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Because of the negative side-effects of synthetic preservatives, the naturally-occurring polyphenols aroused intense interest of researchers. It has been suggested that chlorogenic acid (CA) and isochlorogenic acid A (iso-CAA) were good candidates to replace the synthetic preservatives. Moreover, the bactericidal activity of iso-CAA was stronger than CA, and the anti-bacterial activities of iso-CAA and CA were highly membrane-dependent. However, the mechanisms were still unclear. Therefore, in the present study, we investigated the mechanisms of the interactions between the two polyphenols and lipid bilayers through molecular dynamics simulations. The results revealed that iso-CAA could be inserted much deeper into POPG lipid bilayer than CA. We also found that hydrophobic interactions and hydrogen bonds both contributed to the insertion of iso-CAA into the POPG lipid bilayer, and the quinic acid moiety was the key structure in iso-CAA to form hydrogen bonds with POPG lipid bilayer. We believed that these findings would provide more useful information to explain the stronger bactericidal activity of iso-CAA than CA at the atomic level., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Neuropsychiatric sequalae to coronavirus disease 2019 (COVID-19) infection are beginning to emerge, like previous Spanish influenza and severe acute respiratory syndrome episodes. Streptococcal infection in paediatric patients causing obsessive compulsive disorder (PANDAS) is another recent example of an infection-based psychiatric disorder. Inflammation associated with neuropsychiatric disorders has been previously reported but there is no standard clinical management approach established. Part of the reason is that it is unclear what factors determine the specific neuronal vulnerability and the efficacy of anti-inflammatory treatment in neuroinflammation. The emerging COVID-19 data suggested that in the acute stage, widespread neuronal damage appears to be the result of abnormal and overactive immune responses and cytokine storm is associated with poor prognosis. It is still too early to know if there are long-term-specific neuronal or brain regional damages associated with COVID-19, resulting in distinct neuropsychiatric disorders. In several major psychiatric disorders where neuroinflammation is present, patients with abnormal inflammatory markers may also experience less than favourable response or treatment resistance when standard treatment is used alone. Evidence regarding the benefits of co-administered anti-inflammatory agents such as COX-2 inhibitor is encouraging in selected patients though may not benefit others. Disease-modifying therapies are increasingly being applied to neuropsychiatric diseases characterised by abnormal or hyperreactive immune responses. Adjunct anti-inflammatory treatment may benefit selected patients and is definitely an important component of clinical management in the presence of neuroinflammation.

Potato is a major food crop with enormous biomass straw, but lignocellulose recalcitrance causes a costly bioethanol conversion. Here, we selected the cytochimera (Cyt) potato samples showing significantly-modified lignocellulose and much increased soluble sugars and starch by 2-4 folds in mature straws. Under two pretreatments (8 min liquid hot water; 5% CaO) at minimized conditions, the potato Cyt straw showed complete enzymatic saccharification. Further performing yeast fermentation with all hexoses released from soluble sugars, starch and lignocellulose in the Cyt straw, this study achieved a maximum bioethanol yield of 24 % (% dry matter), being higher than those of other bioenergy crops as previously reported. Hence, this study has proposed a novel mechanism model on the reduction of major lignocellulose recalcitrance and regulation of carbon assimilation to achieve cost-effective bioethanol production under optimal pretreatments. This work also provides a sustainable strategy for utilization of potato straws with minimum waste release., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: A breast cancer polygenic risk score (PRS) comprising 313 common variants reliably predicts disease risk. We examined possible relationships between genetic variation, regulation, and expression to clarify the molecular alterations associated with these variants., Methods: Genome-wide methylomic variation was quantified (MethylationEPIC) in Asian breast cancer patients (1152 buffy coats from peripheral whole blood). DNA methylation (DNAm) quantitative trait loci (mQTL) mapping was performed for 235 of the 313 variants with minor allele frequencies > 5%. Stability of identified mQTLs (p < 5e-8) across lifetime was examined using a public mQTL database. Identified mQTLs were also mapped to expression quantitative trait loci (eQTLs) in the Genotype-Tissue Expression Project and the eQTLGen Consortium., Results: Breast cancer PRS was not associated with DNAm. A higher proportion of significant cis-mQTLs were observed. Of 822 significant cis-mQTLs (179 unique variants) identified in our dataset, 141 (59 unique variants) were significant (p < 5e-8) in a public mQTL database. Eighty-six percent (121/141) of the matched mQTLs were consistent at multiple time points (birth, childhood, adolescence, pregnancy, middle age, post-diagnosis, or treatment). Ninety-three variants associated with DNAm were also cis-eQTLs (35 variants not genome-wide significant). Multiple loci in the breast cancer PRS are associated with DNAm, contributing to the polygenic nature of the disease. These mQTLs are mostly stable over time., Conclusions: Consistent results from DNAm and expression data may reveal new candidate genes not previously associated with breast cancer., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Long non-coding RNA (lncRNA), a type of non-protein coding transcripts with lengths exceeding 200 nucleotides, is reported to be widely involved in many cellular and developmental processes. However, few roles of lncRNA in oocyte development have been defined. In this study, to uncover the effect of lncRNA during oocyte maturation, bovine germinal vesicle (GV) and in vitro matured metaphase II (MII) oocytes underwent RNA sequencing. Results revealed a wealth of candidate lncRNAs, which might participate in the biological processes of stage-specific oocytes. Furthermore, their trans- and cis-regulatory effects were investigated in-depth by using bioinformatic software. Functional enrichment analysis of target genes showed that these lncRNAs were likely involved in the regulation of many key signaling pathways during bovine oocyte maturation from GV to MII stage, as well as multiple lncRNA-mRNA networks. One novel lncRNA (MSTRG.19140) was particularly interesting, as it appeared to mediate the regulation of oocyte meiotic resumption, progesterone-mediated oocyte maturation, and cell cycle. Therefore, this study enhanced insights into the regulation of molecular mechanisms of bovine oocyte maturation from a lncRNA-mRNA network perspective., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Previous studies suggested that naturally occurring EGCG primarily acted on the bacterial cell membrane then damaged the membrane and the gallate moiety in EGCG was very important to its anti-bacterial activity. However, the detailed mechanisms were still poorly understood. In this paper, EGCG and EGC were selected to study the great contribution of gallate moiety on the anti-bacterial activities of polyphenols. The results indicated that EGCG could penetrate deeper into the POPG lipid bilayer and possess more potent structure-perturbing potency on the POPG lipid bilayer than EGC. We also found that EGCG had the ability to form hydrogen bonds with the deeper inside oxygen atoms in the POPG lipid bilayer and the gallate moiety was the key functional group for EGCG forming hydrogen bonds with the POPG lipid bilayer. Moreover, results from the binding free energy analysis demonstrated that the gallate moiety made great contribution to the high affinity between EGCG and the POPG lipid bilayer. We believed that these findings could yield useful insights into the influence mechanisms of gallate moiety on the anti-bacterial activities of polyphenols., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Antimicrobial peptides (AMPs) have emerged as a promising alternative to small molecule antibiotics. Although AMPs have previously been isolated in many organisms, efforts on the systematic identification of AMPs in fish have been lagging. Here, we collected peptides from the plasma of medaka (Oryzias latipes) fish. By using mass spectrometry, 6399 unique sequences were identified from the isolated peptides, among which 430 peptides were bioinformatically predicted to be potential AMPs. One of them, a thermostable 13-residue peptide named BING, shows a broad-spectrum toxicity against pathogenic bacteria including drug-resistant strains, at concentrations that presented relatively low toxicity to mammalian cell lines and medaka. Proteomic analysis indicated that BING treatment induced a deregulation of periplasmic peptidyl-prolyl isomerases in gram-negative bacteria. We observed that BING reduced the RNA level of cpxR, an upstream regulator of envelope stress responses. cpxR is known to play a crucial role in the development of antimicrobial resistance, including the regulation of genes involved in drug efflux. BING downregulated the expression of efflux pump components mexB, mexY and oprM in P. aeruginosa and significantly synergised the toxicity of antibiotics towards these bacteria. In addition, exposure to sublethal doses of BING delayed the development of antibiotic resistance. To our knowledge, BING is the first AMP shown to suppress cpxR expression in Gram-negative bacteria. This discovery highlights the cpxR pathway as a potential antimicrobial target.

Natural killer (NK) cells harbor efficient cytotoxicity against tumor cells without causing life-threatening cytokine release syndrome (CRS) or graft-versus-host disease (GvHD). When compared to chimeric antigen receptor (CAR) technology, Antibody-Cell Conjugation (ACC) technology has been developed to provide an efficient platform to arm immune cells with cancer-targeting antibodies to recognize and attack cancer cells. Recently, we established an endogenous CD16-expressing oNK cell line (oNK) with a favorable expression pattern of NK activation/inhibitory receptors. In this study, we applied ACC platform to conjugate oNK with trastuzumab and an anti-human epidermal growth factor receptor 2 (HER2) antibody. Trastuzumab-conjugated oNK, ACE-oNK-HER2, executed in vitro and in vivo cytotoxicity against HER2-expressing cancer cells and showed enhanced T cell-recruiting capability and secretion of IFNγ. The irradiated and cryopreserved ACE-oNK-HER2, designated as ACE1702, retained superior HER2-specific in vitro and in vivo potency with no tumorigenic potential. In conclusion, this study provides the evidence to support the potential clinical application of ACE1702 as a novel off-the-shelf NK cell therapy against HER2-expressing solid tumors.

Improving biomass enzymatic saccharification is effective for crop straw utilization, whereas phytoremediation is efficient for trace metal elimination from polluted agricultural soil. Here, we found that the green proteins extracted from Amaranthus leaf tissue could act as active biosurfactant to remarkably enhance lignocellulose enzymatic saccharification for high bioethanol production examined in eight grassy and woody plants after mild chemical and green-like pretreatments were performed. Notably, this study estimated that total green proteins supply collected from one-hectare-land Amaranth plants could even lead to additional 6400-12,400 tons of bioethanol, being over 10-fold bioethanol yield higher than those of soybean seed proteins and chemical surfactant. Meanwhile, the Amaranth green proteins were characterized as a dominated biosorbent for multiple trace metals (Cd, Pb, As) adsorption, being 2.9-6 folds higher than those of its lignocellulose. The Amaranth plants were also assessed to accumulate much more trace metals than all other plants as previously examined from large-scale contaminated soils. Furthermore, the Amaranth green proteins not only effectively block lignin to release active cellulases for the mostly enhanced biomass hydrolyzes, but also efficiently involve in multiple chemical bindings with Cd, which should thus address critical issues of high-costly biomass waste utilization and low-efficient trace metal remediation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Natural killer (NK) cells, as a potential source for off-the-shelf cell therapy, attack tumor cells with low risk of severe cytokine release syndrome (CRS) or graft-versus-host disease (GvHD). Fcγ receptor IIIA, also known as CD16, further confers NK cells with antibody-dependent cell-mediated cytotoxicity (ADCC), one mechanism of action of antibody-based immunotherapy. Here, we establish a novel human NK cell line, oNK-1, endogenously expressing CD16 along with high levels of NK activation markers and low levels of NK inhibitory markers. The long-term expansion and CD16 expression of oNK-1 cells were demonstrated. Furthermore, oNK-1 cells elicit superior cytotoxicity against cancer cells than primary NK cells. In conclusion, this study suggests that endogenous CD16-expressing oNK-1 has the potential to develop an effective NK-based therapy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Zih-Fei Cheng, Hao-Kang Li, Hsiu-Ping Yang, Chia-Yun Lee, Sai-Wen Tang, and Yan-Liang Lin are employees of Acepodia Biotech Inc. Shih-Chia Hsiao is the co-founder of Acepodia Biotech Inc. Zih-Fei Cheng, Hao-Kang Li, Hsiu-Ping Yang, Chia-Yun Lee, Yan-Liang Lin and Shih-Chia Hsiao are inventors of the patent of international application number PCT/US20/13,883 related to this study., (© 2021 The Authors.)

Background: Infectious disease hospitals (IDHs) play very important roles in the battle against the infectious disease. The present study aims to systematically analyze the development trends and possible problems of IDHs in China., Methods: Most of the data came from the China Health Statistics Yearbook 2003-2019. Joinpoint Regression Model was used to analyze the development trends of IDHs between 2002 and 2018., Results: From 2002 to 2018, the number of IDHs in China increased from 126 to 167, with an average annual percent change (AAPC) of 1.82%. The ratio of nurses to beds increased from 0.38 to 0.46 with the AAPC of 0.88%, and average business housing area per bed increased with an AAPC of 1.97%. The percentage of liabilities to total assets increased year by year and the percentage of medical business costs to total expenditure decreased. The segmented trend of daily visits per physician from 2014 to 2018 was stable, and the segmented trend of daily inpatients per physician from 2012 to 2018 decreased significantly. In 2017, the rates of surgical inpatients leaving the hospital without the doctor's advice and surgical inpatients mortality were higher than 2016., Conclusion: Although the development of IDHs was generally good in China, the scale of IDHs was generally small, the ability to respond to major emergencies was weak, the problem of irrational resource allocation was still prominent, and the operation of IDHs was facing a dilemma., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Wang et al.)

Objective: To summarize the different teaching models and their effects in evidence-based medicine at home and abroad by qualitative method and systematic review. Methods: We searched the following databases (from inception to 13 May, 2019): PubMed, Embase, Proquest, Cochrane, Web of Science database and the Chinese databases (CNKI, Wanfang, SinoMed and VIP). To assess data strength and validity, risk of bias assessments were undertaken. Results: A total of 52 literatures were included in this study, including 21 Chinese-language literature and 31 English-language literature. PBL teaching model, mixed teaching model and workshop teaching model were the three teaching models with the largest number of studies in 20 teaching models. Conclusion: The evidence-based medicine teaching effect was closely related to the teaching models, so it is necessary to explore more suitable teaching models for the evidence-based medicine to improve the teaching effects.

One of the most crucial components of regenerative medicine is the controlled differentiation of embryonic or adult stem cells into the desired cell lineage. Although most of the reported protocols of stem cell differentiation involve the use of soluble growth factors, it is increasingly evident that stem cells also undergo differentiation when cultured in the appropriate microenvironment. When cultured in decellularized tissues, for instance, stem cells can recapitulate the morphogenesis and functional specialization of differentiated cell types with speed and efficiency that often surpass the traditional growth factor-driven protocols. This suggests that the tissue microenvironment (TME) provides stem cells with a holistic "instructive niche" that harbors signals for cellular reprogramming. The translation of this into medical applications requires the decoding of these signals, but this has been hampered by the complexity of TME. This problem is often addressed by a reductionist approach, in which cells are exposed to substrates decorated with simple, empirically designed geometries, textures, and chemical compositions ("bottom-up" approach). Although these studies are invaluable in revealing the basic principles of mechanotransduction mechanisms, their physiological relevance is often uncertain. This review examines the recent progress of an alternative, "top-down" approach, in which the TME is treated as a holistic biological entity. This approach is made possible by recent advances in systems biology and fabrication technologies that enable the isolation, characterization, and reconstitution of TME. It is hoped that these new techniques will elucidate the nature of niche signals so that they can be extracted, replicated, and controlled. This review summarizes these emerging techniques and how the data they generated are changing our view on TME. Impact statement This review summarizes the current state of art of the understanding of instructive niche in the field of tissue microenvironment. Not only did we survey the use of different biochemical preparations as stimuli of stem cell differentiation and summarize the recent effort in dissecting the biochemical composition of these preparations, through the application of extracellular matrix (ECM) arrays and proteomics, but we also introduce the use of open-source, high-content immunohistochemistry projects in contributing to the understanding of tissue-specific composition of ECM. We believe this review would be highly useful for our peer researching in the same field. "Mr. Tulkinghorn is always the same… so oddly out of place and yet so perfectly at home." -Charles Dickens, Bleak House .

Hallucinations are important diagnostic symptoms in schizophrenia, but also occur in other medical and neuropsychiatric conditions. Not all patients with hallucinations are psychotic. There has been a surge of interest in the topic of hallucinations, as new research data have begun to reveal their neurobiology. Hallucinogenic molecules may also serve as new scaffolds for the development of new psychotropic drugs. We searched and reviewed recent literature, focusing on the refinement of clinical management, which was inspired by new data regarding the neurobiology of hallucination subtypes. We concluded that the successful management of hallucinations depends on accurate differential diagnosis to identify subtypes, which would then determine the most appropriate treatment.

Alzheimer's disease is the most common form of neurodegenerative disease and the formation of Aβ amyloid aggregates has been widely demonstrated to be the principal cause of Alzheimer's disease. Our previous study and other studies suggested that the gallate moiety played an obligatory role in the inhibition process of naturally occurring polyphenols on Aβ amyloid fibrils formation. However, the detailed mechanisms were still unknown. Thus, in the present study, the gallic acid (GA) was specially selected and the molecular recognition mechanisms between GA molecules and Aβ 1 - 40 monomer were examined and analyzed by molecular dynamics simulation. The in silico experiments revealed that GA significantly prevented the conformational changes of Aβ 1 - 40 monomer with no β-sheet structure during the whole 100 ns. By analyzing the binding sites of GA molecules to Aβ 1 - 40 monomer, we found that both hydrophilic and hydrophobic amino acid residues were participated in the binding of GA molecules to Aβ 1 - 40 monomer. Moreover, results from the binding free energy analysis further demonstrated that the strength of polar interactions was significantly stronger than that of nonpolar interactions. We believed that our results could help to elucidate the underlying mechanisms of gallate moiety on the anti-amyloidogenic effects of polyphenols at the atomic level., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The use of decellularized tissues or organs as cell culture scaffolds has proven to be a promising approach for tissue engineering and regenerative medicine, as these decellularized tissues can provide the instructive niche for cell differentiation and functions. Cartilage is a largely avascular tissue with limited regenerative capacity. Lesions caused by arthritis can lead to severe cartilage degeneration. Previous studies have indicated that decellularized cartilage can be used as scaffolds that support the chondrogenic differentiation of adult stem cells. However, these decellularization protocols all require the use of denaturing agents, such as high salt and detergents, that lead to the artifactual disruption of the chemical and physical integrity of the tissue microenvironment. Here, we established a new decellularization method for cartilage, through a combined effect of freezing-thawing, sectioning, and sonication in water. This protocol achieved the complete removal of cells within minutes, instead of hours or days required by existing procedures, and does not use any detergent. The resulting decellularized cartilage preserved the native ultrastructure and biochemical contents, including glycosaminoglycans, which is typically depleted by traditional decellularization methods. Human mesenchymal stem cells could readily adhere onto the decellularized cartilage. Together, this work unveils a simple new method for decellularizing cartilage, which will be useful in studying how tissue microenvironment supports chondrocyte growth and functions. Impact statement In this study, we develop a simple, fast cartilage decellularization method that does not require any detergent, so that the decellularized cartilage chemistry is preserved. Traditional detergent-based decellularization removes the tissue biochemical contents (i.e., glycosaminoglycans). In this new water decellularization protocol, the biochemical contents of cartilage can be preserved. This allows the study of biochemistry and physical content in extracellular matrix as a whole, and this protocol would definitely be useful for studying the effect of tissue microenvironment in supporting chondrocyte growth and functions.

Schlafen 11 (SLFN11) was recently discovered as a cellular restriction factor against replication stress. Here, we show that SLFN11 increases chromatin accessibility genome wide, prominently at active promoters in response to replication stress induced by the checkpoint kinase 1 (CHK1) inhibitor prexasertib or the topoisomerase I (TOP1) inhibitor camptothecin. Concomitantly, SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the immediate early genes (IEGs), including JUN, FOS, EGR1, NFKB2, and ATF3, together with the cell cycle arrest genes CDKN1A (p21 WAF1 ) and GADD45. Both chromatin remodeling and IEG activation require the putative ATPase and helicase activity of SLFN11, whereas canonical extrinsic IEG activation is SLFN11 independent. SLFN11-dependent IEG activation by camptothecin is also observed across 55 non-isogenic NCI-60 cell lines. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the innate immune activation in response to replicative stress., Competing Interests: Declaration of Interests The authors declare no competing interests., (Published by Elsevier Inc.)

Cadmium (Cd) is one of the most hazardous trace metals, and rapeseed is a major oil crop over the world with considerable lignocellulose residues applicable for trace metal phytoremediation and cellulosic ethanol co-production. In this study, we examined that two distinct rapeseed cultivars could accumulate Cd at 72.48 and 43.70 ug/g dry stalk, being the highest Cd accumulation among all major agricultural food crops as previously reported. The Cd accumulation significantly increased pectin deposition as a major factor for trace metal association with lignocellulose. Meanwhile, the Cd-accumulated rapeseed stalks contained much reduced wall polymers (hemicellulose, lignin) and cellulose degree of polymerization, leading to improved lignocellulose enzymatic hydrolysis. Notably, three optimal chemical pretreatments were performed for enhanced biomass enzymatic saccharification and bioethanol production by significantly increasing cellulose accessibility and lignocellulose porosity, along with a complete Cd release for collection and recycling. Hence, this study proposed a mechanism model interpreting why rapeseed stalks are able to accumulate much Cd and how the Cd-accumulated stalks are of enhanced biomass saccharification. It has also provided a powerful technology for both cost-effective Cd phytoremediation and value-added bioethanol co-production with minimum waste release., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Cytokine-induced killer (CIK) cells are an ex vivo-expanded cellular therapy product with potent anti-tumor activity in a subset of patients with solid and hematologic malignancies. We hypothesize that directing CIK cells to a specific tumor antigen will enhance CIK cell anti-tumor cytotoxicity., Methods: We present a newly developed method for affixing antibodies directly to cell surface proteins. First, we evaluated the anti-tumor potential of CIK cells after affixing tumor-antigen targeting monoclonal antibodies. Second, we evaluated whether this antibody-conjugation method can profile the surface proteome of CIK cells., Results: We demonstrated that affixing rituximab or daratumumab to CIK cells enhances cytotoxic killing of multiple lymphoma cell lines in vitro. These 'armed' CIK cells exhibited enhanced intracellular signaling after engaging tumor targets. Cell surface proteome profiling suggested mechanisms by which antibody-armed CIK cells concurrently activated multiple surface proteins, leading to enhanced cytolytic activity. Our surface proteome analysis indicated that CIK cells display enhanced protein signatures indicative of immune responses, cellular activation and leukocyte migration., Conclusions: Here, we characterize the cell surface proteome of CIK cells using a novel methodology that can be rapidly applied to other cell types. Our study also demonstrates that without genetic modification CIK cells can be rapidly armed with monoclonal antibodies, which endows them with high specificity to kill tumor targets., (Copyright © 2020. Published by Elsevier Inc.)

In this work, recessed gate AlGaN/GaN metal-insulator-semiconductor high-electron-mobility transistors (MIS-HEMTs) with double AlGaN barrier designs are fabricated and investigated. Two different recessed depths are designed, leading to a 5 nm and a 3 nm remaining bottom AlGaN barrier under the gate region, and two different Al% (15% and 20%) in the bottom AlGaN barriers are designed. First of all, a double hump trans-conductance ( g m )-gate voltage ( V G ) characteristic is observed in a recessed gate AlGaN/GaN MIS-HEMT with a 5 nm remaining bottom Al 0.2 Ga 0.8 N barrier under the gate region. Secondly, a physical model is proposed to explain this double channel characteristic by means of a formation of a top channel below the gate dielectric under a positive V G . Finally, the impacts of Al% content (15% and 20%) in the bottom AlGaN barrier and 5 nm/3 nm remaining bottom AlGaN barriers under the gate region are studied in detail, indicating that lowering Al% content in the bottom can increase the threshold voltage ( V TH ) toward an enhancement-mode characteristic., Competing Interests: The authors declare no conflict of interest.

Purpose: To determine the accuracy of a handheld ultrasound-guided optoacoustic tomography (US-OT) probe developed for human deep-tissue imaging in ex vivo assessment of tumor margins postlumpectomy., Methods: A custom-built two-dimensional (2D) US-OT-handheld probe was used to scan 15 lumpectomy breast specimens. Optoacoustic signals acquired at multiple wavelengths between 700 and 1100 nm were reconstructed using model linear algorithm, followed by spectral unmixing for lipid and deoxyhemoglobin (Hb). Distribution maps of lipid and Hb on the anterior, posterior, superior, inferior, medial, and lateral margins of the specimens were inspected for margin involvement, and results were correlated with histopathologic findings. The agreement in tumor margin assessment between US-OT and histopathology was determined using the Bland-Altman plot. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of margin assessment using US-OT were calculated., Results: Ninety margins (6 × 15 specimens) were assessed. The US-OT probe resolved blood vessels and lipid up to a depth of 6 mm. Negative and positive margins were discriminated by marked differences in the distribution patterns of lipid and Hb. US-OT assessments were concordant with histopathologic findings in 87 of 89 margins assessed (one margin was uninterpretable and excluded), with diagnostic accuracy of 97.9% (kappa = 0.79). The sensitivity, specificity, PPV, and NPV were 100% (4/4), 97.6% (83/85), 66.7% (4/6), and 100% (83/83), respectively., Conclusion: US-OT was capable of providing distribution maps of lipid and Hb in lumpectomy specimens that predicted tumor margins with high sensitivity and specificity, making it a potential tool for intraoperative tumor margin assessment., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The prostanoid EP4 receptor is one of the key receptors associated with inflammatory mediator PGE 2 -elicited immunosuppression in the tumor microenvironment. Blockade of EP4 signaling to enhance immunity-mediated tumor elimination has recently emerged as a promising strategy for cancer immunotherapy. In our efforts to discover novel subtype-selective EP4 antagonists, we designed and synthesized a class of 1 H -1,2,3-triazole-based ligands that display low nanomolar antagonism activity toward the human EP4 receptor and excellent subtype selectivity. The most promising compound 59 exhibits single-digit nanomolar potency in the EP4 calcium flux and cAMP-response element reporter assays and effectively suppresses the expression of multiple immunosuppression-related genes in macrophage cells. On the basis of its favorable ADMET properties, compound 59 was chosen for further in vivo biological evaluation. Oral administration of compound 59 significantly inhibited tumor growth in the mouse CT26 colon carcinoma model accompanied by enhanced infiltration of cytotoxic T lymphocytes in the tumor tissue.

Cells in tissues are enveloped by an instructive niche made of the extracellular matrix. These instructive niches contain three general types of information: topographical, biochemical and mechanical. While the combined effects of these three factors are widely studied, the functions of each individual one has not been systematically characterised, because it is impossible to alter a single factor in a tissue microenvironment without simultaneously affecting the other two. Silica BioReplication (SBR) is a process that converts biological samples into silica, faithfully preserving the original topography at the nano-scale. We explored the use of this technique to generate inorganic replicas of intact mammalian tissues, including tendon, cartilage, skeletal muscle and spinal cord. Scanning electron and atomic force microscopy showed that the resulting replicas accurately preserved the three-dimensional ultrastructure of each tissue, while all biochemical components were eradicated by calcination. Such properties allowed the uncoupling the topographical information of a tissue microenvironment from its biochemical and mechanical components. Here, we showed that human mesenchymal stem cells (MSC) cultured on the replicas of different tissues displayed vastly different morphology and focal adhesions, suggesting that the topography of the tissue microenvironment captured by SBR could profoundly affect MSC biology. MSC cultured on tendon replica elongated and expressed tenocytes marker, while MSC on the spinal cord replica developed into spheroids that resembled neurospheres, in morphology and in the expression of neurosphere markers, and could be further differentiated into neuron-like cells. This study reveals the significance of topographical cues in a cell niche, as tissue-specific topography was sufficient in initiating and directing differentiation of MSC, despite the absence of any biochemical signals. SBR is a convenient and versatile method for capturing this topographical information, facilitating the functional characterisation of cell niches. STATEMENT OF SIGNIFICANCE: Various studies have shown that three major factors, topographical, biochemical and mechanical, in a tissue microenvironment (TME) are essential for cellular homeostasis and functions. Current experimental models are too simplistic to represent the complexity of the TME, hindering the detailed understanding of its functions. In particular, the importance each factor in a tissue microenvironment have not been individually characterised, because it is challenging to alter one of these factors without simultaneously affecting the other two. Silica bioreplication (SBR) is a process that converts biological samples into silica replicas with high structural fidelity. SBR is a convenient and versatile method for capturing this topographical information on to a biologically inert material, allowing the functional characterisation of the architecture of a TME., (Copyright © 2019. Published by Elsevier Ltd.)

Traditional medicines in the form of health food and supplements are highly popular nowadays. They are often aggressively promoted with unsubstantiated health benefit claims. Patients suffering from chronic illness, such as psychiatric disorders may be attracted to these products and use them concurrently with their prescribed drugs. The potential danger of these health supplements and traditional medicines containing products have prompted repeated warnings by the US Food and Drug Administration in recent years. A new initiative by the Food and Drug Administration in 2019 was also implemented to strengthen the oversight of these supplements. The WHO global compendium will include traditional medicines in 2019, which has generated much debate about their safety. Many practising psychiatrists are not familiar with traditional medicines, and clinically useful information is also not easily available. In this review, we examine the nature and safety of commonly encountered traditional medicine in these health food products and supplements.

Acute graft-versus-host disease (GVHD) is a leading cause of mortality after allogeneic hematopoietic cell transplantation (HCT) mediated by dysregulated T-cell immune reconstitution. Given the role of the T-cell immunoglobulin and mucin 1 (TIM-1) surface protein in many immune processes, including organ transplantation tolerance, we asked if TIM-1 might drive post-transplant inflammation and acute GVHD. TIM-1 binds to phosphatidylserine (PtdSer), and agonism of TIM1 on immune cells is proinflammatory. HCT conditioning results in a significant supply of PtdSer from apoptosis and cellular debris. Using murine models, treatment with an antagonistic anti-TIM-1 monoclonal antibody (mAb) protects against acute GVHD while maintaining graft-versus-tumor effects. In contrast, the addition of exogenous free PtdSer worsened GVHD in a TIM-1-dependent manner. Importantly, TIM-1 blockade did not alter the expansion of donor T cells in vitro or in vivo. Instead, TIM-1 blockade reduces proinflammatory cytokines and promotes anti-inflammatory factors like carbonic anhydrase 1 and serum amyloid A1 in the gut tissue. This is mediated by TIM-1 on donor cells, as HCT of wild-type (WT) bone marrow (BM) and conventional T (Tcon) cells into TIM-1-/- knockout (KO) recipient mice showed little survival advantage compared with WT recipients, whereas WT recipients of TIM-1-/- KO Tcon cells or TIM1-/- KO BM had improved survival, in part due to the expression of TIM-1 on donor invariant natural killer T cells, which drives inflammation. Finally, in a humanized mouse xenograft GVHD model, treatment with anti-human TIM-1 antagonist mAb reduced GVHD disease burden and mortality. This supports TIM-1 as important for GVHD pathogenesis and as a target for the prevention of GVHD., (© 2019 by The American Society of Hematology.)

Purpose: Physiologically-based pharmacokinetic (PBPK) modeling offers a unique modality to predict age-specific pharmacokinetics. The objective of this study was to assess the ability of PBPK model to predict plasma exposure of oxycodone, a widely used opioid for pain management, in adults and children., Methods: A full PBPK model of oxycodone following intravenous and oral administration was developed using a 'bottom-up' and 'top-down' combined strategy. The model was then extrapolated to pediatrics through a reasonable scaling method. The adult and pediatric model was evaluated using data from 17 clinical PK studies by testing predicted/observed goodness of fit. The mean fold error for PK parameters was calculated. Finally, we used the validated PBPK model to visualize adult-children dose conversion for oxycodone., Results: The developed PBPK model successfully predicted the oxycodone disposition in adults, wherein the predicted versus observed AUC, C max, and t max were within 0.90 to 1.20-fold difference. After scaling anatomy/physiology, protein binding, and clearance, the model showed satisfactory prediction performance for pediatric populations as predicted AUC were within the 1.50-fold range of the observed values. According to the application of PBPK model, we found that different intravenous doses should be given in children of different ages compared to a standard 0.1 mg/kg in adults, while a progressive increasing dose with age growth following oral administration is recommended for children., Conclusions: The current example provides the opportunity for using the PBPK model to guide dose adjustment of oxycodone in the design of future pediatric clinical studies.

Objectives: Herbs are frequently and concurrently used with prescribed drugs by patients worldwide. While clinical trials have found some herbs to be as useful as standard psychiatric drugs, most clinicians are unaware of their pharmacological mechanisms. Methods: We searched English language and other language literature with English abstracts listed in PubMed website, supplemented by additional through Google Scholar's free academic paper abstract website for publications on herbs, focussing on their clinical use in mental disorders, their neurobiology and their pharmacology. Results: A major reason for herbs remaining outside of mainstream psychiatry is that the terminology and concepts in herbal medicine are not familiar to psychiatrists in general. Many publications regarding the use of herbal medicine for psychiatric disorders are deficient in details regarding diagnosis, criteria for response and the neurobiology details compared with publications on standard psychotropic drugs. Nomenclature for herbal medicine is usually confusing and is not conducive to an easy understanding of their mode of action in psychiatric disorders. Conclusions: The recent neuroscience-based nomenclature (NbN) for psychotropics methodology would be a logical application to herbal medicine in facilitating a better understanding of the use of herbal medicine in psychiatry.

Knockdown or gene disruption of the ubiquitously expressed cell surface receptor CD47 protects non-malignant cells from genotoxic stress caused by ionizing radiation or cytotoxic chemotherapy but sensitizes tumors in an immune competent host to genotoxic stress. The selective radioprotection of non-malignant cells is mediated in part by enhanced autophagy and protection of anabolic metabolism pathways, but differential H2AX activation kinetics suggested that the DNA damage response is also CD47-dependent. A high throughput screen of drug sensitivities indicated that CD47 expression selectively sensitizes Jurkat T cells to inhibitors of topoisomerases, which are known targets of Schlafen-11 (SLFN11). CD47 mRNA expression positively correlated with schlafen-11 mRNA expression in a subset of human cancers but not the corresponding non-malignant tissues. CD47 mRNA expression was also negatively correlated with SLFN11 promoter methylation in some cancers. CD47 knockdown, gene disruption, or treatment with a CD47 function-blocking antibody decreased SLFN11 expression in Jurkat cells. The CD47 signaling ligand thrombospondin-1 also suppressed schlafen-11 expression in wild type but not CD47-deficient T cells. Re-expressing SLFN11 restored radiosensitivity to a CD47-deficient Jurkat cells. Disruption of CD47 in PC3 prostate cancer cells similarly decreased schlafen-11 expression and was associated with a CD47-dependent decrease in acetylation and increased methylation of histone H3 in the SLFN11 promoter region. The ability of histone deacetylase or topoisomerase inhibitors to induce SLFN11 expression in PC3 cells was lost when CD47 was targeted in these cells. Disrupting CD47 in PC3 cells increased resistance to etoposide but, in contrast to Jurkat cells, not to ionizing radiation. These data identify CD47 as a context-dependent regulator of SLFN11 expression and suggest an approach to improve radiotherapy and chemotherapy responses by combining with CD47-targeted therapeutics., (Copyright © 2019 Kaur, Schwartz, Jordan, Soto-Pantoja, Kuo, Elkahloun, Mathews Griner, Thomas, Ferrer, Thomas, Tang, Rajapakse, Pommier and Roberts.)

Eukaryotic cells share a basic scheme of internal organization featuring membrane-based organelles. The use of fluorescent proteins (FPs) greatly facilitated live-cell imaging of organelle dynamics and protein trafficking. One major limitation of this approach is that the fusion of an FP to a target protein can and often does compromise the function of the target protein and alter its subcellular localization. The optimization process to obtain a desirable fusion construct can be time-consuming or even unsuccessful. In this work, we set out to provide a validated set of FP-based markers for major organelles in the budding yeast ( Saccharomyces cerevisiae ). Out of over 160 plasmids constructed, we present a final set of 42 plasmids, the recommendations for which are backed up by meticulous evaluations. The tool set includes three colors (green, red, and blue) and covers the endoplasmic reticulum (ER), nucleus, Golgi apparatus, endosomes, vacuoles, mitochondria, peroxisomes, and lipid droplets. The fidelity of the markers was established by systematic cross-comparison and quantification. Functional assays were performed to examine the impact of marker expression on the secretory pathway, endocytic pathway, and metabolic activities of mitochondria and peroxisomes. Concomitantly, our work constitutes a reassessment of organelle identities in this model organism. Our data support the recognition that "late Golgi" and "early endosomes," two seemingly distinct terms, denote the same compartment in yeast. Conversely, all other organelles can be visually separated from each other at the resolution of conventional light microscopy, and quantification results justify their classification as distinct entities. IMPORTANCE Cells contain elaborate internal structures. For eukaryotic cells, like those in our bodies, the internal space is compartmentalized into membrane-bound organelles, each tasked with specialized functions. Oftentimes, one needs to visualize organelles to understand a complex cellular process. Here, we provide a validated set of fluorescent protein-based markers for major organelles in budding yeast. Yeast is a commonly used model when investigating basic mechanisms shared among eukaryotes. Fluorescent proteins are produced by cells themselves, avoiding the need for expensive chemical dyes. Through extensive cross-comparison, we make sure that each of our markers labels and only labels the intended organelle. We also carefully examined if the presence of our markers has any negative impact on the functionality of the cells and found none. Our work also helps answer a related question: are the structures we see really what we think they are?, (Copyright © 2019 Zhu et al.)

Multiple initiatives at the national and international level support natural drug discovery. Psychiatrists and patients are not well informed about natural psychotropics in general. Existing antidepressant and antipsychotic drugs were developed from atropine, a natural product. Subsequent drug developments were largely based on extension and modification of earlier molecular scaffolds. This limits their mechanisms of action to similar neuropathways. Natural psychotropic substances, particularly those with hallucinogenic and psychedelic properties and different chemical structures, may serve as new paths to novel psychotropic drug development., (© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.)

Whistler and Alfvén waves are known to scatter mirror-trapped electrons and protons into the loss cone of the earth's dipole magnetic field. An array of satellites with properly phased antennas can be used to artificially reduce the flux of energetic particles from regions where their flux has been naturally or artificially pumped. In any space based system, the power required to drive antennas is at a premium. We present here experimental evidence that the efficiency of an antenna can be greatly enhanced with the use of ferrite cores with high relative magnetic permeability μ. Ferrite-based antennas were constructed to launch Alfvén waves in a magnetized plasma. The wave magnetic field of shear Alfvén waves launched with a ferrite core was by the magnetization factor μ larger than that of a similar antenna without a ferrite. Combining multiple ferrite antennas allowed control of the injected perpendicular wavelength. This novel technique can be used to efficiently launch low frequency waves with amplitude above the threshold required for nonlinear triggering.

Thermal scanning probe lithography (t-SPL) is a nanofabrication technique in which an immobilized thermolabile resist, such as polyphthalaldehyde (PPA), is locally vaporized by a heated atomic force microscope tip. Compared with other nanofabrication techniques, such as soft lithography and nanoimprinting lithography, t-SPL is more efficient and convenient as it does not involve time-consuming mask productions or complicated etching procedures, making it a promising candidate technique for the fast prototyping of nanoscale topographies for biological studies. Here, we established the direct use of PPA-coated surfaces as a cell culture substrate. We showed that PPA is biocompatible and that the deposition of allylamine by plasma polymerization on a silicon wafer before PPA coating can stabilize the immobilization of PPA in aqueous solutions. When seeded on PPA-coated surfaces, human mesenchymal stem cells (MSC) adhered, spread, and proliferated in a manner indistinguishable from cells cultured on glass surfaces. This allowed us to subsequently use t-SPL to generate nanotopographies for cell culture experiments. As a proof of concept, we analyzed the surface topography of bovine tendon sections, previously shown to induce morphogenesis and differentiation of MSC, by means of atomic force microscopy, and then "wrote" topographical data on PPA by means of t-SPL. The resulting substrate, matching the native tissue topography on the nanoscale, was directly used for MSC culture. The t-SPL substrate induced similar changes in cell morphology and focal adhesion formation in the MSC compared to native tendon sections, suggesting that t-SPL can rapidly generate cell culture substrates with complex and spatially accurate topographical signals. This technique may greatly accelerate the prototyping of models for the study of cell-matrix interactions.

BACKGROUNDIn preclinical murine and early clinical studies of hematopoietic cell transplantation, engineering of donor grafts with defined ratios of CD4+CD25+FoxP3+ Tregs to conventional T cells (Tcons) results in the prevention of graft-versus-host disease and improved immune reconstitution. The use of highly purified primary graft Tregs for direct cell infusion has potential advantages over impure immunomagnetic selection or culture expansion, but has not been tested clinically. We performed a phase I study of the timed addition of CD34-selected hematopoietic stem cells and Tregs, followed by Tcons for the treatment of patients with high-risk hematological malignancies.METHODSWe present interim evaluation of a single-center open phase I/II study of administration of human leukocyte-matched Tregs and CD34-selected hematopoietic cells, followed by infusion of an equal ratio of Tcons in adult patients undergoing myeloablative hematopoietic stem cell transplantation (HCT) for high-risk or active hematological malignancies. Tregs were purified by immunomagnetic selection and high-speed cell sorting.RESULTSHere we report results for the first 12 patients who received Tregs of between 91% and 96% purity. Greater than grade II GVHD was noted in 2 patients in the first cohort of 5 patients, who received cryopreserved Tregs, but neither acute nor chronic GVHD was noted in the second cohort of 7 patients, who received fresh Tregs and single-agent GVHD prophylaxis. Patients in the second cohort appeared to have normal immune reconstitution compared with patients who underwent transplantation and did not develop GVHD.CONCLUSIONOur study shows that the use of highly purified fresh Tregs is clinically feasible and supports continued investigation of the strategy.TRIAL REGISTRATIONClinicalTrials.gov NCT01660607.FUNDINGNIH NHBLI R01 HL114591 and K08HL119590.

Purpose: To investigate the prognostic impact of 4L lymph node (LN) dissection in left lung cancer and to analyze the relative risk factors for 4L LN metastasis., Patients and Methods: We retrospectively collected data from 657 patients with primary left lung cancer who underwent surgical pulmonary resection from January 2005 to December 2009. One hundred thirty-nine patients underwent 4L LN dissection (4L D+ group); the other 518 patients did not receive 4L LN dissection (4L D- group). Propensity score weighting was applied to reduce the effects of observed confounding between the two groups. Study end points were disease-free survival (DFS) and overall survival (OS)., Results: The metastasis rate of station 4L was 20.9%, which was significantly higher than those of station 7 (14.0%; P = .048) and station 9 (9.8%; P < .001). Station 4L metastasis was associated with most other LN station metastases in univariate analysis, but only station 10 LN metastasis was an independent risk factor for 4L LN metastasis (odds ratio, 0.253; 95% CI, 0.109 to 0.588; P = .001) in multivariate logistic analysis. The 4L D + group had a significantly better survival than the 4L D - group (5-year DFS, 54.8% v 42.7%; P = .0376; 5-year OS, 58.9% v 47.2%; P = .0200). After allowing potential confounders in multivariate survival analysis, dissection of 4L LN retained its independent favorable effect on DFS (hazard ratio, 1.502; 95% CI, 1.159 to 1.947; P = .002) and OS (hazard ratio, 1.585; 95% CI, 1.222 to 2.057; P = .001). Propensity score weighting further confirmed that the 4L D + group had a more favorable DFS ( P = .0014) and OS ( P < .001) than the 4L D - group., Conclusion: Station 4L LN involvement is not rare in left lung cancer, and dissection of the 4L LN station seems to be associated with a more favorable prognosis as compared with those who did not undergo this dissection.

This paper introduces the tools related to Quality In Prognosis Studies (QUIPS) to assess the risk of bias in studies of prognostic factors and the relevant points of assessment and to illustrate the application of QUIPS in published prognostic research. The QUIPS tool identified 6 important areas to consider when evaluating validity and bias in studies of prognostic factors including participation, attrition, measurement on prognostic factors, outcomes, confounding factors, statistical analysis and reporting. It also provided a new method for evaluation on bias in the areas of prognostic research.

The existence of only natural brown and green cotton fibers (BCF and GCF, respectively), as well as poor fiber quality, limits the use of naturally colored cotton ( Gossypium hirsutum L.). A better understanding of fiber pigment regulation is needed to surmount these obstacles. In this work, transcriptome analysis and quantitative reverse transcription PCR revealed that 13 and 9 phenylpropanoid (metabolic) pathway genes were enriched during pigment synthesis, while the differential expression of phenylpropanoid (metabolic) and flavonoid metabolic pathway genes occurred among BCF, GCF, and white cotton fibers (WCF). Silencing the chalcone flavanone isomerase gene in a BCF line resulted in three fiber phenotypes among offspring of the RNAi lines: BCF, almost WCF, and GCF. The lines with almost WCF suppressed chalcone flavanone isomerase, while the lines with GCF highly expressed the glucosyl transferase ( 3GT ) gene. Overexpression of the Gh3GT or Arabidopsis thaliana 3GT gene in BCF lines resulted in GCF. Additionally, the phenylpropanoid and flavonoid metabolites of BCF and GCF were significantly higher than those of WCF as assessed by a metabolomics analysis. Thus, the flavonoid biosynthetic pathway controls both brown and green pigmentation processes. Like natural colored fibers, the transgenic colored fibers were weaker and shorter than WCF. This study shows the potential of flavonoid pathway modifications to alter cotton fibers' color and quality., Competing Interests: The authors declare there are no competing interests. Hai-Feng Liu, Cheng Luo, Wu Song, Zhi-Gang He, Wen-Gang Chen, Yan-Yan Cao, Fang Huang and Shou-Wu Tang are employees of China Colored-cotton (Group) Co., Ltd.

Purpose: Schlafen 11 (SLFN11), a putative DNA/RNA helicase is a dominant genomic determinant of response to DNA-damaging agents and is frequently not expressed in cancer cells. Whether histone deacetylase (HDAC) inhibitors can be used to release SLFN11 and sensitize SLFN11-inactivated cancers to DNA-targeted agents is tested here. Experimental Design: SLFN11 expression was examined in The Cancer Genome Atlas (TCGA), in cancer cell line databases and in patients treated with romidepsin. Isogenic cells overexpressing or genetically inactivated for SLFN11 were used to investigate the effect of HDAC inhibitors on SLFN11 expression and sensitivity to DNA-damaging agents. Results: SLFN11 expression is suppressed in a broad fraction of common cancers and cancer cell lines. In cancer cells not expressing SLFN11 , transfection of SLFN11 sensitized the cells to camptothecin, topotecan, hydroxyurea, and cisplatin but not to paclitaxel. SLFN11 mRNA and protein levels were strongly induced by class I (romidepsin, entinostat), but not class II (roclinostat) HDAC inhibitors in a broad panel of cancer cells. SLFN11 expression was also enhanced in peripheral blood mononuclear cells of patients with circulating cutaneous T-cell lymphoma treated with romidepsin. Consistent with the epigenetic regulation of SLFN11 , camptothecin and class I HDAC inhibitors were synergistic in many of the cell lines tested. Conclusions: This study reports the prevalent epigenetic regulation of SLFN11 and the dominant stimulatory effect of HDAC inhibitors on SLFN11 expression. Our results provide a rationale for combining class I HDAC inhibitors and DNA-damaging agents to overcome epigenetic inactivation of SLFN11 -mediated resistance to DNA-targeted agents. Clin Cancer Res; 24(8); 1944-53. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Modern societies are moving toward an information-oriented environment. To gather and utilize information around people's modern life, tiny devices with all kinds of sensing devices and various sizes of gateways need to be deployed and connected with each other through the Internet or proxy-based wireless sensor networks (WSNs). Within this kind of Internet of Things (IoT) environment, how to authenticate each other between two communicating devices is a fundamental security issue. As a lot of IoT devices are powered by batteries and they need to transmit sensed data periodically, it is necessary for IoT devices to adopt a lightweight authentication protocol to reduce their energy consumption when a device wants to authenticate and transmit data to its targeted peer. In this paper, a lightweight continuous authentication protocol for sensing devices and gateway devices in general IoT environments is introduced. The concept of valid authentication time period is proposed to enhance robustness of authentication between IoT devices. To construct the proposed lightweight continuous authentication protocol, token technique and dynamic features of IoT devices are adopted in order to reach the design goals: the reduction of time consumption for consecutive authentications and energy saving for authenticating devices through by reducing the computation complexity during session establishment of continuous authentication. Security analysis is conducted to evaluate security strength of the proposed protocol. In addition, performance analysis has shown the proposed protocol is a strong competitor among existing protocols for device-to-device authentication in IoT environments., Competing Interests: The authors declare no conflict of interest.

SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block, and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites., (Published by Elsevier Inc.)

A significant number of patients with major depression do not respond optimally to current antidepressant drugs. As depression is likely to be a heterogeneous disorder, it is possible that existing neurotransmitter-based antidepressant drugs do not fully address other pathologies that may exist in certain cases. Biological pathologies related to depression that have been proposed and studied extensively include inflammation and immunology, hypercortisolemia, oxidative stress, and impaired angiogenesis. Such pathologies may induce neurodegeneration, which in turn causes cognitive impairment, a symptom increasingly being recognized in depression. A neurotoxic brain hypothesis unifying all these factors may explain the heterogeneity of depression as well as cognitive decline and antidepressant drug resistance in some patients. Compared with neurotransmitter-based antidepressant drugs, many botanical compounds in traditional medicine used for the treatment of depression and its related symptoms have been discovered to be anti-inflammatory, immunoregulatory, anti-infection, antioxidative, and proangiogenic. Some botanical compounds also exert actions on neurotransmission. This multitarget nature of botanical medicine may act through the amelioration of the neurotoxic brain environment in some patients resistant to neurotransmitter-based antidepressant drugs. A multitarget multidimensional approach may be a reasonable solution for patients resistant to neurotransmitter-based antidepressant drugs.

Cellular therapies based on permanent genetic modification of conventional T cells have emerged as a promising strategy for cancer. However, it remains unknown if modification of T cell subsets, such as Tregs, could be useful in other settings, such as allograft transplantation. Here, we use a modular system based on a chimeric antigen receptor (CAR) that binds covalently modified mAbs to control Treg activation in vivo. Transient expression of this mAb-directed CAR (mAbCAR) in Tregs permitted Treg targeting to specific tissue sites and mitigated allograft responses, such as graft-versus-host disease. mAbCAR Tregs targeted to MHC class I proteins on allografts prolonged islet allograft survival and also prolonged the survival of secondary skin grafts specifically matched to the original islet allograft. Thus, transient genetic modification to produce mAbCAR T cells led to durable immune modulation, suggesting therapeutic targeting strategies for controlling alloreactivity in settings such as organ or tissue transplantation.

Polypharmacy is common in psychiatry. Usage of cognitive enhancers is increasing in the psychiatric population. Many clinicians are not familiar with these new psychoactive compounds. This paper reviews the potential drug-drug interactions when these cognitive enhancers are used together with psychotropic drugs and their confounding effects on diagnosis and clinical management.

Fish blood is one of the crucial tissues of innate immune system, but the full repertoire of fish serum components involved in antibacterial defense is not fully identified. In this study, we demonstrated that turbot serum, but not the heat-inactivated control, significantly reduced the number of Edwardsiella tarda (E. tarda). By conjugating serum proteins with fluorescent dyes, we showed that E. tarda were coated with multiple fish proteins. In order to identify these proteins, we used E. tarda to capture turbot serum proteins and subjected the samples to shotgun proteomic analysis. A total of 76 fish proteins were identified in high confidence, including known antimicrobial proteins such as immunoglobins and complement components. 34 proteins with no previously known immunological functions were also identified. The expression of one of these proteins, IQ motif containing H (IQCH), was exclusively in fish brain and gonads and was induced during bacterial infection. This approach also allowed the study of the corresponding proteomic changes in E. tarda exposed to turbot serum, which is a general decrease of bacterial protein expression except for an upregulation of membrane components after serum treatment. Interestingly, while most other known stresses stimulate bacterial antioxidant enzymes, fish serum induced a rapid suppression of antioxidant proteins and led to an accumulation of reactive oxygen species. Heat treatment of fish serum eliminated this effect, suggesting that heat labile factors in the fish serum overrode bacterial antioxidant defenses. Taken together, this work offers a comprehensive view of the interactions between fish serum proteins and bacteria, and reveals previously unknown factors and mechanisms in fish innate immunity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Populations using herbs and herbal preparations are widespread and growing. As many herbal ingredients exert actions on psychotropic drug targets, psychiatrists should be well informed and aware of potential drug-drug interactions in clinical practice. Reliable and clinically useful information in this area, however, is fragmented, if not deficient. This paper reviewed the clinical aspects of herb-drug interactions, focusing in particular on the monoamine oxidase enzyme and P450 cytochrome enzyme-inhibitory properties of herbs and their potential interference with psychotropic drug actions and clinical judgement.

Hepatocellular carcinoma (HCC) remains the leading cause of cancer mortality with limited therapeutic targets. The endoplasmic reticulum (ER) plays a pivotal role in maintaining proteostasis in normal cells. However, alterations in proteostasis are often found in cancer cells, making it a potential target for therapy. Polygonum bistorta is used in traditional Chinese medicine owing to its anticancer activities, but the molecular and pharmacological mechanisms remain unclear. Using hepatoma cells as a model system, this study demonstrated that P. bistorta aqueous extract (PB) stimulated ER stress by increasing autophagosomes but by blocking degradation, followed by the accumulation of ubiquitinated proteins and cell apoptosis. In addition, an autophagy inhibitor did not enhance ubiquitinated protein accumulation whereas a reactive oxygen species (ROS) scavenger diminished both ubiquitinated protein accumulation and ligand-stimulated epidermal growth factor receptor (EGFR) expression, suggesting that ROS generation by PB may be upstream of PB-triggered cell death. Nevertheless, PB-exerted proteostasis impairment resulted in cytoskeletal changes, impairment of cell adhesion and motility, and inhibition of cell cycle progression. Oral administration of PB delayed tumour growth in a xenograft model without significant body weight loss. These findings indicate that PB may be a potential new alternative or complementary medicine for HCC., Competing Interests: The authors declare no competing financial interests.

Prevention of deterioration of brain function over time is important in the long-term management of chronic brain disorders such as dementia, schizophrenia, and mood disorders. Although the possibility of neurogenesis in the adult human brain is attractive, and there are psychiatric drugs proven to be effective inducers of neurogenesis in animals, we have yet to see their utility in clinical practice. The terms neurodegeneration and neuroregeneration are often used in a nonspecific manner. Neuroregeneration may mean neurogenesis, dendritogenesis, spinogenesis, or axonogenesis. The term "neuroprotection" is attractive clinically and may involve different mechanisms. Many causative and protective factors of neurodegeneration and neuroregeneration have been proposed. However, the specificity of these factors and agents and differential neuronal vulnerability factors have generally been ignored in past studies. It is also hard to separate disease-modifying from "neuroprotective" effects of a drug. The application of stringent long-term neuroanatomical, neurochemical, neurophysiological, and therapeutic efficacy criteria should improve future research in this important area., (© 2017 S. Karger AG, Basel.)