed in the second trial. Evidence for internal consistency and test-retest reliability was robust. Known-groups validity was supported by comparison of healthy controls with patients with schizophrenia. Correlations indicated moderate associations between PRECIS and functioning instruments like the Schizophrenia Cognition Rating Scale (SCoRS), but weak correlations with performance-based outcomes like MATRICS Consensus Cognitive Battery (MCCB). Discussion Using two clinical trial samples, we identified a robust factor structure for the PRECIS and were able to replicate it in the second sample. Evaluation of the meaningful score difference (MSD) should be repeated in future studies, as these samples did not show enough change for it to be evaluated. Conclusions This analysis provides strong evidence for the reliability and validity of the PRECIS, a 28-item, patient-reported instrument to assess cognitive impairment associated with schizophrenia. The correlation with functioning and the weak correlation with performance on cognitive tasks suggests that patient reports of cognitive impairment measure a unique aspect of patient experience.

Abstract Background The Insomnia Severity Index (ISI) is a widely used measure of insomnia severity. Various ISI research findings suggest different factor solutions and meaningful within-individual change (MWIC) to detect treatment response in patients with insomnia. This study examined an ISI factor solution and psychometric indices to define MWIC in a robust patient sample from clinical trial settings. Methods We endeavored to improve upon previous validation of ISI by examining structural components of confirmatory factor analysis (CFA) models using two large, placebo-controlled clinical trials of lemborexant for insomnia. Using the best-fitting two-factor solution, we evaluated anchor-based, distribution-based and receiver operating characteristic (ROC) curve methods to derive an estimate of the MWIC. Results The model structure for the 7-item scale proposed in other research did not fit the observed data from our two lemborexant clinical trials (N = 1956) as well as a two-factor solution based on 6 items did. Using triangulation of anchor-based, distribution-based, and ROC methods, we determined that a 5-point reduction using 6 items best represented a clinically meaningful improvement in individuals with insomnia in our patient sample. Conclusions A 6-item two-factor scale had better psychometric properties than the 7-item scale in this patient sample. On the 6-item scale, a reduction of 5 points in the ISI total score represented the MWIC. Generalizability of the proposed MWIC may be limited to patient populations with similar demographic and clinical characteristics.

The effects of vitamin E on the activity of membrane-dependent enzymes suggest that it acts indirectly by modifying some properties of the lipid host. The effects of α-tocopherol (α-T) and α-tocopherol hemisuccinate (α-THS) on phospholipid monolayer structure, curvature, and bending elasticity were examined using X-ray diffraction and the osmotic stress method. These ligands were mixed with the hexagonal phase-forming lipid, dioleoylphosphatidylethanolamine (DOPE). Increasing levels up to 50 mol% α-T in DOPE in excess water result in a systematic decrease in the lattice dimension. Analysis of the structural changes imposed by α-T shows that it contributes a spontaneous radius of curvature of −13.7 Å. This unusually negative value is comparable to diacylglycerols. α-T does not affect the bending elasticity of these monolayers. α-THS in its charged form decreases membrane curvature, but in its undissociated neutral form has a qualitatively similar but reduced effect on monolayer curvature, as does α-T.We discuss these results in terms of the local stresses such ligands would produce in the vicinity of a membrane protein, and how one might expect proteins to respond to such stress.

The Bacchae, as we know it, was first produced in Athens under the direction of Euripides’ son, also called Euripides, in perhaps 405 BC,2 a year or two after his father’s death, but when the tragedian first presented the play he was in Macedonia at the court of Archelaus. So I want to take you on a journey from Athens, north towards Macedon. This means travelling over Cithaeron, and past the site of ancient Thebes; then through the pass at Thermopylae. The fall of Thermopylae to Xerxes in 480 signalled the invasion of Greece by the Persians, and when Philip of Macedon marched towards Thermopylae in 346, the liberty of Greece was threatened. North of Thermopylae the next major barrier was the Vale of Tempe: in 480 the Greeks had thoughts of holding Tempe against the invading army of Xerxes and the Persians, but were forced to make a tactical withdrawal to Thermopylae. Beyond Tempe one passes from Thessaly into Macedonian territory and arrives in the coastal plan of Pieria, about which the Chorus waxes lyrical in Bacchae 409-410 (“Pieria the incomparably beautiful”) and 565- 575. Along the main road north through Pieria, Mt Olympus can be seen to the west, and at about 50 km from Tempe are found the remains of ancient Dion. King Archelaus (413-399) built a temple to Zeus at Dion and a theatre, and we can imagine that Euripides was commissioned to present tragedies here, perhaps even the Bacchae, as Seaford (1996:184) suggests.

IntroductionThe sinus node (SN) is the main pacemaker site of the heart, located in the upper right atrium at the junction of the superior vena cava and right atrium. The precise morphology of the SN in the human heart remains relatively unclear especially the SN microscopical anatomy in the hearts of aged and obese individuals. In this study, the histology of the SN with surrounding right atrial (RA) muscle was analyzed from young non-obese, aged non-obese, aged obese and young obese individuals. The impacts of aging and obesity on fibrosis, apoptosis and cellular hypertrophy were investigated in the SN and RA. Moreover, the impact of obesity on P wave morphology in ECG was also analyzed to determine the speed and conduction of the impulse generated by the SN.MethodsHuman SN/RA specimens were dissected from 23 post-mortem hearts (preserved in 4% formaldehyde solution), under Polish local ethical rules. The SN/RA tissue blocks were embedded in paraffin and histologically stained with Masson’s Trichrome. High and low-magnification images were taken, and analysis was done for appropriate statistical tests on Prism (GraphPad, USA). 12-lead ECGs from 14 patients under Polish local ethical rules were obtained. The P wave morphologies from lead II, lead III and lead aVF were analyzed.ResultsCompared to the surrounding RA, the SN in all four groups has significantly more connective tissue (P ≤ 0.05) (young non-obese individuals, aged non-obese individuals, aged obese individuals and young obese individuals) and significantly smaller nodal cells (P ≤ 0.05) (young non-obese individuals, aged non-obese individuals, aged obese individuals, young obese individuals). In aging, overall, there was a significant increase in fibrosis, apoptosis, and cellular hypertrophy in the SN (P ≤ 0.05) and RA (P ≤ 0.05). Obesity did not further exacerbate fibrosis but caused a further increase in cellular hypertrophy (SN P ≤ 0.05, RA P ≤ 0.05), especially in young obese individuals. However, there was more infiltrating fat within the SN and RA bundles in obesity. Compared to the young non-obese individuals, the young obese individuals showed decreased P wave amplitude and P wave slope in aVF lead.DiscussionAging and obesity are two risk factors for extensive fibrosis and cellular hypertrophy in SN and RA. Obesity exacerbates the morphological alterations, especially hypertrophy of nodal and atrial myocytes. These morphological alterations might lead to functional alterations and eventually cause cardiovascular diseases, such as SN dysfunction, atrial fibrillation, bradycardia, and heart failure.

This study examined physical education teacher education (PETE) majors' common content knowledge (CCK), performance, and specialized content knowledge (SCK) of volleyball to see whether there is a difference between non-PETE majors, and how much they improved, while they were in the PETE program. Twenty-two participants from a PETE major volleyball content course and 21 participants from a non-PETE major basic instruction volleyball course for the comparison group. Pre- and post-tests of CCK, performance, and two SCK variables were used for the majors, and one pretest SCK variable (task progression) was used for the comparison group. Data are reported both descriptively and inferentially. The PETE majors showed better scores on the pretest for the SCK variable (task progression). Also, the PETE majors had significantly improved scores from pre- to post-test for all four variables. It needs further research studies for the content course of the PETE program to find the best way to proceed.

Abstract The Eyes Absent proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour-promoting across a range of cancer types. To date, the targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as an interactor and phosphatase substrate of EYA4 and EYA1, with pY445 on PLK1 being the primary target site. Dephosphorylation of pY445 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and PLK1-activation complexes. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a phosphotyrosine signalling network governing PLK1 and mitosis.

Abstract Cochlear melanocytes are intermediate cells in the stria vascularis that generate endocochlear potentials required for auditory function. Human PAX3 mutations cause Waardenburg syndrome and abnormalities of skin and retinal melanocytes, manifested as congenital hearing loss (~ 70%) and hypopigmentation of skin, hair and eyes. However, the underlying mechanism of hearing loss remains unclear. Cochlear melanocytes in the stria vascularis originated from Pax3-traced melanoblasts and Plp1-traced Schwann cell precursors, both of which derive from neural crest cells. Here, using a Pax3-Cre knock-in mouse that allows lineage tracing of Pax3-expressing cells and disruption of Pax3, we found that Pax3 deficiency causes foreshortened cochlea, malformed vestibular apparatus, and neural tube defects. Lineage tracing and in situ hybridization show that Pax3 + derivatives contribute to S100+, Kir4.1 + and Dct + melanocytes (intermediate cells) in the developing stria vascularis, all of which are significantly diminished in Pax3 mutant animals. Taken together, these results suggest that Pax3 is required for the development of neural crest cell-derived cochlear melanocytes, whose absence may contribute to congenital hearing loss of Waardenburg syndrome in humans.

IMPORTANCE AND OBJECTIVES:. COVID-19-related acute respiratory distress syndrome (ARDS) is associated with high mortality and often necessitates invasive mechanical ventilation (IMV). Previous studies on non-COVID-19 ARDS have shown driving pressure to be robustly associated with ICU mortality; however, those studies relied on “static” driving pressure measured periodically and manually. As “continuous” automatically monitored driving pressure is becoming increasingly available and reliable with more advanced mechanical ventilators, we aimed to examine the effect of this “dynamic” driving pressure in COVID-19 ARDS throughout the entire ventilation period. DESIGN, SETTING, AND PARTICIPANTS:. This retrospective, observational study cohort study evaluates the association between driving pressure and ICU mortality in patients with concurrent COVID-19 and ARDS using multivariate joint modeling. The study cohort (n = 544) included all adult patients (≥ 18 yr) with COVID-19 ARDS between March 1, 2020, and April 30, 2021, on volume-control mode IMV for 12 hours or more in a Mass General Brigham, Boston, MA ICU. MEASUREMENTS AND MAIN RESULTS:. Of 544 included patients, 171 (31.4%) died in the ICU. Increased dynamic ΔP was associated with increased risk in the hazard of ICU mortality (hazard ratio [HR] 1.035; 95% credible interval, 1.004–1.069) after adjusting for other relevant dynamic respiratory biomarkers. A significant increase in risk in the hazard of death was found for every hour of exposure to high intensities of driving pressure (≥ 15 cm H2O) (HR 1.002; 95% credible interval 1.001–1.003). CONCLUSIONS:. Limiting patients’ exposure to high intensities of driving pressure even while under lung-protective ventilation may represent a critical step in improving ICU survival in patients with COVID-19 ARDS. Time-series IMV data could be leveraged to enhance real-time monitoring and decision support to optimize ventilation strategies at the bedside.

Abstract Background Pre-procedural fasting to reduce aspiration risk is usual care prior to surgery requiring anesthesia. Prolonged fasting, however, can result in dehydration and may adversely affect patient experience and outcomes. Previous studies suggest that providing a supplemental beverage to patients undergoing cardiac and a variety of other surgical procedures improves patients’ subjective assessment of thirst and hunger and potentially decreases the need for inotrope and vasopressor therapy. Less is known, however, about the effects of ad libitum clear liquids up to 2 h prior to surgery. Methods Adult patients undergoing transcatheter aortic valve replacement (TAVR) or arrhythmia ablation were randomized (1:1) to ad libitum clear liquids up to 2 h prior to their procedure vs. nil per os (NPO) after midnight (control group, usual care). The primary endpoint was a composite satisfaction score that included patient-reported thirst, hunger, headache, nausea, lightheadedness, and anxiousness prior to surgery. The incidence of case-delay was recorded. Intraoperative vasopressor administration, changes in creatinine, anti-emetic use, and hospital length of stay (LOS) were recorded. Safety endpoints including aspiration were assessed. Results A total of 200 patients were randomized and 181 patients were included in the final analysis. Overall, 92% of patients were ASA class III or IV and 23% of patients had NYHA class III or IV symptoms. Groups were well balanced with no significant differences in age, sex or baseline cardiac or renal disease. The composite satisfaction score (primary endpoint) was not significantly different between groups (Ad libitum median = 12, IQR = [6, 17], vs Standard NPO median = 10, IQR = [5, 15], [95% CI = [-1, 4]). No significant differences between the two groups were observed in any of the individual survey questions (thirst, hunger, headache, nausea, lightheadedness, anxiousness). No significant differences between groups were observed for intra-operative vasopressor use, changes in creatinine, rescue anti-emetic use or hospital LOS. There were no case delays attributed to the intervention. There were no cases of suspected aspiration. Conclusion No adverse events or case delays were observed in the ad libitum clears group. No significant benefit, however, was observed in patient satisfaction or any of the pre-specified secondary endpoints in patients randomized to ad libitum clear liquids up to 2 h prior to their procedure. Trial registration NCT04079543.

Glioblastoma stem-like cells (GSLCs) in glioblastoma limit effective treatment and promote therapeutic resistance and tumor recurrence. Using a combined radiation and drug-screening platform, we tested the combination of a histone deacetylase inhibitor (HDACi) and MAPK/ERK kinase inhibitor (MEKi) with radiation to predict the efficacy against GSLCs. To mimic a stem-like phenotype, glioblastoma-derived spheres were used and treated with a combination of HDACi (MS-275) and MEKi (TAK-733 or trametinib) with 4 Gy irradiation. The sphere-forming ability after the combined radiochemotherapy was investigated using a sphere formation assay, while the expression levels of the GSLC markers (CD44, Nestin and SOX2) after treatment were analyzed using Western blotting and flow cytometry. The combined radiochemotherapy treatment inhibited the sphere formation in both glioblastoma-derived spheres, decreased the expression of the GSLC markers in a cell-line dependent manner and increased the dead cell population. Finally, we showed that the combined treatment with radiation was more effective at reducing the GSLC markers compared to the standard treatment of temozolomide and radiation. These results suggest that combining HDAC and MEK inhibition with radiation may offer a new strategy to improve the treatment of glioblastoma.

The sinus node (SN) is the heart’s primary pacemaker and has a unique expression of pacemaking ion channels and immune cell markers. The role of microribonucleic acids (miRNAs) in control of ion channels and immune function of the sinus node is not well understood. We have recently shown that hsa-miR-486-3p downregulates the main pacemaking channel HCN4 in the SN. In addition, we recently demonstrated that immune cells are significantly more abundant in the SN compared to the right atrium. The aim of this study was to validate the previously predicted interactions between miRNAs and mRNAs of key Ca2+ ion channels (involved in peacemaking) and mRNA of TPSAB1—(a mast cells marker) using luciferase assay. We now show that miR-486 significantly downregulates Cav1.3, Cav3.1, and TPSAB1-mediated luciferase activity, while miR-938 significantly downregulates only TPSAB1-mediated luciferase activity. This makes miR-486-3p a potential therapeutic target in the treatment of SN dysfunctions.

Radiation-induced cardiovascular disease is associated with metabolic remodeling in the heart, mainly due to the inactivation of the transcription factor peroxisome proliferator-activated receptor alpha (PPARα), thereby inhibiting lipid metabolic enzymes. The objective of the present study was to investigate the potential protective effect of fenofibrate, a known agonist of PPARα on radiation-induced cardiac toxicity. To this end, we compared, for the first time, the cardiac proteome of fenofibrate- and placebo-treated mice 20 weeks after local heart irradiation (16 Gy) using label-free proteomics. The observations were further validated using immunoblotting, enzyme activity assays, and ELISA. The analysis showed that fenofibrate restored signalling pathways that were negatively affected by irradiation, including lipid metabolism, mitochondrial respiratory chain, redox response, tissue homeostasis, endothelial NO signalling and the inflammatory status. The results presented here indicate that PPARα activation by fenofibrate attenuates the cardiac proteome alterations induced by irradiation. These findings suggest a potential benefit of fenofibrate administration in the prevention of cardiovascular diseases, following radiation exposure.

Achieving multi-million-hectare commitments from countries around the world to restore degraded lands in resilient and sustainable ways requires, among other things, huge volumes of tree planting material. Seed systems encompassing all forest reproductive material (e.g., seeds, cuttings, stakes, and wildings), are key to ensuring that sufficient planting material with a diverse range of suitable species, adapted to local conditions and capable of persisting under a changing climate, is available for restoration projects. The ideal structure of a seed system integrates five components: seed selection and innovation, seed harvesting and production, market access, supply and demand, quality control, and an enabling environment. We propose 15 indicators to evaluate these key components and trial them by assessing national seed systems in 7 Latin American countries. We conclude that the indicators enable a straightforward assessment of the strengths and weaknesses of national seed systems, thus assisting governments to identify key areas for improvement and opportunities for horizontal learning.