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Northern Hemisphere forests changed drastically in the early Eocene with the diversification of the oak family (Fagaceae). Cooling climates over the next 20 million years fostered the spread of temperate biomes that became increasingly dominated by oaks and their chestnut relatives. Here we use phylogenomic analyses of nuclear and plastid genomes to investigate the timing and pattern of major macroevolutionary events and ancient genome-wide signatures of hybridization across Fagaceae. Innovation related to seed dispersal is implicated in triggering waves of continental radiations beginning with the rapid diversification of major lineages and resulting in unparalleled transformation of forest dynamics within 15 million years following the K-Pg extinction. We detect introgression at multiple time scales, including ancient events predating the origination of genus-level diversity. As oak lineages moved into newly available temperate habitats in the early Miocene, secondary contact between previously isolated species occurred. This resulted in adaptive introgression, which may have further amplified the diversification of white oaks across Eurasia. Fagaceae are diverse family including trees of ecological and economic importance. This phylogenomic analysis of nuclear and plastid genomes reconstructs evolutionary history and finds evidence of multiple adaptive introgression events in this important plant family.

Aims/hypothesis Endothelial cell (EC) damage is a key mechanism causing retinal microvascular injury in diabetes. Several microRNAs (miRNAs) have been found to regulate sirtuin 1 (SIRT1, which is involved in regulation of the cell cycle, survival and metabolism) in various tissues and disease states, but no studies have been conducted on the role of miRNA in regulation of SIRT1 in diabetic retinopathy. Here we investigated the effect of miRNA-195 (miR-195), a SIRT1 -targeting miRNA, on the development of diabetes-induced changes in ECs and retina. Methods The level of miR-195 was measured in human retinal and dermal microvascular ECs (HRECs, HMECs) following exposure to 25 mmol/l glucose (high glucose, HG) and 5 mmol/l glucose (normal glucose, NG). SIRT1 and fibronectin levels were examined following transfection with miR-195 mimic or antagomir or forced expression of SIRT1 . Retinal tissues from diabetic rats were similarly studied following intravitreal injection of an miR-195 antagomir or mimic. In situ hybridisation was used to localise retinal miR-195. Results HG caused increased miR-195 levels and decreased SIRT1 expression (compared with NG) in both HRECs and HMECs. Transfection with miR-195 antagomir and forced expression of SIRT1 prevented such changes, whereas transfection with miR-195 mimic produced HG-like effects. A luciferase assay confirmed the binding of miR-195 to the 3′ untranslated region of SIRT1 . miR-195 expression was upregulated in retinas of diabetic rats and intravitreal injection of miR-195 antagomir ameliorated levels of SIRT1. Conclusions/interpretation These studies identified a novel mechanism whereby miR-195 regulates SIRT1-mediated tissue damage in diabetic retinopathy.

To examine whether the long non‐coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is altered in the endothelial cells in response to glucose and the significance of such alteration. We incubated human umbilical vein endothelial cells with media containing various glucose levels. We found an increase in MALAT1 expression peaking after 12 hrs of incubation in high glucose. This increase was associated with parallel increase in serum amyloid antigen 3 (SAA3), an inflammatory ligand and target of MALAT1 and was further accompanied by increase in mRNAs and proteins of inflammatory mediators, tumour necrosis factor alpha (TNF‐α) and interleukin 6 (IL‐6). Renal tissue from the diabetic animals showed similar changes. Such cellular alterations were prevented following MALAT1 specific siRNA transfection. Results of this study indicate that LncRNA MALAT1 regulates glucose‐induced up‐regulation of inflammatory mediators IL‐6 and TNF‐α through activation of SAA3. Identification of such novel mechanism may lead to the development of RNA‐based therapeutics targeting MALAT1 for diabetes‐induced micro and macro vascular complications.

A bstract Recently, the Belle II collaboration announced the first measurement of the branching ratio B B + → K + ν ν ¯ , which is found to be about 2 . 7 σ higher than the Standard Model (SM) prediction. We decipher the data with two new physics scenarios: the underlying quark-level b → sν ν ¯ transition is, besides the SM contribution, further affected by heavy new mediators that are much heavier than the electroweak scale, or amended by an additional decay channel with undetected light final states like dark matter or axion-like particles. These two scenarios can be most conveniently analyzed in the SM effective field theory (SMEFT) and the dark SMEFT (DSMEFT) framework, respectively. We consider the flavour structures of the resulting effective operators to be either generic or satisfy the minimal flavour violation (MFV) hypothesis, both for the quark and lepton sectors. In the first scenario, once the MFV assumption is made, only one SM-like low-energy effective operator induced by the SMEFT dimension-six operators can account for the Belle II excess, whose parameter space is, however, excluded by the Belle upper bound of the branching ratio B B 0 → K ∗ 0 ν ν ¯ . In the second scenario, it is found that the Belle II excess can be accommodated by 22 of the DSMEFT operators involving one or two scalar, fermionic, or vector dark matters as well as axion-like particles. These operators also receive dominant constraints from the B 0 → K *0 + inv and B s → inv decays. Once the MFV hypothesis is assumed, the number of viable operators is reduced to 14, and the B + → π + + inv and K + → π + + inv decays start to put further constraints on them. Within the parameter space allowed by all the current experimental data, the q 2 distributions of the B → K (*) + inv decays are then studied for each viable operator. We find that the resulting prediction of the operator Q qχ = q ¯ p γ μ q r χ ¯ γ μ χ with a fermionic dark matter mass m χ ≈ 700 MeV can closely match the Belle II event distribution in the bins 2 ≤ q 2 ≤ 7 GeV 2 . In addition, we, for the first time, calculate systematically the longitudinal polarization fraction F L of K * in the B → K * + inv decays within the DLEFT. By combining the decay spectra and F L , almost all the DSMEFT operators are found to be distinguishable from each other. Finally, the future prospects at Belle II, CEPC and FCC-ee are also discussed for some of these FCNC processes.

Despite possessing limited protein-coding potential, long non-coding RNAs (lncRNAs) have been implicated in a myriad of pathologic conditions. Most well documented in cancer, one prominent intergenic lncRNA known as MALAT1 is notorious for its role in impacting epigenetic mechanisms. In this study, we established a novel epigenetic paradigm for MALAT in diabetic retinopathy (DR) by employing siRNA-mediated MALAT1 knockdown in human retinal endothelial cells (HRECs), a Malat1 knockout animal model, vitreous humor from diabetic patients, pharmacological inhibitors for histone and DNA methylation, RNA immunoprecipitation, western blotting, and a unique DNA methylation array to determine glucose-related alterations in MALAT1 . Our findings indicated that MALAT1 is capable of impacting the expressions of inflammatory transcripts through its association with components of the PRC2 complex in diabetes. Furthermore, the vitreous humors from diabetic patients revealed increased expressions of MALAT1, TNF-α, and IL-6. Intriguingly, our DNA methylation array demonstrated that transient high glucose exposure in HRECs does not contribute to significant methylation alterations at CpG sites across the MALAT1 gene. However, global inhibition of DNA methyltransferases induced significant increases in MALAT1 and associated inflammatory transcripts in HRECs. Our findings collectively demonstrate the importance of MALAT1 in inflammation and epigenetic regulation in DR.

Abstract The heterogeneous landscape of genomic variation has been well documented in population genomic studies. However, disentangling the intricate interplay of evolutionary forces influencing the genetic variation landscape over time remains challenging. In this study, we assembled a chromosome-level genome for Castanopsis eyrei and sequenced the whole genomes of 276 individuals from 12 Castanopsis species, spanning a broad divergence continuum. We found highly correlated genomic variation landscapes across these species. Furthermore, variations in genetic diversity and differentiation along the genome were strongly associated with recombination rates and gene density. These results suggest that long-term linked selection and conserved genomic features have contributed to the formation of a common genomic variation landscape. By examining how correlations between population summary statistics change throughout the species divergence continuum, we determined that background selection alone does not fully explain the observed patterns of genomic variation; the effects of recurrent selective sweeps must be considered. We further revealed that extensive gene flow has significantly influenced patterns of genomic variation in Castanopsis species. The estimated admixture proportion correlated positively with recombination rate and negatively with gene density, supporting a scenario of selection against gene flow. Additionally, putative introgression regions exhibited strong signals of positive selection, an enrichment of functional genes, and reduced genetic burdens, indicating that adaptive introgression has played a role in shaping the genomes of hybridizing species. This study provides insights into how different evolutionary forces have interacted in driving the evolution of the genomic variation landscape.

Chronic diabetic complications affect multiple organs causing widespread organ damage. Although there are some commonalities, the phenotype of such changes show tissue specific variation. Given this, we examined whether differences in circular RNA (circRNA) mediated gene regulatory mechanisms contribute to changes in gene expression at the basal level and in diabetes. CircRNAs are single-stranded RNA with covalently closed loop structures and act as miRNA sponges, factors of RNA splicing, scaffolding for proteins, regulators of transcription, and modulators of the expression of parental genes, among other roles. We examined heart and retinal tissue from Streptozotocin-induced diabetic mice with established diabetes related tissue damage and tissue from non-diabetic controls. A custom array analysis was performed and the data were analysed. Two major circRNA mediated processes were uniquely upregulated in diabetic heart tissue, namely, positive regulation of endothelial cell migration and regulation of mitochondria: mitochondrial electron transport. In the retina, circRNAs regulating extracellular matrix protein production and endothelial to mesenchymal transition (EndMT) were found to be upregulated. The current study identified regulatory and potential pathogenetic roles of specific circRNA in diabetic retinopathy and cardiomyopathy. Understanding such novel mechanisms, may in the future, be useful to develop RNA based treatment strategies.

Synthetic lethality (SL) occurs when mutations in two genes together lead to cell or organism death, while a single mutation in either gene does not have a significant impact. This concept can also be extended to three or more genes for SL. Computational and experimental methods have been developed to predict and verify SL gene pairs, especially for yeast and Escherichia coli . However, there is currently a lack of a specialized platform to collect microbial SL gene pairs. Therefore, we designed a synthetic interaction database for microbial genetics that collects 13,313 SL and 2,994 Synthetic Rescue (SR) gene pairs that are reported in the literature, as well as 86,981 putative SL pairs got through homologous transfer method in 281 bacterial genomes. Our database website provides multiple functions such as search, browse, visualization, and Blast. Based on the SL interaction data in the S . cerevisiae , we review the issue of duplications’ essentiality and observed that the duplicated genes and singletons have a similar ratio of being essential when we consider both individual and SL. The Microbial Synthetic Lethal and Rescue Database (Mslar) is expected to be a useful reference resource for researchers interested in the SL and SR genes of microorganisms. Mslar is open freely to everyone and available on the web at http://guolab.whu.edu.cn/Mslar/ .

A bstract Scalar singlets under the Standard Model gauge group appear naturally in many well-motivated New Physics scenarios, such as the composite Higgs models. Unlike the Higgs boson in the Standard Model, they can induce large flavour-changing neutral currents (FCNCs) in the top sector. We investigate systematically the effects of a light scalar singlet S with top-quark FCNC couplings, by including the low-energy constraints from the B s → μ + μ − decay, the muon anomalous magnetic moment ( g − 2) μ and the neutron Electric Dipole Moment (EDM). We also perform a detailed Monte-Carlo simulation of the channel pp → tS + j with S → μ + μ − and S → b b ¯ , and investigate the LHC sensitivity to the tcS couplings. It is found that the scalar singlet S can induce scalar-type contributions to the B s → μ + μ − decay, which do not suffer from the helicity suppression and contain a large CKM factor V cs ∗ V tb . As a result, constraints on the tcS couplings from the measured branching ratio B ( B s → μ + μ − ) are quite stringent, being even stronger than the expected LHC sensitivity in some parameter spaces. Besides the CP-conserving tcS couplings, we have also considered the case of CP-violating tcS couplings, with y R , L ct = y R , L ct e i θ R , L . It is found that the CP observables A Δ Γ s μμ and S μμ of the B s → μ + μ − decay are sensitive to the phase θ R , while the neutron EDM can provide bounds on the phase difference θ L − θ R . Therefore, they are complementary to each other in probing the CP phases of the tcS couplings.

In diabetes, some of the cellular changes are similar to aging. We hypothesized that hyperglycemia accelerates aging-like changes in the endothelial cells (ECs) and tissues leading to structural and functional damage. We investigated glucose-induced aging in 3 types of ECs using senescence associated β-gal (SA β-gal) staining and cell morphology. Alterations of sirtuins (SIRTs) and their downstream mediator FOXO and oxidative stress were investigated. Relationship of such alteration with histone acetylase (HAT) p300 was examined. Similar examinations were performed in tissues of diabetic animals. ECs in high glucose (HG) showed evidence of early senescence as demonstrated by increased SA β-gal positivity and reduced replicative capacities. These alterations were pronounced in microvascular ECs. They developed an irregular and hypertrophic phenotype. Such changes were associated with decreased SIRT (1-7) mRNA expressions. We also found that p300 and SIRT1 regulate each other in such process, as silencing one led to increase of the others' expression. Furthermore, HG caused reduction in FOXO1's DNA binding ability and antioxidant target gene expressions. Chemically induced increased SIRT1 activity and p300 knockdown corrected these abnormalities slowing aging-like changes. Diabetic animals showed increased cellular senescence in renal glomerulus and retinal blood vessels along with reduced SIRT1 mRNA expressions in these tissues. Data from this study demonstrated that hyperglycemia accelerates aging-like process in the vascular ECs and such process is mediated via downregulation of SIRT1, causing reduction of mitochondrial antioxidant enzyme in a p300 and FOXO1 mediated pathway.