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The coronavirus disease 2019 (COVID-19) pandemic has driven major advances in virus research. The role of glycans in viral infection has been revealed, with research demonstrating that terminal sialic acids are key receptors during viral attachment and infection into host cells. However, there is an urgent demand for universal tools to study the mechanism of sialic acids in viral infections, as well as to develop therapeutic agents against epidemic viruses through the downregulation of terminal sialic acid residues on glycans acting as a glyco-virus checkpoint to accelerate virus clearance. In this study, we developed a robust sialic acids blockade tool termed local and noninvasive glyco-virus checkpoint nanoblockades (LONG NBs), which blocked cell surface sialic acids by endogenously and continuously inhibiting the de novo sialic acids biosynthesis pathway. Furthermore, LONG NBs could accurately characterize the sialic acid-dependent profiles of multiple virus variants and protected the host against partial SARS-CoV-2, rotavirus, and influenza A virus infections after local and noninvasive administration. Our results suggest that LONG NBs represent a promising tool to facilitate in-depth research on the mechanism of viral infection, and serve as a broad-spectrum protectant against existing and emerging viral variants via glyco-virus checkpoint blockade.

Herein, we developed a Lewis acid-mediated O-glycosylation and C-glycosylation protocol using stable glycosyl 2'-hydroxy-2'-methylpropionates as donors. These glycosylation reactions reached completion within 1 h at room temperature. The practicality of this protocol is characterized by their straightforward operation and efficient applicability to various substrates, including both disarmed and armed glycosyl donors, through the remote activation of easily accessible TMSOTf., (© 2024 Wiley-VCH GmbH.)

Immune checkpoint blockade (ICB) has significantly improved the prognosis of patients with cancer, although the majority of such patients achieve low response rates; consequently, new therapeutic approaches are urgently needed. The upregulation of sialic acid-containing glycans is a common characteristic of cancer-related glycosylation, which drives disease progression and immune escape via numerous pathways. Herein, the development of self-assembled core-shell nanoscale coordination polymer nanoparticles loaded with a sialyltransferase inhibitor, referred to as NCP-STI which effectively stripped diverse sialoglycans from cancer cells, providing an antibody-independent pattern to disrupt the emerging Siglec-sialic acid glyco-immune checkpoint is reported. Furthermore, NCP-STI inhibits sialylation of the concentrated nucleoside transporter 1 (CNT1), promotes the intracellular accumulation of anticancer agent gemcitabine (Gem), and enhances Gem-induced immunogenic cell death (ICD). As a result, the combination of NCP-STI and Gem (NCP-STI/Gem) evokes a robust antitumor immune response and exhibits superior efficacy in restraining the growth of multiple murine tumors and pulmonary metastasis. Collectively, the findings demonstrate a novel form of small molecule-based chemo-immunotherapy approach which features sialic acids blockade that enables cooperative effects of cancer cell chemosensitivity and antitumor immune responses for cancer treatment., (© 2024 Wiley‐VCH GmbH.)

In the process of searching for anti-breast cancer agents, five sesquiterpene lactones (1-5), including two previously undescribed ones, yjaponica B-C (1-2), were isolated from the herb of Youngia japonica. Their structures were elucidated by spectroscopic data analyses and Marfey's method. Cytotoxic activities of all compounds against A549, U87, and 4T1 cell lines were tested using the CCK8 assay. The result showed that compound 3 possessed the highest cytotoxic activity against 4T1 cells with an IC 50 value of 10.60 μM. Furthermore, compound 3 distinctly induced apoptosis, inhibited immigration, and blocked the cell cycle of 4T1 cells. In addition, compound 3 induced the production of reactive oxygen species. Further anticancer mechanism studies showed that compound 3 significantly upregulated expression of the cleaved caspase 3 and PARP, whereas it downregulated the expression of Bcl-2, cyclin D1, cyclin A2, CDK4, and CDK2. Taken together, our results demonstrate that compound 3 has a high potential of being used as a leading compound for the discovery of new anti-breast cancer agent., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Vitamin D is a critical fat-soluble vitamin for the nervous system. Research suggests a potential link between vitamin D deficiency and attention-deficit hyperactivity disorder (ADHD), particularly in children and adolescents. The core symptoms of ADHD are associated with deficits in striatal functions, and maintaining sufficient levels of vitamin D may help prevent or alleviate ADHD symptoms. However, the molecular changes in the striatum caused by vitamin D supplementation that may contribute to the brain processes linked to ADHD symptoms remain unclear. In this study, we established a mouse model fed diets with three different dose gradients of vitamin D3 (0, 500, and 2000 IU/kg·day) from postnatal day 21 (P21) to 14 weeks of age. Striatal tissues from mice with gradient vitamin D3 intake were subjected to reduced representation bisulfite sequencing (RRBS), RNA-sequencing, and neurotransmitter profiling by liquid chromatography-mass spectrometry (LC-MS). Our findings indicate that vitamin D supplementation since childhood influenced the overall landscape of DNA methylations and the expression of many genes involved in critical neurological functions in a dose-dependent manner. Additionally, our data demonstrate how vitamin D modulated neuropeptide signaling pathways, as well as cholinergic and dopaminergic synapses in the striatum, through an orchestrated mechanism involving epigenetic and transcriptional regulations. Furthermore, we observed a synergistic effect of vitamin D on dopamine release following acute methylphenidate injection into our mouse model. In summary, this study provides mechanistic insights into how dietary vitamin D supplementation since childhood can modulate specific signal transductions among striatal cells, underscoring the importance of vitamin D supplementation for ADHD management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The preliminary study revealed that the ethyl acetate eluate of Youngia japonica (YJ-E) could inhibit the expression of key proteins of p-p65, p-IκBα, p-IKKα/β, and p-AKT in LPS stimulated BV2 cell. Further phytochemical study led to the isolation of eight compounds from YJ-E, including one new sesquiterpene lactone. Their structures were elucidated by several spectroscopic data, and comparing the NMR data of known compound. In addition, all of the isolates were evaluated for the anti-inflammatory effect. As a result, compounds 3 and 4 distinctly attenuated the expressions of p-IκBα, p-p65, and p-AKT in LPS stimulated BV2 cell, respectively.

Two novel phenylpropanoids (compounds 1 and 2) and 11 known compounds were isolated from Smilax china L. Their structures were determined by NMR (1D and 2D) and high-resolution electrospray ionization mass spectrometry. Further, the cytotoxic activity of all the isolated compounds against HeLa, 4T1, and U251 tumor cells was evaluated using the cell counting kit-8 assay, revealing that compound 13 showed significant cytotoxicity toward HeLa cells. Further investigations explored the impact of compound 13 on the mitochondrial membrane potential, concentration of reactive oxygen species, wound-healing distance, and cell cycle of HeLa cells. Notably, compound 13 significantly decreased mitochondrial membrane potential, suppressed cell migration, and increased intracellular reactive oxygen species levels in HeLa cells. Furthermore, compound 13 inhibited HeLa cell-cycle progression in the S phase. These findings indicate that compound 13 is a potential drug lead for the treatment of cervical cancer., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

An increasing number of epidemiological studies have explored the relationship between the risk of gastric cancer and specific dietary patterns, but the findings remain inconclusive. We, therefore, performed this comprehensive systematic review and meta-analysis to analyze the available evidence regarding the associations between a priori and a posteriori dietary patterns and the risk of gastric cancer. A systematic search of six electronic databases, including PubMed, Web of Science, EBSCO, Scopus, China National Knowledge Infrastructure (CNKI), and Wanfang Data, was carried out to retrieve the relevant articles published up to March 2024. Thirty-six studies (10 cohort and 26 case-control studies) with a total of 2 181 762 participants were included in the final analyses. Combining 15 effect sizes extracted from 12 articles, we observed a reduced risk of gastric cancer in the highest versus the lowest categories of the Mediterranean diet [relative risk (RR), 0.72; 95% confidence interval (CI), 0.61-0.85; P < 0.001]. Combining 11 effect sizes from 10 articles (involving 694 240 participants), we found that the highest Dietary Inflammatory Index scores were significantly associated with an increased risk of gastric cancer (RR, 1.32; 95% CI, 1.11-1.57; P < 0.001). A reduced risk of gastric cancer was shown for the highest compared with the lowest categories of healthy dietary pattern (RR, 0.78; 95% CI, 0.67-0.91; P = 0.002). Conversely, the highest adherence to the Western dietary pattern was associated with an increased risk of gastric cancer (RR, 1.33; 95% CI, 1.19-1.49; P < 0.001). Our study demonstrated that the Mediterranean diet and a healthy dietary pattern were associated with a decreased risk of gastric cancer. Conversely, the Dietary Inflammatory Index and Western dietary pattern were associated with an increased risk of gastric cancer., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Carbohydrates are called the third chain of life. Carbohydrates participate in many important biochemical functions in living species, and the biological information carried by them is several orders of magnitude larger than that of nucleic acids and proteins. However, due to the intrinsic complexity and heterogeneity of carbohydrate structures, furnishing pure and structurally well-defined glycans for functional studies is a formidable task, especially for homogeneous large-size glycans. To address this issue, we have developed a donor preactivation-based one-pot glycosylation strategy enabling multiple sequential glycosylations in a single reaction vessel.The donor preactivation-based one-pot glycosylation refers to the strategy in which the glycosyl donor is activated in the absence of a glycosyl acceptor to generate a reactive intermediate. Subsequently, the glycosyl acceptor with the same anomeric leaving group is added, leading to a glycosyl coupling reaction, which is then iterated to rapidly achieve the desired glycan in the same reactor. The advantages of this strategy include the following: (1) unique chemoselectivity is obtained after preactivation; (2) it is independent of the reactivity of glycosyl donors; (3) multiple-step glycosylations are enabled without the need for intermediate purification; (4) only stoichiometric building blocks are required without complex protecting group manipulations. Using this protocol, a range of glycans including tumor-associated carbohydrate antigens, various glycosaminoglycans, complex N -glycans, and diverse bacterial glycans have been synthesized manually. Gratifyingly, the synthesis of mycobacterial arabinogalactan containing 92 monosaccharide units has been achieved, which created a precedent in the field of polysaccharide synthesis. Recently, the synthesis of a highly branched arabinogalactan from traditional Chinese medicine featuring 140 monosaccharide units has been also accomplished to evaluate its anti-pancreatic-cancer activity. In the spirit of green and sustainable chemistry, this strategy can also be applied to light-driven glycosylation reactions, where either UV or visible light can be used for the activation of glycosyl donors.Automated synthesis is an advanced approach to the construction of complex glycans. Based on the two preactivation modes (general promoter activation mode and light-induced activation mode), a universal and highly efficient automated solution-phase synthesizer was further developed to drive glycan assembly from manual to automated synthesis. Using this synthesizer, a library of oligosaccharides covering various glycoforms and glycosidic linkages was assembled rapidly, either in a general promoter-activation mode or in a light-induced-activation mode. The automated synthesis of a fully protected fondaparinux pentasaccharide was realized on a gram scale. Furthermore, the automated synthesis of large-size polysaccharides was performed, allowing the assembly of arabinans up to an astonishing 1080-mer using the automated multiplicative synthesis strategy, taking glycan synthesis to a new height far beyond the synthesis of nucleic acids (up to 200-mer) and proteins (up to 472-mer).

Fourteen sesquiterpenes, including one undescribed sesquiterpene lactone, were isolated from Youngia japonica, and their structures were identified by NMR, HRESIMS, ECD and calculated ECD. Cytotoxic activities of all isolates against A549, HeLa, and 4 T1 cell lines were detected by CCK8 assay. Among them, 2 showed obvious cytotoxic activity against A549 cells. Subsequently, the production of ROS, and apoptosis of A549 cells treated with 2 were evaluated. The result showed that 2 distinctly increased the ROS level, and induced the apoptosis of A549 cells. Further anticancer mechanism studies showed that 2 increased the expression of cleaved caspase 3. Taken together, our results demonstrated that 2 might become potential leading compounds for the treatment of lung cancer., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study aims to investigate the protective effect of salidroside(SAL) on renal damage in diabetic nephropathy(DN) mice based on the receptor for advanced glycation end products/janus activated kinase 1/signal transduction and activator of transcription 3(RAGE/JAK1/STAT3) signaling pathway. The mouse DN model was established by high-fat/high-sucrose diets combined with intraperitoneal injection of streptozocin(STZ). Mice were randomly divided into normal group, model group, low-dose SAL group(20 mg·kg~(-1)), high-dose SAL group(100 mg·kg~(-1)), and metformin group(140 mg·kg~(-1)), with 12 mice in each group. After establishing the DN model, mice were given drugs or solvent intragastrically, once a day for consecutive 10 weeks. Body weight, daily water intake, and fasting blood glucose(FBG) were measured every two weeks. After the last dose, the glucose tolerance test was performed, and the samples of 24-hour urine, serum, and kidney tissue were collected. The levels of 24 hours urinary total protein(24 h-UTP), serum creatinine(Scr), blood urea nitrogen(BUN), triglyceride(TG), total cholesterol(TC), low density lipoprotein cholesterol(LDL-C), and high density lipoprotein cholesterol(HDL-C) were detected by biochemical tests. Periodic acid-schiff(PAS) staining was used to observe the pathological changes in the kidney tissue. The protein expressions of α-smooth muscle actin(α-SMA), vimentin, and advanced glycation end products(AGEs) in kidneys were detected by immunohistochemical staining. The activities of superoxide dismutase(SOD), catalase(CAT), glutathione peroxidase(GSH-PX), and the level of malondialdehyde(MDA) in kidneys were detected by using a corresponding detection kit. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of AGEs, carboxymethyllysine(CML), and carboxyethyllysine(CEL) in serum. The protein expressions of RAGE and the phosphorylation level of JAK1 and STAT3 in kidneys were detected by Western blot. Compared with the normal group, the levels of FBG, the area under the curve of glucose(AUCG), water intake, kidney index, 24 h-UTP, tubular injury score, extracellular matrix deposition ratio of the renal glomerulus, the serum levels of Scr, BUN, TG, LDL-C, AGEs, CEL, and CML, the level of MDA, the protein expressions of α-SMA, vimentin, AGEs, and RAGE, and the phosphorylation level of JAK1 and STAT3 in kidney tissue were increased significantly(P&lt;0.01), while the level of HDL-C in serum and the activity of SOD, CAT, and GSH-PX in kidney tissue were decreased significantly(P&lt;0.01). Compared with the model group, the above indexes of the high-dose SAL group were reversed significantly(P&lt;0.05 or P&lt;0.01). In conclusion, this study suggests that SAL can alleviate oxidative stress and renal fibrosis by inhibiting the activation of AGEs-mediated RAGE/JAK1/STAT3 signaling axis, thus playing a potential role in the treatment of DN.

Four undescribed coumarin derivatives, ficusalt A (1) and ficusalt B (2), a pair of racemic coumarins, (±) ficudimer A (3a/3b), along with ten known amides, were isolated from the roots of Ficus hirta. Their structures were elucidated by several spectroscopic data analyses, including HRESIMS, NMR, and X-ray single-crystal diffraction. The cytotoxic activities of all compounds against HeLa, HepG2, MCF-7, and H460 cell lines were detected using the MTT assay. Among these, 5 showed the highest activity against HeLa cells. Subsequently, the apoptotic, anti-invasive, and anti-migration effects of 5 on HeLa cells were determined by flow cytometer, transwell invasion assay, and wound-healing assay, respectively. The result suggested that 5 distinctly induced the apoptosis in HeLa cells and inhibited their invasion and migration. Further studies on anticancer mechanisms were conducted using Western blotting. As a result, 5 increased the cleavage of PARP and the expression of pro-apoptotic protein Bax. Moreover, 5 notably upregulated the phosphorylation of p38 and JNK, whereas inhibited the expression of p-ERK and p-AKT. Our results demonstrated that 5 could be a potential leading compound for further application in the treatment of cervical cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Photochemical glycosylation has attracted considerable attention in carbohydrate chemistry. However, to the best of our knowledge, visible-light-promoted glycosylation via photoactive glycosyl donor has not been reported. In the study, we report a photosensitizer-free visible-light-mediated glycosylation approach using a photoactive 2-glycosyloxy tropone as the donor. This glycosylation reaction proceeds at ambient temperature to give a wide range of O-glycosides or oligosaccharides with yields up to 99%. This method is further applied in the stereoselective preparation of various functional glycosyl phosphates/phosphosaccharides, the construction of N-glycosides/nucleosides, and the late-stage glycosylation of natural products or pharmaceuticals on gram scales, and the iterative synthesis of hexasaccharide. The protocol features uncomplicated conditions, operational simplicity, wide substrate scope (58 examples), excellent compatibility with functional groups, scalability of products (7 examples), and high yields. It provides an efficient glycosylation method for accessing O/N-glycosides and glycans., (© 2023. The Author(s).)

Chemical O-glycosylation is a key step for the synthesis of sugar-containing molecules such as glycolipids. However, traditional carbohydrate chemistry is characterized by extensive use of protective groups, resulting in laborious manipulations and poor atom economy. Here, we present a protecting-group-free glycosylation strategy employing dibenzyloxy-1,3,5-triazin-2-yl glycosides (DBT-glycosides) as glycosyl donors. The DBT-glycosyl donors could be prepared directly through an alkaline nucleophilic substitution from unprotected sugars in aqueous media. The O-glycosylation of alcohols by using DBT-glycosyl donors has been carried out under mild hydrogenolytic conditions, affording the corresponding alkyl glycosides stereo-selectively in good yields., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The efficient synthesis of N-glycosides via direct N-glycosylation of amides/azacycles has been reported. The glycosylation of amides/azacycles with glycosyl halides in the presence of a catalytic amount of urea proceeded smoothly to provide the corresponding N-glycosylated amides or nucleosides in good to excellent yields with 1,2-trans-stereoselectivity. Moreover, by the addition of terpyridine, the 1,2-cis-stereoselectivity was achieved., (© 2023 Wiley-VCH GmbH.)

Abnormal glycosylation is a hallmark of tumor development, and tumor-associated carbohydrate antigens are potential immune targets for tumor therapy. Tumor-associated extracellular microvesicles are subcellular vesicles released from cell membranes that have immunogenicity similar to that of precursor cells. However, unmodified tumor-derived microvesicles have weaknesses, such as low immunogenicity, poor biostability, and short half-life in vivo . For the first time, we herein generated extracellular microvesicles containing modified tumor-associated carbohydrate antigens by constructing a cell line with highly expressed antigen-processing enzymes utilizing fluorine-modified monosaccharide substrates via a metabolic oligosaccharide engineering strategy. The microvesicles were applied to tumor immunity, achieving enhanced immunoprophylaxis and immunotherapy effects. Furthermore, the mechanisms of antitumor immunity were explored. Our findings may provide new insights into the adhibition of suitably modified extracellular microvesicles and the development of more effective carbohydrate-based anticancer vaccines.

Objectives: To explore the characteristics of postmortem examination, chemical examination and scene investigation of deaths caused by oral diphenidol hydrochloride poisoning, and so as to provide a reference for proper settlement and prevention of such deaths., Methods: The data of 22 deaths caused by oral diphenidol hydrochloride poisoning in a city from January 2018 to August 2020 were collected, including case details, scene investigations, autopsies, chemical examinations and digital evidence. Thirty-one cases of deaths caused by oral diphenidol hydrochloride poisoning reported in previous literature were also collected., Results: In the 53 oral diphenidol hydrochloride poisoning death cases, 50 cases were suicide, 2 cases were accidental, while 1 case was undetermined. Fifty-two cases were found in the medical records or crime scene investigation reports with doses ranging from 775 mg to 12 500 mg, and 23 deceased were detected with postmortem blood concentrations ranging from 2.71 mg/L to 83.1 mg/L. Clinical symptoms were recorded in 6 patients, including conscious disturbance and convulsion. Among the 45 cases which were performed with external examination, 23 cases autopsied., Conclusions: Most of the deceased of oral diphenidol hydrochloride poisoning were suicide. No significant correlation was found between dose and blood concentration through the retrospective analysis of cases.

Despite hypersialylation of cancer cells together with a significant upregulation of sialyltransferase (ST) activity contributes to the metastatic cascade at multiple levels, there are few dedicated tools to interfere with their expression. Although transition state-based ST inhibitors are well-established, they are not membrane permeable. To tackle this problem, herein, we design and construct long-circulating, self-assembled core-shell nanoscale coordination polymer (NCP) nanoparticles carrying a transition state-based ST inhibitor, which make the inhibitor transmembrane and potently strip diverse sialoglycans from various cancer cells. In the experimental lung metastasis and metastasis prevention models, the nanoparticle device (NCP/STI) significantly inhibits metastases formation without systemic toxicity. This strategy enables ST inhibitors to be applied to cells and animals by providing them with a well-designed nanodelivery system. Our work opens a new avenue to the development of transition state-based ST inhibitors and demonstrates that NCP/STI holds great promise in achieving metastases inhibition for multiple cancers.

Objective: To understand the prevalence of Chlamydia trachomatis (CT) infection and its associated factors among asymptomatic outpatients attending sexually transmitted disease (STD)-related clinics in Shenzhen and provide evidence for development of future interventions. Methods: From April 15 to May 16, 2018, a cross-sectional study was conducted and patients attending STD-related Clinics were recruited from 22 medical institutions in Nanshan, Luohu, Bao'an, Longgang, Yantian, and Longhua districts of Shenzhen. After the informed consent from each participant was obtained, social-demographic information was collected through a structured questionnaire and urine samples were collected for CT nucleic acid detection. In addition, logistic regression was used to explore associated factors of CT infection. Results: In asymptomatic outpatients, the prevalence of CT infection was 7.16% (250/3 492). Being single (a OR =2.29, 95% CI :1.65-3.16), without registered Shenzhen residency (a OR =1.49, 95% CI :1.04-2.13), and without previous CT testing in the past year (a OR =2.04, 95% CI :1.03-4.05) were the risk factors of CT infection in asymptomatic outpatients. Among participants without registered Shenzhen residency, 89.25% (2 176/2 438) were college-degree or below, and 51.29% (1 255/2 447) were aged ≤30 years, and the risk of CT infection among those ≤30 years old was 1.73 times higher than those >30 years old (95% CI :1.28-2.34). Conclusions: The prevalence of CT infection was high among asymptomatic outpatients attending STD-related clinics in Shenzhen. Routine CT screening should be carried out for this population, especially for those with sexually active age, being single, with low educational level, and without previous CT testing in the past year. Also, raising their awareness of knowledge and adverse outcomes of CT infection should be considered to promote routine CT screening and timely treatment.

One undescribed lignan, one new natural product, along with fourteen known compounds, were isolated from the roots of Ficus hirta . The structures of the isolates were elucidated by comprehensive spectroscopic technologies, including UV, IR, HRESIMS, and NMR. The absolute configuration of 1 was determined by comparison of experimental and calculated ECD data. The cytotoxicity of all the compounds against HeLa and HepG2 cell lines was evaluated and compound 7 showed considerable cytotoxic effect towards HepG2 cells. Also, the apoptotic effect of 7 on HepG2 cells and the effect of 7 on the key proteins (p-JNK and p-p38) in MAPK (Mitogen-activated protein kinases) pathways were studied by flow cytometry and western blotting experiment. As a result, compound 7 induced the apoptosis of HepG2 cells, and dose-dependently increased the phosphorylation of JNK and p38. Thus, 7 might trigger HepG2 cells apoptosis via JNK/p38 MAPK signaling pathway.

Objective: To evaluate the influence of duodenal stump reinforcing on the short-term complications after laparoscopic radical gastrectomy. Methods: A retrospective cohort study with propensity score matching (PSM) was conducted. Clinical data of 1204 patients with gastric cancer who underwent laparoscopic radical gastrectomy at the First Affiliated Hospital of Army Medical University from April 2009 to December 2018 were collected. The digestive tract reconstruction methods included Billroth II anastomosis, Roux-en-Y anastomosis and un-cut-Roux- en-Y anastomosis. A linear stapler was used to transected the stomach and the duodenum. Among 1204 patients, 838 were males and 366 were females with mean age of (57.0±16.0) years. Duodenal stump was reinforced in 792 cases (reinforcement group) and unreinforced in 412 cases (non-reinforcement group). There were significant differences in resection range and anastomotic methods between the two groups (both P <0.001). The two groups were matched by propensity score according to the ratio of 1∶1, and the reinforcement group was further divided into purse string group and non-purse string group. The primary outcome was short-term postoperative complications (within one month after operation). Complications with Clavien-Dindo grade ≥ III a were defined as severe complications, and the morbidity of complication between the reinforcement group and the non-reinforcement group, as well as between the purse string group and the non-purse string group was compared. Results: After PSM, 411 pairs were included in the reinforcement group and the non-reinforcement group, and there were no significant differences in baseline data between the two groups (all P >0.05). No perioperative death occurred in any patient.The short-term morbidity of postoperative complication was 7.4% (61/822), including 14 cases of anastomotic leakage (23.0%), 11 cases of abdominal hemorrhage (18.0%), 8 cases of duodenal stump leakage (13.1%), 2 cases of incision dehiscence (3.3%), 6 cases of incision infection (9.8%) and 20 cases of abdominal infection (32.8%). Short-term postoperative complications were found in 25 patients (6.1%) and 36 patients (8.8%) in the reinforcement group and the non-reinforcement group, respectively, without significant difference (χ 2 =2.142, P =0.143). Nineteen patients (2.3%) developed short-term severe complications (Clavien-Dindo grade ≥IIIa), while no significant difference in severe complications was found between the two groups (1.7% vs. 2.9%, χ 2 =1.347, P =0.246). Sub-group analysis showed that the morbidity of short-term postoperative complication of the purse string group was 2.6% (9/345), which was lower than 24.2% (16/66) of the non-purse string group (χ 2 =45.388, P <0.001). Conclusion: Conventional reinforcement of duodenal stump does not significantly reduce the incidence of duodenal stump leakage, so it is necessary to choose whether to reinforce the duodenal stump individually, and purse string suture should be the first choice when decided to reinforce.

Dense glycosylation and the trimeric conformation of the human immunodeficiency virus-1 (HIV-1) envelope protein limit the accessibility of some cellular glycan processing enzymes and end up with high-mannose-type N -linked glycans on the envelope spike, among which the Man 5 GlcNAc 2 structure occupies a certain proportion. The Man 5 GlcNAc 2 glycan composes the binding sites of some potent broadly neutralizing antibodies, and some lectins that can bind Man 5 GlcNAc 2 show HIV-neutralizing activity. Therefore, Man 5 GlcNAc 2 is a potential target for HIV-1 vaccine development. Herein, a highly convergent and effective strategy was developed for the synthesis of Man 5 and its monofluoro-modified, trifluoro-modified, and S -linked analogues. We coupled these haptens to carrier protein CRM197 and evaluated the immunogenicity of the glycoconjugates in mice. The serological assays showed that the native Man 5 conjugates failed to induce Man 5 -specific antibodies in vivo , while the modified analogue conjugates induced stronger antibody responses. However, these antibodies could not bind the native gp120 antigen. These results demonstrated that the immune tolerance mechanism suppressed the immune responses to Man 5 -related structures and the conformation of glycan epitopes on the synthesized glycoconjugates was distinct from that of native glycan epitopes on gp120.

The photoinitiated intramolecular hydroetherification of alkenols has been used to form C-O bonds, but the intermolecular hydroetherification of alkenes with alcohols remains an unsolved challenge. We herein report the visible-light-promoted 2-deoxyglycosylation of alcohols with glycals. The glycosylation reaction was completed within 2 min in a high quantum yield (ϕ=28.6). This method was suitable for a wide array of substrates and displayed good reaction yields and excellent stereoselectivity. The value of this protocol was further demonstrated by the iterative synthesis of 2-deoxyglycans with α-2-deoxyglycosidic linkages up to a 20-mer in length and digoxin with β-2-deoxyglycosidic linkages. Mechanistic studies indicated that this reaction involved a glycosyl radical cation intermediate and a photoinitiated chain process., (© 2022 Wiley-VCH GmbH.)

Lymphocyte infiltration is an important feature of cancer. There is a complex network of chemokines that influence the degree and phenotype of lymphocyte infiltration, as well as the growth, survival, migration, and angiogenesis of tumor cells. High heterogeneity metastasis is a major obstacle to the treatment of breast cancer. Herein, we showed that O-GlcNAcylation of B lymphocyte-induced maturation protein-1 (Blimp-1) in lymphocytes inhibited the migration and invasion of breast cancer cells. It was found that Blimp-1 O-GlcNAcylation at Ser448 and Ser472 in lymphocytes promoted its nuclear localization, and blocked the bindings to three regions upstream of the ccl3l1 promoter to inhibit its expression. Decreased expression of CCL3L1 in lymphocytes not only decreased CCR5 expression in breast cancer cells, but also inhibited the membrane localization and activation of CCR5, thus blocking the migration and invasion of breast cancer cells in vitro. Therefore, O-GlcNAcylation of Blimp-1 in lymphocytes may serve as a new target for the treatment of metastatic breast cancer., Implications: This study reveals a new mechanism by which the lymphatic system promotes breast cancer cell metastasis., (©2021 American Association for Cancer Research.)

O-GlcNAcylation is a post-translational modification that links metabolism with signal transduction. High O-GlcNAcylation appears to be a general characteristic of cancer cells. It promotes the invasion, metastasis, proliferation and survival of tumor cells, and alters many metabolic pathways. Glycogen metabolism increases in a wide variety of tumors, suggesting that it is an important aspect of cancer pathophysiology. Herein we focused on the O-GlcNAcylation of liver glycogen phosphorylase (PYGL)-an important catabolism enzyme in the glycogen metabolism pathway. PYGL expressed in both HEK 293T and HCT116 was modified by O-GlcNAc. And both PYGL O-GlcNAcylation and phosphorylation of Ser15 (pSer15) were decreased under glucose and insulin, whereas increased under glucagon and Na2S2O4 (hypoxia) conditions. Then, we identified the major O-GlcNAcylation site to be Ser430, and demonstrated that pSer15 and Ser430 O-GlcNAcylation were mutually reinforced. Lastly, we found that Ser430 O-GlcNAcylation was fundamental for PYGL activity. Thus, O-GlcNAcylation of PYGL positively regulated pSer15 and therefore its enzymatic activity. Our results provided another molecular insight into the intricate post-translational regulation network of PYGL., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To compare the clinical efficacy and quality of life between uncut Roux-en-Y and Billroth II with Braun anastomosis in laparoscopic distal gastrectomy for gastric cancer patients. Methods: A retrospective cohort study was performed. Inclusion criteria: (1) 18 to 75 years old; (2) gastric cancer proved by preoperative gastroscopy, CT and pathological results and tumor was suitable for D2 radical distal gastrectomy; (3) postoperative pathological diagnosis stage was T1-4aN0-3M0 (according to the AJCC-7th TNM tumor stage), and the margin was negative; (4) Eastern Cooperative Oncology Group (ECOG) physical status score <2 points, and American Association of Anesthesiologists (ASA) grade 1 to 3; (5) no mental illness; (6) able to answer questionnaires independently; (7) patients agreed to undergo laparoscopic distal gastrectomy and signed an informed consent. Exclusion criteria: (1) patients with severe chronic diseases and American Association of Anesthesiologists (ASA) grade >3; (2) patients with other malignant tumors; (3) patients suffered from serious mental diseases; (4) patients received neoadjuvant chemotherapy or immunotherapy. According to the above criteria, clinical data of 200 patients who underwent laparoscopic distal gastrectomy at the Department of General Surgery of the First Affiliated Hospital of Army Medical University from January 2016 to December 2019 were collected. Of the 200 patients, 108 underwent uncut Roux-en-Y anastomosis and 92 underwent Billroth II with Braun anastomosis. The general data, intraoperative and postoperative conditions, complications, and endoscopic evaluation 1 year after the surgery were compared. Besides, the quality of life of two groups was also compared using the Chinese version of the European Organization For Research and Treatment of Cancer (EORTC) quality of life questionnaire-Core 30 (QLQ-C30) and quality of life questionnaire-stomach 22 (QLQ-STO22). Results: There were no significant differences in baseline data between the two groups (all P >0.05). All the 200 patients successfully underwent laparoscopic distal gastrectomy without intraoperative complications, conversion to open surgery or perioperative death. There were no significant differences between two groups in operative time, intraoperative blood loss, postoperative complications, time to flatus, time to removal of gastric tube, time to liquid diet, time to removal of drainage tube or length of postoperative hospital stay (all P >0.05). Endoscopic evaluation was conducted 1 year after surgery. Compared to Billroth II with Braun group, the uncut Roux-en-Y group had a significantly lower incidences of gastric stasis [19.8% (17/86) vs. 37.0% (27/73), χ(2)=11.199, P =0.024], gastritis [11.6% (10/86) vs. 34.2% (25/73), χ(2)=20.892, P <0.001] and bile reflux [1.2% (1/86) vs. 28.8% (21/73), χ(2)=25.237, P <0.001], and the differences were statistically significant. The EORTC questionnaire was performed 1 year after surgery, there were no significant differences in the scores of QLQ-C30 scale between the two groups (all P >0.05), while the scores of QLQ-STO22 showed that, compared to the Billroth II with Braun group, the uncut Roux-en-Y group had a lower pain score (median: 8.3 vs. 16.7, Z =-2.342, P =0.019) and reflux score (median: 0 vs 5.6, Z =-2.284, P =0.022), and the differences were statistically significant (all P <0.05), indicating milder symptoms. Conclusion: The uncut Roux-en-Y anastomosis is safe and reliable in laparoscopic distal gastrectomy, which can reduce the incidences of gastric stasis, gastritis and bile reflux, and improve the quality of life of patients after surgery.

Herein, the convenient one-step electrochemical bromination of glycals using Bu 4 NBr as the brominating source under metal-catalyst-free and oxidant-free reaction conditions was described. A series of 2-bromoglycals bearing different electron-withdrawing or electron-donating protective groups were successfully synthesized in moderate to excellent yields. The coupling of tri- O -benzyl-2-bromogalactal with phenylacetylene, potassium phenyltrifluoroborate, or a 6-OH acceptor was achieved to afford 2C-branched carbohydrates and disaccharides via Sonogashira coupling, Suzuki coupling, and Ferrier rearrangement reactions with high efficiency. The radical trapping and cyclic voltammetry experiments indicated that bromine radicals may be involved in the reaction process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Luo, Liu, Li, Xiong and Ye.)

Cornusdiridoid A-F (1-6), six unusual cornuside-morroniside secoiridoid dimers, and their possible new biogenetic precursor, 3″,5″-dehydroxycornuside (7), together with four known secoiridoids (8-11), were obtained from the fruits of Cornus officinalis. Their structures were elucidated on the basis of various spectroscopic and chemical methods. A plausible biosynthetic pathway of compounds 1-11 was proposed. The α-glucosidase inhibitory, antioxidant and anti-inflammatory activities of these isolates were evaluated. Some of them emerged out as potent antidiabetic, anti-inflammatory and free radical scavenging agents. Molecular docking was also carried out for antidiabetic target α-glucosidase to investigate the possible binding modes of the most potent α-glucosidase inhibitor, vincosamide (9). These results revealed that the secoiridoids from C. officinalis fruits may be served as new potential antidiabetic agents to prevent and treat type 2 diabetes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Carbohydrates play essential roles in various physiological and pathological processes. Trifluoromethylated compounds have wide applications in the field of medicinal chemistry. Herein, we report a practical and efficient trifluoromethylation of glycals by an electrochemical approach using CF 3 SO 2 Na as the trifluoromethyl source and MnBr 2 as the redox mediator. A variety of trifluoromethylated glycals bearing different protective groups are obtained in 60-90% yields with high regioselectivity. The successful capture of a CF 3 radical indicates that a radical mechanism is involved in this reaction.

Glycans have been hot topics in recent years due to their exhibition of numerous biological activities. However, the heterogeneity of their natural source and the complexity of their chemical synthesis impede the progress in their biological research. Thus, the development of glycan assembly strategies to acquire plenty of structurally well-defined glycans is an important issue in carbohydrate chemistry. In this review, the latest advances in glycan assembly strategies from concepts to their applications in carbohydrate synthesis, including chemical and enzymatic/chemo-enzymatic approaches, as well as solution-phase and solid-phase/tag-assisted synthesis, are summarized. Furthermore, the automated glycan assembly techniques are also outlined., (© 2021 The Chemical Society of Japan & Wiley-VCH GmbH.)

A new glycosylation method promoted by visible light with 3,5-dimethoxyphenyl glycoside as the donor was developed. This protocol delivers both O -glycosides and N -glycosides in moderate to excellent yields using a wide range of O -nucleophiles and nucleobases as the glycosyl acceptors.

Rapid diagnosis and vaccine development are critical to prevent the threat posed by viruses. However, rapid tests, such as colloidal gold assays, yield false-negative results due to the low quantities of viruses; moreover, conventional virus purification, including ultracentrifugation and nanofiltration, is multistep and time-consuming, which limits laboratory research and commercial development of viral vaccines. A rapid virus enrichment and purification technique will improve clinical diagnosis sensitivity and simplify vaccine production. Hence, we developed the surface-glycosylated microbeads (glycobeads) featuring chemically synthetic glycoclusters and reversible linkers to selectively capture the influenza virus. The surface plasmon resonance (SPR) evaluation indicated broad spectrum affinity of S -linked glycosides to various influenza viruses. The magnetic glycobeads were integrated into clinical rapid diagnosis, leading to a 30-fold lower limit of detection. Additionally, the captured viruses can be released under physiological conditions, delivering purified viruses with >50% recovery and without decreasing their native infectivity. Notably, this glycobead platform will facilitate the sensitive detection and continuous one-step purification of the target virus that contributes to future vaccine production.

Bergenin, which is isolated from Bergenia species, exhibits various pharmacological properties. In the search for new types of immunosuppressants, a series of bergenin derivatives were designed and synthesized, and their immunosuppressive effects were evaluated by the CCK-8 assay. The experimental data demonstrated that compounds 7 and 13 showed the strongest inhibition effects on mouse splenocyte proliferation (IC 50 = 3.52 and 5.39 μM, respectively). Further studies revealed that the inhibitory effect may come from the suppression of both IFN-γ and IL-4 cytokines. Alkylated derivatives of bergenin with n -hexyl and n -heptyl on the two phenolic hydroxyl groups showed better inhibitory activities. The hydrophobicity of bergenin derivatives, the configuration of the 4-OH in bergenin, and the ability to form hydrogen bonds of the substituents on the C -4 position are important to the immunosuppressive activity. This work proved that the modifications of bergenin may represent a new route to the discovery of a new class of immunosuppressive agents., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associates with transforming growth factor β-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators., (© 2021 The Authors.)

Globo H is a tumor-associated carbohydrate antigen (TACA), which serves as a valuable target for antitumor vaccine or cancer immunotherapies. However, most TACAs are T-cell-independent, and they cannot induce powerful immune response due to their poor immunogenicity. To address this problem, herein, several Globo H analogues with modification on the N -acyl group were prepared through a preactivation-based glycosylation strategy from the non-reducing end to the reducing end. These modified Globo H derivatives were then conjugated with carrier protein CRM197 to form glycoconjugates as anticancer vaccine candidates, which were used in combination with adjuvant glycolipid C34 for immunological studies. The immunological effects of these synthetic vaccine candidates were evaluated on Balb/c mice. The results showed that the fluorine-modified N -acyl Globo H conjugates can induce higher titers of IgG antibodies that can recognize the naturally occurring Globo H antigen on the surface of cancer cells and can eliminate cancer cells in the presence of a complement, indicating the potential of these synthetic glycoconjugates as anticancer vaccine candidates., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A pair of undescribed enantiomers, (±) ficusflavonid A (1a/1b), along with five known analogues, were isolated from the roots of Ficus hirta. Their structures were determined by the analysis of extensive spectroscopic data (including UV, IR, HRESIMS and NMR). Two enantiomers (1a and 1b) were successfully separated by chiral chromatographic column and their absolute configurations were assigned by the comparison of experimental and calculated ECD data. The cytotoxicity of all the isolates against HeLa, MCF-7, HepG2 and H460 cell lines were evaluated by MTT assay. Among them, 4 suppressed the proliferation of HeLa cells with the IC 50 value of 28.88 μM. Furthermore, the apoptotic effect of 4 on HeLa cells and the level of several crucial proteins in AKT/MAPKs signaling pathways were analyzed by flow cytometer and western blot assay. As a result, 4 induced HeLa cell apoptosis in a dose dependent manner and significantly increased the protein levels of p-JNK and p-p38, whereas distinctly reduced the expression of p-AKT, and p-ERK. Thus, compound 4 might induce HeLa cells apoptosis via MAPK and AKT signaling pathways, which could be considered as a potential leading compound for the development of anticancer drugs., (Copyright © 2021. Published by Elsevier Ltd.)

Two new compounds, triacremoniate (1) and dietziamide C (2) along with known compounds β-Adenosine (3) and acrepyrone A (4) were obtained from the mangrove-derived fungus Acremonium citrinum. MMF4. Their structures were unambiguously determined by extensive spectroscopic methods, including UV, IR, HRESIMS and NMR. Triacremoniate (1) can promote apoptosis of HeLa cells by increasing the PARP cleavage and the phosphorylation of JNK and p38., (Copyright © 2020. Published by Elsevier B.V.)

A series of novel pyrano[2, 3-d]trizaole compounds were synthesized and their α-glucosidase inhibitory activities were evaluated by in vitro enzyme assay. The experimental data demonstrated that compound 10f showed up to 10-fold higher inhibition (IC 50 74.0 ± 1.3 μmol·L -1 ) than acarbose. The molecular docking revealed that compound 10f could bind to α-glucosidase via the hydrophobic, π-π stacking, and hydrogen bonding interactions. The results may benefit further structural modifications to find new and potent α-glucosidase inhibitors., (Copyright © 2020 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Carbohydrates play important roles in life science, but their synthesis is always hampered by their complicated chemical structures. Scientists have never stopped trying to solve the problem of glycan synthesis from various aspects. Here a brief overview of recent progress in glycan synthesis, including chemical approaches, chemoenzymatic approaches, and automated synthesis, will be discussed, focusing on the efficiency of new glycosylation methods, the stereoselectivity of coupled products, and their applications in the assembly of complex glycan chains., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We report a novel and highly stereoselective electro-2-deoxyglycosylation from glycals. This method features excellent stereoselectivity, scope, and functional-group tolerance. This process can also be applied to the modification of a wide range of natural products and drugs. Furthermore, a scalable synthesis of glycosylated podophyllotoxin and a one-pot trisaccharide synthesis through iterative electroglycosylations were achieved., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR + ) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2 , and FGFR2 , and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA , or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in AKT1, RAS , and AURKA -have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR + metastatic breast cancer. This article is highlighted in the In This Issue feature, p. 1079 ., (©2020 American Association for Cancer Research.)

A novel transformation from rhamnose-type C -glycosides to 2-cyclopentenones is described. With the promotion of fluoroboric acid, C -glycosides underwent ring opening and subsequent Nazarov cyclization to afford 2-cyclopentenones in good to excellent yields. The solvent and the concentration of acid are crucial to the yield of this transformation.

In a groundwater plant, removal of iron, manganese, and ammonia nitrogen was performed via a purification process using a filter column at a low temperature (5-6℃). Iron, manganese and ammonia [Fe(Ⅱ) 0-19.26 mg·L -1 , Mn(Ⅱ) 0.52-2.05 mg·L -1 , and NH 4 + -N 0.37-2.59 mg·L -1 ] were analyzed to explore the ammonia nitrogen removal efficiency under different iron and manganese concentrations. The results showed that when the concentration of manganese in the inlet water was maintained at approximately 0.6 mg·L -1 and the concentration of ferrous iron in the inlet water was increased, with the increase of iron oxides in the filter layer, the ratio of ammonia nitrogen removed by adsorption of iron oxides increased, while the ratio of ammonia nitrogen removed by nitrification will decreased and adsorption preceded nitrification. When the concentration of ferrous iron in the water was maintained at approximately 8 mg·L -1 and 11 mg·L -1 , and the concentration of manganese in the water was increased, the proportion of ammonia nitrogen removed by adsorption did not increase with the increase of manganese oxide, and the removal route of ammonia nitrogen hardly changed. This is because less manganese oxides were formed 20 cm before the filter layer, which had little effect on the ammonia nitrogen adsorbed in this range. The production area of manganese oxides was concentrated below 20 cm of the filter layer, and most ammonia nitrogen was removed by adsorption and nitrification before this area, and the manganese oxides in this area did not adsorb ammonia nitrogen.

The C-glycosylation of C-nucleophiles including allyltrimethylsilane, silyl enol ethers and phenols with N-(glycosyloxy)acetamides as glycosyl donors has been realized. This protocol provides a convenient and practical route for the synthesis of alkyl C-glycosides and aryl 2-deoxy-β-C-glycosides under mild reaction conditions.

Aberrant activation of mitogenic signaling pathways in cancer promotes growth and proliferation of cells by activating mTOR and S6 phosphorylation, and D-cyclin kinases and Rb phosphorylation, respectively. Correspondingly, inhibition of phosphorylation of both Rb and S6 is required for robust anti-tumor efficacy of drugs that inhibit cell signaling. The best-established mechanism of mTOR activation in cancer is via PI3K/Akt signaling, but mTOR activity can also be stimulated by CDK4 and PIM kinases. In this study, we show that the CDK4/6 inhibitor abemaciclib inhibits PIM kinase and S6 phosphorylation in cancer cells and concurrent inhibition of PIM, CDK4, and CDK6 suppresses both S6 and Rb phosphorylation. TSC2 or PIK3CA mutations obviate the requirement for PIM kinase and circumvent the inhibition of S6 phosphorylation by abemaciclib. Combination with a PI3K inhibitor restored suppression of S6 phosphorylation and synergized to curtail cell growth. By combining abemaciclib with a PI3K inhibitor, three pathways (Akt, PIM, and CDK4) to mTOR activation are neutralized, suggesting a potential combination strategy for the treatment of PIK3CA -mutant ER+ breast cancer., Competing Interests: CONFLICTS OF INTEREST All authors are current or former employees and shareholders of Eli Lilly and Company.

Terminal α-2,6-sialylation of N-glycans is a humanized glycosylation that affects the properties and efficacy of therapeutic glycoproteins. Fc di-sialylation (a biantennary N-glycan with two α-2,6-linked sialic acids) of IgG antibodies imparts them with enhanced anti-inflammatory activity and other roles. However, the microheterogeneity of N-glycoforms presents a challenge for therapeutic development. Therefore, controlled sialylation has drawn considerable attention, but direct access to well-defined di-sialylated antibodies remains limited. Herein, a one-pot three-enzyme protocol was developed by engineering a bacterial sialyltransferase to facilitate the modification of therapeutic antibodies with N-acetylneuraminic acid or its derivatives towards optimized glycosylation. To overcome the low proficiency of bacterial sialyltransferase in antibody remodeling, the Photobacterium sp. JT-ISH-224 α-2,6-sialyltransferase (Psp2,6ST) was genetically engineered by terminal truncation and site-directed mutagenesis based on its protein crystal structure. With the optimized reaction conditions and using activity-based screening of various Psp2,6ST variants, a truncated mutant Psp2,6ST (111-511)-His6 A235M/A366G was shown to effectively improve the catalytic efficiency of antibody di-sialylation. Herceptin and the donor substrate promiscuity allow the introduction of bioorthogonal modifications of N-acetylneuraminic acid into antibodies for site-specific conjugation. 2-AB hydrophilic interaction chromatography analysis of the released N-glycans and intact mass characterization confirmed the high di-sialylation of Herceptin via the optimized one-pot three-enzyme reaction. This study established a versatile enzymatic approach for producing highly di-sialylated IgG antibodies. It provides new insights into engineering bacterial sialyltransferase for adaptation to the enzymatic glycoengineering of therapeutic antibodies and the glycosite-specific conjugation of antibodies.

In a groundwater plant we carried out a process operation test of biological removal of iron and manganese nitrification coupled with completely autotrophic ammonium removal over nitrite (CANON) (Fe(Ⅱ) 2.91-6.35 mg·L -1 , Mn(Ⅱ) 0.47-0.98 mg·L -1 , NH 4 + -N 1.15-2.26 mg·L -1 ) at low temperature (6-8℃), to explore the effects of filter speed and water quality on ammonia nitrogen removal. The results showed that the mature low-temperature biological filter column, which had been out of service for one month, was cultured for 40 days at a filtration rate of 2 m·h -1 and successfully started. In this process, when the water inlet concentration remained the same, the improved filter speed would reduce the efficiency of ammonia nitrogen capture by the filter column, increase the concentration of ammonia nitrogen in the depth of the filter layer, and improve the efficiency of ammonia nitrogen ions capture by anaerobic ammonia oxidation bacteria (AnAOB) in the depth of the filter layer, so that the ammonia nitrogen removed by CANON in the water increased, while the ammonia nitrogen removed by nitrification decreased. When the filter speed remained unchanged, the concentration of ammonia nitrogen in water was increased to make the ammonia nitrogen with higher concentration enter the filter layer, which increased the concentration of ammonia nitrogen in the zone where ammonia nitrogen and nitrous nitrogen coexist, and improved the net catching efficiency of AnAOB on ammonia nitrogen ions in the filter layer, thus resulting in an increase in ammonia nitrogen removed by CANON.

Corni Fructus, also known as the fruit of Cornus officinalis Sieb. et Zucc., has long been used as a traditional Chinese medicine and is widely consumed as a nutritional food in the form of function drink and wine. Recently, Corni Fructus has attracted considerable interest because of its anti-diabetic effects. A systematic phytochemical investigation of Corni Fructus was performed to find anti-diabetic components, which led to the isolation of 10 unreported iridoid glycosides, cornusdiglycosides A-J (1-8, 9a/9b and 10a/10b). Their chemical structures were determined through spectroscopic analysis (ultraviolet [UV], infrared [IR], high-resolution electrospray ionisation mass spectroscopy [HRESIMS], one-dimensional [1D] and two-dimensional [2D] nuclear magnetic resonance [NMR]). Such morroniside-type diglycosides were first reported from natural sources, and all isolates were evaluated for α-glucosidase inhibitory activity. The results showed that all compounds (1-10) exhibited α-glucosidase (from Saccharomyces cerevisiae) inhibitory activities with IC 50 values ranging from 78.9 ± 4.09 to 162.2 ± 9.17 μM, whereas acarbose, the positive control, displayed α-glucosidase inhibitory activity with IC 50 value of 118.9 ± 7.89 μM., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Three prokaryotic predator strains, BL9 T , BL10 and BL28, were isolated with Vibrio alginolyticus from coastal seawater of PR China. Cells of the strains were Gram-negative, vibrioid-shaped and motile with a single sheathed flagellum (25-28 nm wide). Cells were around 0.3×0.5-1.0 µm in size. The three strains were obligate predators that exhibited a biphasic life cycle: a free-swimming attack phase and an intraperiplasmic growth phase within the prey. Bdelloplasts were formed. NaCl was required for growth. Optimum growth occurred at ~37 °C, with 2-4 % (w/v) NaCl and at pH 7.0-8.0. The results of phylogenetic analyses based on 16S rRNA gene sequences indicated that the three strains shared 99.9 % similarity to each other, were affiliated with the genus Halobacteriovorax in the class Oligoflexia , and represented the same new species. Strain BL9 T (=MCCC 1K03527 T =JCM 32962 T ) was designated as the type strain. Genome sequencing of strain BL9 T revealed a genome size of 3.14 Mb and a G+C content of 35.8 mol%. The estimated digital DNA-DNA hybridization (dDDH) values and the whole genome average nucleotide identity (gANI) values between the genome of strain BL9 T and those of Bdellovibrionales and Bacteriovoracales were 12.5-19 and 63.49-76.15 %, respectively. On the basis of life cycle features, results of physiological analyses, gANI data and dDDH data, strain BL9 T represents a new species within the genus Halobacteriovorax , for which the name Halobacteriovoraxvibrionivorans sp. nov. is proposed.

Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform-selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A-selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo , persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition-associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A-selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent., (©2019 American Association for Cancer Research.)