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Inferring the geographic mode of speciation is essential for explaining the generation and assembly of biodiversity, but has been rarely applied to the temperate flora of China. Fagus longipetiolata and F. lucida are a sister pair of beech species with largely overlapping ranges in subtropical China, however, little is known about the geographic mode of speciation and the formation of their sympatric distributions. In this study, we used IMa2 and fastsimcoal2 to simulate the speciation history of the two sisters. On the basis of 11 nuclear loci screened for 27 populations/species, their divergence time was estimated to 8.37 Mya by IMa2, and weak interspecific gene flow was detected. The simulation by fastsimcoal2 found that F. longipetiolata and F. lucida diverged ~8.53 Mya, then came into contact and hybridized at 0.8 Mya. The extended Bayesian skyline plots indicated that F. lucida began demographic expansion prior to the Pleistocene at 3 Mya, whereas F. longipetiolata increased its effective population size during the Quaternary, between 0.8 and 0.5 Mya. Ecological niche analysis and niche modelling showed that the two beeches had subtle niche differentiation and their projected distributions were largely overlapped across the late Quaternary. These results, coupled with well-studied fossil records in Fagus , demonstrate that these two beech species diverged allopatrically at the high latitudes of the Northern Hemisphere, and came into contact and hybridized with each other after successive migrations into subtropical (i.e. warm temperate) China recently. However, the two beeches may have developed strong intrinsic reproductive barriers due to long-term allopatry, allowing them to coexist in subtropical China. Our results illuminate the assembly history of the temperate woody flora in subtropical China, supporting that many relict temperate lineages in subtropical China may have established their populations recently. [ABSTRACT FROM AUTHOR]

Long gamma-ray bursts (GRBs) are typically associated with massive star core collapse, while the short GRBs are associated with compact binary mergers. However, recent evidence indicates that some peculiar long-duration bursts may correspond to compact binary mergers origins. In this paper, we use the data of the Fermi Gamma-ray Burst Monitor to search for peculiar long-duration bursts which may be from compact binary mergers based on outlier events in the |$E_{p,z}\!-\!E_{\gamma ,\rm iso}$| relation. We obtained 10 outlier events by systematically analysing bursts with |$T_{90}\gt 4.2 \rm \ s$| from 2008 August to 2021 July. In order to determine whether these outlier events were from compact binary mergers, we analysed their properties, including spectral lag, hardness ratio, and energy-hardness parameter. Based on the distributions of T 90 − HR and T 90 − Ep , we calculated the probability of outlier events belonging to the short GRBs. Our analysis indicates that GRB 120304B is likely to arise from the merger of a neutron star and a massive white dwarf. GRB 150210A is likely to arise from massive star core collapse. The other eight GRBs are fuzzy bursts that have both long and short GRBs properties. Additionally, we find that outlier samples have relatively high Ep and low fluences. [ABSTRACT FROM AUTHOR]

Oropharyngeal candidiasis (OPC) is an opportunistic infection treated with anti-fungal agents. Herein, we evaluate the efficacy and safety of miconazole buccal tablets (MBT) and itraconazole capsules in the localized treatment of patients with OPC. In this multi-centered, double-blinded, phase III trial (CTR20130414), both males and non-pregnant females (≥18 years) with OPC were randomized (1:1) to MBT plus placebo (experimental group) or itraconazole capsules plus placebo (control group). The primary endpoint was clinical cure at the end-of-treatment period [visit 4 (V4)] while secondary endpoints were clinical remission rates, partial remission rates, mycological cure, clinical relapse, and adverse events (AEs). All endpoints were statistically analyzed in both the full analysis set (FAS) and per-protocol (PP) set. A total of 431 (experimental: 216; control: 215) subjects were included. At V4, in the FAS set, the clinical cure was achieved in 68% and 59% patients in experimental and control groups, respectively with a treatment difference of 9% [95% confidence interval (CI): −1,19; P <.001] demonstrating non-inferiority of MBT over itraconazole. At V4, mycological cure rates were 68.2% and 42.0% in the experimental group and control groups (P <.001), respectively in FAS. The relapse rates were 5.4% and 6.6%, respectively, in the experimental and control groups. A total of 210 patients experienced AEs during treatment with 47.7% in the experimental group and 49.8% in the control group with no deaths. This study demonstrated that once-daily treatment with MBT was non-inferior to itraconazole with higher mycological cure rates and was tolerable with mild AE in patients with OPC. [ABSTRACT FROM AUTHOR]

Accurate identification of drug–target interactions (DTIs) plays a crucial role in drug discovery. Compared with traditional experimental methods that are labor-intensive and time-consuming, computational methods are more and more popular in recent years. Conventional computational methods almost simply view heterogeneous networks which integrate diverse drug-related and target-related dataset instead of fully exploring drug and target similarities. In this paper, we propose a new method, named DTIHNC, for |$\mathbf{D}$| rug– |$\mathbf{T}$| arget |$\mathbf{I}$| nteraction identification, which integrates |$\mathbf{H}$| eterogeneous |$\mathbf{N}$| etworks and |$\mathbf{C}$| ross-modal similarities calculated by relations between drugs, proteins, diseases and side effects. Firstly, the low-dimensional features of drugs, proteins, diseases and side effects are obtained from original features by a denoising autoencoder. Then, we construct a heterogeneous network across drug, protein, disease and side-effect nodes. In heterogeneous network, we exploit the heterogeneous graph attention operations to update the embedding of a node based on information in its 1-hop neighbors, and for multi-hop neighbor information, we propose random walk with restart aware graph attention to integrate more information through a larger neighborhood region. Next, we calculate cross-modal drug and protein similarities from cross-scale relations between drugs, proteins, diseases and side effects. Finally, a multiple-layer convolutional neural network deeply integrates similarity information of drugs and proteins with the embedding features obtained from heterogeneous graph attention network. Experiments have demonstrated its effectiveness and better performance than state-of-the-art methods. Datasets and a stand-alone package are provided on Github with website https://github.com/ningq669/DTIHNC. [ABSTRACT FROM AUTHOR]

The U.S. Food and Drug Administration (FDA) has been concerned with minimizing the unnecessary radiation exposure of people for half a century. Manufacturers of medical X-ray imaging devices are important partners in this effort. Medical X-ray imaging devices are regulated by FDA under both its electronic product regulations andits medical device regulations. FDA also publishes guidance documents that represent FDA's current thinking on a topic and provide a suggested or recommended approach to meet the requirements of a regulation or statute. FDA encourages manufacturers to develop medical devices that conform to voluntary consensus standards. Use of these standards is a central element of FDA's system to ensure that all medical devices marketed in the U.S. meet safety and effectiveness requirements. FDA staff participate actively in the development and maintenance of these standards, often advancing or introducing new safety and dose management requirements. Use of voluntary consensus standards reduces the amount of time necessary to evaluate a premarket submission and reduces the burden on manufacturers. FDA interacts with industry and other stakeholders through meetings with industry groups, public meetings, public communications, and through the development of voluntary consensus standards. In these interactions, FDA staff introduce new concepts for improving the safety of these devices and provide support for similar initiatives from professional organizations. FDA works with all stakeholders to achieve its mission of protecting and promoting the public health. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies in the head and neck with a poor prognosis. Oral cancer development is a multistep process involving carcinogenesis. Though significant advances in cancer immunotherapy over the years, there is lack of evidence for T-cell exhaustion during oral carcinogenesis. Clinical specimens from healthy donors and patients diagnosed with oral leukoplakia (OLK) or OSCC were collected for immunohistochemical staining with PD-L1, CD86, CD8, PD-1 and CTLA-4 antibodies. Meanwhile, chemically induced mouse models of oral carcinogenesis were constructed with 4-nitroquinolone- N -oxide induction. Exhaustion status of T cells was measured by flow cytometry for spleens and by multiplex immunohistochemistry for formalin-fixed paraffin-embedded lesions in multiple stages of oral carcinogenesis. The efficacy of PD-1 blockade with or without cisplatin treatment was evaluated on the mice in precancerous and OSCC stages. We observed higher expression of PD-1 in the human OLK and OSCC tissues compared with the normal, while low expression CTLA-4 in all oral mucosa tissues. Animal experiments showed that the exhausted CD4+ T cells existed much earlier than exhausted CD8+ T cells, and an increased ratio of stem-like exhausted T cells and partially exhausted T cells were detected in the experimental groups. Besides, the expression of immune checkpoint markers (PDCD1, CTLA4 and HAVCR2) was strongly positively correlated with cytokines (IFNG and IL-2). In summary, T-cell exhaustion plays a vital role in oral carcinogenesis, and PD-1 blockade can prevent the progression of oral carcinogenesis. [ABSTRACT FROM AUTHOR]

Background and Aims Compensatory base changes (CBCs) that occur in stems of ribosomal internal transcribed spacer 2 (ITS2) can have important phylogenetic implications because they are not expected to occur within a single species and also affect selection of appropriate DNA substitution models. These effects have been demonstrated when studying ancient lineages. Here we examine these effects to quantify their importance within a more recent lineage by using both DNA- and RNA-specific models. Methods We examined the phylogenetic implications of the CBC process by using a comprehensive sampling of ITS2 from ten closely related species of Corydalis. We predicted ITS2 secondary structures by using homology modelling, which was then used for a structure-based alignment. Paired and unpaired regions were analysed separately and in combination by using both RNA-specific substitution models and conventional DNA models. We mapped all base-pair states of CBCs on the phylogenetic tree to infer their evolution and relative timing. Key Results Our results indicate that selection acted to increase the thermodynamic stability of the secondary structure. Thus, the unpaired and paired regions did not evolve under a common substitution model. Only two CBCs occurred within the lineage sampled and no striking differences in topology or support for the shared clades were found between trees constructed using DNA- or RNA-specific substitution models. Conclusions Although application of RNA-specific substitution models remains preferred over more conventional DNA models, we infer that application of conventional DNA models is unlikely to be problematic when conducting phylogenetic analyses of ITS2 within closely related lineages wherein few CBCs are observed. Each of the two CBCs was found within the same lineages but was not observed within a given species, which supports application of the CBC species concept. [ABSTRACT FROM AUTHOR]

China's ties with Africa are evolving into a multi-faceted relationship of increasing complexity. After nearly two decades of debt-financed infrastructure development, Beijing's exposure to African debt is reaching disquieting proportions with an estimated US$132 billion owed to China in 2016. Managing this new role as Africa's creditor poses uncomfortable questions for creditor and debtor alike. Concurrently, the quiet surge of Chinese investment in manufacturing in Africa is transforming local economies in ways that are beginning to alter the continent's position within the global economy. Finally, the proliferation of Chinese businesses and migrants across Africa is inspiring greater Chinese involvement in UN peacekeeping and private security initiatives. This article examines how these structural changes are challenging core practices and principles which guided China–Africa relations in its formative decades. For instance, under the banner of an alternative to western policies China promoted the absence of conditionalities attached to its concessional loans and grants. Equally, promotion of industrialization of African economies marks a key shift away from China's resource-centric engagement with the continent. And, in the case of security, Beijing's commitment to avoid intervention in domestic affairs is being set aside with implications for its principles, and ultimately status, in Africa. [ABSTRACT FROM AUTHOR]

Super elongation complex (SEC) controls gene transcription by releasing Pol II from pausing. Previous studies have shown that dysfunction of SEC was associated with multiple human cancers, such as leukemia and breast cancer. However, the role of SEC in head and neck squamous cell carcinoma (HNSCC) development remains largely unknown. In this study, we found expression of AF4/FMR2 family member 4 (AFF4), the core component of SEC, was upregulated dramatically in HNSCC cell lines and tumor tissues. By using siRNA-mediated depletion and overexpression of AFF4, we demonstrated AFF4 promoted proliferation, migration and invasion of HNSCC cells. Moreover, we found AFF4 enhanced the aldehyde dehydrogenase (ALDH) activity and sphere formatting activity and was required for the tumor-initiation capacity of stem-like cells in HNSCC cell lines. Mechanistically, we found the role of AFF4 in regulation of HNSCC cell behaviors was mainly mediated by sex-determining region Y box2 (SOX2), a critical regulator involved in development of several human cancers. SOX2 expression changed in parallel with AFF4 expression in response to depletion and overexpression of AFF4, respectively. More importantly, overexpression of SOX2 rescued the inhibited proliferation, migration, invasion and ALDH activity induced by knockdown of AFF4 in HNSCC cells, at least in part. Collectively, our findings indicate AFF4 may serve as a biomarker and a potential target of therapies for patients with HNSCC. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cells (hiPSC) have been shown to differentiate into a variety of replacement cell types. Detailed evaluation and comparison with their human embryonic stem cell (hESC) counterparts is critical for assessment of their therapeutic potential. Using established methods, we demonstrate here that hiPSCs are capable of generating hemangioblasts/blast cells (BCs), endothelial cells, and hematopoietic cells with phenotypic and morphologic characteristics similar to those derived from hESCs, but with a dramatic decreased efficiency. Furthermore, in distinct contrast with the hESC derivatives, functional differences were observed in BCs derived from hiPSCs, including significantly increased apoptosis, severely limited growth and expansion capability, and a substantially decreased hematopoietic colony-forming capability. After further differentiation into erythroid cells. >l,000-fold difference in expansion capability was observed in hiPSC-BCs versus hESC-BCs. Although endothelial cells derived from hiPSCs were capable of taking up acetylated low-density lipoprotein and forming capillary-vascular-like structures on Matrigel, these cells also demonstrated early cellular senescence (most of the endothelial cells senesced after one passage). Similarly, retinal pigmented epithelium cells derived from hiPSCs began senescing in the first passage. Before clinical application, it will he necessary to determine the cause and extent of such abnormalities and whether they also occur in hiPSCs generated using different reprogramming methods. [ABSTRACT FROM AUTHOR]

Citrate synthase (CS) is an important enzyme in energy conversion and material circulation, participating in many important biochemical processes. In the present study, CS from Microcystis aeruginosa PCC7806 (MaCS) was cloned and expressed in Escherichia coli Rosetta (DE3). The recombinant MaCS was purified and its enzymological properties were characterized. The results showed that MaCS formed dimers in native status. The optimum temperature and pH of MaCS was 30°C and 8.2, respectively. MaCS displayed relative high thermal stability. Treatment at 50°C for 20 min only decreased 11.30% activity of MaCS and the half-life of MaCS was approximately 35 min at 55°C. The k cat and K m of acetyl-CoA and oxaloacetic acid were 17.133 s−1 (k cat) and 11.62 μM (K m), 24.502 s−1 and 103.00 μM, respectively. MaCS activity was not drastically inhibited by monovalent ions and NADH but depressed by divalent ions and some small molecular compounds, especially Mg2+, Zn2+, Co2+ and DTT. Overall, these data contributed to further understanding of energy metabolism in cyanobacteria and also provided basic information for industrial application of CS. [ABSTRACT FROM AUTHOR]