H3K9me-Independent Gene Silencing in Fission Yeast Heterochromatin by Clr5 and Histone Deacetylases

Nucleosomes in heterochromatic regions bear histone modifications that distinguish them from euchromatic nucleosomes. Among those, histone H3 lysine 9 methylation (H3K9me) and hypoacetylation have been evolutionarily conserved and are found in both multicellular eukaryotes and single-cell model organisms such as fission yeast. In spite of numerous studies, the relative contributions of the various heterochromatic histone marks to the properties of heterochromatin remain largely undefined. Here, we report that silencing of the fission yeast mating-type cassettes, which are located in a well-characterized heterochromatic region, is hardly affected in cells lacking the H3K9 methyltransferase Clr4. We document the existence of a pathway parallel to H3K9me ensuring gene repression in the absence of Clr4 and identify a silencing factor central to this pathway, Clr5. We find that Clr5 controls gene expression at multiple chromosomal locations in addition to affecting the mating-type region. The histone deacetylase Clr6 acts in the same pathway as Clr5, at least for its effects in the mating-type region, and on a subset of other targets, notably a region recently found to be prone to neo-centromere formation. The genomic targets of Clr5 also include Ste11, a master regulator of sexual differentiation. Hence Clr5, like the multi-functional Atf1 transcription factor which also modulates chromatin structure in the mating-type region, controls sexual differentiation and genome integrity at several levels. Globally, our results point to histone deacetylases as prominent repressors of gene expression in fission yeast heterochromatin. These deacetylases can act in concert with, or independently of, the widely studied H3K9me mark to influence gene silencing at heterochromatic loci

Structural, thermal and dissolution properties of MgO- and CaO-containing borophosphate glasses: effect of Fe2O3 addition

This paper investigated manufacture of high-durability phosphate glass fibres for biomedical applications. Five different borophosphate glass formulations in the systems of 45P2O5–5B2O3–5Na2O–(29 − x)CaO–16MgO–(x)Fe2O3 and 45P2O5–5B2O3–5Na2O–24CaO–(21 − x)MgO–(x)Fe2O3 where x = 5, 8 and 11 mol% were produced via melt quenching. The compositions and amorphous nature of the glasses were confirmed by ICP-MS and XRD, respectively. FTIR results indicated depolymerisation of the phosphate chains with a decrease in Q2 units with increasing Fe2O3 content. DSC analyses showed an increase in Tg by ~5 °C with an increment of 3 mol% in Fe2O3 content. The thermal properties were also used to calculate processing window (i.e. Tc,ons—Tg) and another parameter, Kgl, to determine the suitability for fibre drawing directly from melt, which equals (Tc,ons—Tg)/(Tl—Tc,ons). The degradation study conducted in PBS solution at 37 °C showed a decrease of 25–47% in degradation rate with increasing Fe2O3 content. This confirmed that the chemical durability of the glasses had increased, which was suggested to be due to Fe2O3 addition. Furthermore, the density measured via Archimedes method revealed a linear increase with increasing Fe2O3 content

Functional redundancy and sensitivity of fish assemblages in European rivers, lakes and estuarine ecosystems

The impact of species loss on ecosystems functioning depends on the amount of trait similarity between species, i.e. functional redundancy, but it is also influenced by the order in which species are lost. Here we investigated redundancy and sensitivity patterns across fish assemblages in lakes, rivers and estuaries. Several scenarios of species extinction were simulated to determine whether the loss of vulnerable species (with high propensity of extinction when facing threats) causes a greater functional alteration than random extinction. Our results indicate that the functional redundancy tended to increase with species richness in lakes and rivers, but not in estuaries. We demonstrated that i) in the three systems, some combinations of functional traits are supported by non-redundant species, ii) rare species in rivers and estuaries support singular functions not shared by dominant species, iii) the loss of vulnerable species can induce greater functional alteration in rivers than in lakes and estuaries. Overall, the functional structure of fish assemblages in rivers is weakly buffered against species extinction because vulnerable species support singular functions. More specifically, a hotspot of functional sensitivity was highlighted in the Iberian Peninsula, which emphasizes the usefulness of quantitative criteria to determine conservation prioritiesinfo:eu-repo/semantics/publishedVersio

Fcγ Receptors in Solid Organ Transplantation.

In the current era, one of the major factors limiting graft survival is chronic antibody-mediated rejection (ABMR), whilst patient survival is impacted by the effects of immunosuppression on susceptibility to infection, malignancy and atherosclerosis. IgG antibodies play a role in all of these processes, and many of their cellular effects are mediated by Fc gamma receptors (FcγRs). These surface receptors are expressed by most immune cells, including B cells, natural killer cells, dendritic cells and macrophages. Genetic variation in FCGR genes is likely to affect susceptibility to ABMR and to modulate the physiological functions of IgG. In this review, we discuss the potential role played by FcγRs in determining outcomes in solid organ transplantation, and how genetic polymorphisms in these receptors may contribute to variations in transplant outcome.MRC is supported by the NIHR Cambridge BRC, the NIHR Blood and Transplant Research Unit (Cambridge) and by a Medical Research Council New Investigator Grant (MR/N024907/1).This is the final version of the article. It first appeared from Springer via https://doi.org/10.1007/s40472-016-0116-

N'-isonicotinoylpicolinohydrazonamide: Synthesis, crystal structure, DFT and ADMET studies, and in silico inhibition properties toward a series of COVID-19 proteins

In this work, synthesis as well as detailed structural and computational analyses of the novel isoniazid derivative, namely N'-isonicotinoylpicolinohydrazonamide (1), are reported. The obtained compound was examined by microanalysis, IR, 1H NMR spectroscopy and single crystal X-ray diffraction. The crystal packing was studied by the Hirshfeld surface analysis. Molecules in the crystal structure of 1 are linked through N–H⋯O and N–H⋯N hydrogen bonds, and π⋯π interactions, yielding a 1D supramolecular chain. According to the Hirshfeld surface analysis, crystal packing of 1 is primarily dictated by H⋯H, H⋯C, H⋯N and H⋯O contacts, of which the latter three contacts are highly favoured. The crystal packing is further characterized by highly favoured C⋯C contacts. Compound 1 was also studied using DFT in gas phase, which revealed its pronounced electrophilic features. The most electron-rich (nucleophilic) sites were revealed for the carbonyl oxygen atom, and 4-pyridyl and imine nitrogen atoms, while the most electron-deficient (electrophilic) sites were found for the NH and NH2 hydrogen atoms. Compound 1 was predicted to belong to a fourth class of toxicity and exhibits negative blood–brain barrier penetration and positive gastrointestinal absorption property. In silico molecular docking was applied to probe 1 as a potential inhibitor of a series of the SARS-CoV-2 proteins and it was found that 1 is potentially active against all the applied proteins with the best activity against Nonstructural protein 3 (Nsp3_range 207–379-MES). It was also established that the best docking scores for 1 were found for the cavities, where initial ligands were located, except for the Papain-like protease (PLpro). The best binding affinity of the latter protein with 1 was revealed for the other cavity with about 0.8 kcal/mol being more efficient. Molecular dynamics simulations were also applied to evaluate the stability of complexes PLproI–1, PLproII–1 and Nsp_range 207–379-MES–1. Complex PLproI–1 was found to be highly unstable, while complexes PLproII–1 and Nsp_range 207–379-MES–1 are stable. © 2023 Elsevier Lt

On the pivotal role of tetrel bonding in the supramolecular architectures of PbII-NCS complexes with chelating thiosemicarbazide derivatives

Three new PbII complexes [Pb(LI)(SCN)]n, {[Pb(LII)](SCN)}n and {[Pb(HLIII)(SCN)](SCN)}n (HLI = N′-phenyl(pyridin-2-yl)methylene-N-phenylthiosemicarbazide, HLII = N′-amino(pyrazin-2-yl)methylenethiosemicarbazide, HLIII = N′-amino(pyridin-2-yl)methylenethiosemicarbazide) have been synthesized and characterized by spectroscopic techniques and single crystal X-ray diffraction. In all complexes, the corresponding organic ligand behaves as a tridentate N,N′,S-chelating species. A 1D supramolecular polymeric aggregation in complex [Pb(LI)(SCN)]n is dictated by the Pb⋯NCS and Pb⋯S 00000000 00000000 00000000 00000000 11111111 00000000 11111111 00000000 00000000 00000000 C tetrel bonds formed between the [Pb(LI)(SCN)] species. 1D cationic coordination polymers ([Pb(LII)])nn+ in the structure of complex {[Pb(LII)](SCN)}n are linked into a 2D supramolecular polymeric layer through the Pb⋯NCS tetrel bonds and Pb⋯π(NCS) interactions formed with the nitrogen atom and the conjugated system of the free SCN− anions, respectively. The cationic species [Pb(HLIII)(SCN)]+ in the structure of complex {[Pb(HLIII)(SCN)](SCN)}n produce a 1D supramolecular polymer due to the Pb⋯SCN and Pb⋯S C tetrel bonds, further stabilized by the Pb⋯π(NCS) interactions formed with the conjugated system of the coordinated NCS− anion. The latter anions also link these 1D chains through the Pb⋯SCN tetrel bonds, yielding 1D supramolecular polymeric ribbons. The energetic relevance of the Pb⋯S and Pb⋯N tetrel bonds has been studied by DFT calculations. The tetrel bonds have been characterized using QTAIM and NCIplot analysis and rationalized using molecular electrostatic potential surface calculations. © 2024 The Royal Society of Chemistry.Ministerio de Ciencia, Innovación y Universidades, MCIU; EAI of Spain, (PID2020-115637GB-I00)A. Frontera thanks the MICIU/EAI of Spain for financial support (project PID2020-115637GB-I00 FEDER funds)

The Prevalence of Immunologic Injury in Renal Allograft Recipients with De Novo Proteinuria

Post-transplant proteinuria is a common complication after renal transplantation; it is associated with reduced graft and recipient survival. However, the prevalence of histological causes has been reported with considerable variation. A clinico-pathological re-evaluation of post-transplant proteinuria is necessary, especially after dismissal of the term “chronic allograft nephropathy,” which had been considered to be an important cause of proteinuria. Moreover, urinary protein can promote interstitial inflammation in native kidney, whether this occurs in renal allograft remains unknown. Factors that affect the graft outcome in patients with proteinuria also remain unclear. Here we collected 98 cases of renal allograft recipients who developed proteinuria after transplant, histological features were characterized using Banff scoring system. Cox proportional hazard regression models were used for graft survival predictors. We found that transplant glomerulopathy was the leading (40.8%) cause of post-transplant proteinuria. Immunological causes, including transplant glomerulopathy, acute rejection, and chronic rejection accounted for the majority of all pathological causes of proteinuria. Nevertheless, almost all patients that developed proteinuria had immunological lesions in the graft, especially for interstitial inflammation. Intraglomerular C3 deposition was unexpectedly correlated with the severity of proteinuria. Moreover, the severity of interstitial inflammation was an independent risk factor for graft loss, while high level of hemoglobin was a protective factor for graft survival. This study revealed a predominance of immunological parameters in renal allografts with post-transplant proteinuria. These parameters not only correlate with the severity of proteinuria, but also with the outcome of the graft

Factors associated with COVID-19 vaccine uptake in adolescents: a national cross-sectional study, August 2021-January 2022, England.

OBJECTIVES: To assess socioeconomic and geographical factors associated with COVID-19 vaccine uptake in pupils attending state-funded secondary schools in England. DESIGN: Cross-sectional observational study. SETTING: State-funded schools in England. PARTICIPANTS: Pupils aged 12-17 years attending state-funded schools in England for the academic year 2021/2022. OUTCOME MEASURES: Demographic, socioeconomic and geographical factors associated with vaccination uptake. We linked individual-level data from the English Schools Census to the National Immunisation Management System to obtain COVID-19 vaccination status of 3.2 million adolescents. We used multivariable logistic regression to assess demographic, socioeconomic and geographical factors associated with vaccination. RESULTS: By 9 January 2022, 56.8% of adolescents aged 12-17 years old had received at least one dose, with uptake increasing from 48.7% in those aged 12 years old to 77.2% in those aged 17 years old. Among adolescents aged 12-15 years old, there were large variations in vaccine uptake by region and ethnic group. Pupils who spoke English as an additional language (38.2% vs 55.5%), with special educational needs (48.1% vs 53.5%), eligible for free school meals (35.9% vs 58.9%) and lived in more deprived areas (36.1% in most deprived vs 70.3% in least deprived) had lower vaccine uptake. Socioeconomic variables had greater impact on the odds of being vaccinated than geographical variables. School-level analysis found wide variation in vaccine uptake between schools even within the same region. Schools with higher proportions of pupils eligible for free school meals had lower vaccine uptake. CONCLUSIONS: We found large differences in vaccine uptake by geographical region and ethnicity. Socioeconomic variables had a greater impact on the odds of being vaccinated than geographical variables. Further research is required to identify evidence-based interventions to improve vaccine uptake in adolescents

Value of the First Post-Transplant Biopsy for Predicting Long-Term Cardiac Allograft Vasculopathy (CAV) and Graft Failure in Heart Transplant Patients

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the principal cause of long-term graft failure following heart transplantation. Early identification of patients at risk of CAV is essential to target invasive follow-up procedures more effectively and to establish appropriate therapies. We evaluated the prognostic value of the first heart biopsy (median: 9 days post-transplant) versus all biopsies obtained within the first three months for the prediction of CAV and graft failure due to CAV. METHODS AND FINDINGS: In a prospective cohort study, we developed multivariate regression models evaluating markers of atherothrombosis (fibrin, antithrombin and tissue plasminogen activator [tPA]) and endothelial activation (intercellular adhesion molecule-1) in serial biopsies obtained during the first three months post-transplantation from 172 patients (median follow-up = 6.3 years; min = 0.37 years, max = 16.3 years). Presence of fibrin was the dominant predictor in first-biopsy models (Odds Ratio [OR] for one- and 10-year graft failure due to CAV = 38.70, p = 0.002, 95% CI = 4.00-374.77; and 3.99, p = 0.005, 95% CI = 1.53-10.40) and loss of tPA was predominant in three-month models (OR for one- and 10-year graft failure due to CAV = 1.81, p = 0.025, 95% CI = 1.08-3.03; and 1.31, p = 0.001, 95% CI = 1.12-1.55). First-biopsy and three-month models had similar predictive and discriminative accuracy and were comparable in their capacities to correctly classify patient outcomes, with the exception of 10-year graft failure due to CAV in which the three-month model was more predictive. Both models had particularly high negative predictive values (e.g., First-biopsy vs. three-month models: 99% vs. 100% at 1-year and 96% vs. 95% at 10-years). CONCLUSIONS: Patients with absence of fibrin in the first biopsy and persistence of normal tPA in subsequent biopsies rarely develop CAV or graft failure during the next 10 years and potentially could be monitored less invasively. Presence of early risk markers in the transplanted heart may be secondary to ischemia/reperfusion injury, a potentially modifiable factor