One-Dimensional Covalent Organic Framework-Based Multilevel Memristors for Neuromorphic Computing.

Memristors are essential components of neuromorphic systems that mimic the synaptic plasticity observed in biological neurons. In this study, a novel approach employing one-dimensional covalent organic framework (1D COF) films was explored to enhance the performance of memristors. The unique structural and electronic properties of two 1D COF films (COF-4,4'-methylenedianiline (MDA) and COF-4,4'-oxydianiline (ODA)) offer advantages for multilevel resistive switching, which is a key feature in neuromorphic computing applications. By further introducing a TiO2 layer on the COF-ODA film, a built-in electric field between the COF-TiO2 interfaces could be generated, demonstrating the feasibility of utilizing COFs as a platform for constructing memristors with tunable resistive states. The 1D nanochannels of these COF structures contributed to the efficient modulation of electrical conductance, enabling precise control over synaptic weights in neuromorphic circuits. This study also investigated the potential of these COF-based memristors to achieve energy-efficient and high-density memory devices.

Assessment and Feedback Control of Paving Quality of Earth-Rock Dam Based on OODA Loop.

Paving thickness and evenness are two key factors that affect the paving operation quality of earth-rock dams. However, in the recent study, both of the key factors characterising the paving quality were measured using finite point random sampling, which resulted in subjectivity in the detection and a lag in the feedback control. At the same time, the on-site control of the paving operation quality based on experience results in a poor and unreliable paving quality. To address the above issues, in this study, a novel assessment and feedback control framework for the paving operation quality based on the observe-orient-decide-act (OODA) loop is presented. First, in the observation module, a cellular automaton is used to convert the location of the bulldozer obtained by monitoring devices into the paving thickness of the levelling layer. Second, in the orient module, the learning automaton is used to update the state of the corresponding and surrounding cells. Third, in the decision module, an overall path planning method is developed to realise feedback control of the paving thickness and evenness. Finally, in the act module, the paving thickness and evenness of the entire work unit are calculated and compared to their control thresholds to determine whether to proceed with the next OODA loop. The experiments show that the proposed method can maintain the paving thickness less than the designed standard value and effectively prevent the occurrence of ultra-thick or ultra-thin phenomena. Furthermore, the paving evenness is improved by 21.5% as compared to that obtained with the conventional paving quality control method. The framework of the paving quality assessment and feedback control proposed in this paper has extensive popularisation and application value for the same paving construction scene.

Prospective study of pregnancy outcome between perceived stress and stress-related hormones.

AIM: To evaluate the relationship between physiological and psychological stress on pregnancy outcome in women undergoing in vitro fertilization-embryo transfer (IVF-ET) treatment. METHODS: Women undergoing the first IVF cycle were enrolled to complete the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS). Their blood samples were collected on the 3rd day of the menstrual cycle to measure 5-hydroxytryptamine, renin, norepinephrine, angiotensin II and cortisol. Salivary amylase was obtained on the embryo transfer day. RESULTS: Compared with normal women who came to the hospital for regular physical examination, the incidence of anxiety and depression was higher in women seeking for IVF treatment. After psychological intervention, the condition got improved and the incidence of anxiety and depression was 6.25% and 7.81% separately in these women. There were no significant differences between the anxiety scores in women with and without pregnancy. The depression scores did show some statistically differences, with higher scores in the nonpregnancy group. The level of 5-hydroxytryptamine, renin, norepinephrine and cortisol were not significantly different between the two groups, while angiotensin II and salivary amylase seemed to be negatively correlated with pregnancy outcome. Simultaneously, a positive correlation was found between angiotensin II and anxiety and depression scores. CONCLUSION: Depression during IVF has a negative impact on pregnancy outcome. The measurement of angiotensin II and salivary amylase might be reference index for the psychological status of patients during IVF-ET.

[The Pharmacokinetics, Pharmacodynamics and Bioequivalence of Insulin Aspart Produced by the United Laboratories Evaluated by Euglycemic Clamp Study].

OBJECTIVE: To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of a rapid-acting insulin analog-insulin aspart (the tested formulation) which was manufactured by The United Laboratories and to evaluate the bioequiavailability to the reference formulation (NovoRapid ®) produced by Novo Nordisk in Chinese healthy volunteers. METHODS: A total of 24 male healthy volunteers were recruited from February to April 2016 to participant in this before-after, single dose, and randomized crossover study. And the experimental observation was conducted on 2 test days respectively with a between-period from 7 to10 d. According to a random number table, the volunteers were divided into group A or B, group A was administrated with tested insulin aspart (IAsp) for the first time and reference NovoRapid ® for the second time and group B had the revered order differed from group A. The PK/PD of these insulin analogs were estimated by euglycemic clamp study. RESULTS: The relative biological effectiveness (reflecting gloucose-lowing effect) and bioavailability on behalf of plasma-drug concentration were 98.3±18.8% and 97.3%±8.3% respectively. For PK parameters, the 90% confidence interval ( CI) of peak plasma insulin concentration ( C max) and area under the curve of insulin aspart concentration from 0 to 10 hours ( AUC IAsp, 0-10 h) of IAsp were 88.8%-106% (equivalent range 70%-143%) and 94.0%-100% (equivalent range 80%-125%) respectively; for PD parameters, the 90% CI of the maximum glucose infusion rate ( GIR max) and AUC GIR, 0-10 h were 95.5%-113% (equivalent range 70%-143%) and 89.9%-104% (equivalent range 80%-125%) respectively, which indicated that IAsp and NovoRapid® was bioequivalent. One of the subjects discovered hyperuricemia without clinical symptoms and the rest had no clinically significant abnormalities in the safety indexes before and after the tests. No hypoglycemic events, allergic reactions, or local injection adverse reaction occurred in this trial. CONCLUSION: The tested IAsp has comparable relative bioavailability to the reference NovoRapid ®.

Efficient and Tunable Electroluminescence from In Situ Synthesized Perovskite Quantum Dots.

Semiconductor quantum dots (QDs) are among the most promising next-generation optoelectronic materials. QDs are generally obtained through either epitaxial or colloidal growth and carry the promise for solution-processed high-performance optoelectronic devices such as light-emitting diodes (LEDs), solar cells, etc. Herein, a straightforward approach to synthesize perovskite QDs and demonstrate their applications in efficient LEDs is reported. The perovskite QDs with controllable crystal sizes and properties are in situ synthesized through one-step spin-coating from perovskite precursor solutions followed by thermal annealing. These perovskite QDs feature size-dependent quantum confinement effect (with readily tunable emissions) and radiative monomolecular recombination. Despite the substantial structural inhomogeneity, the in situ generated perovskite QDs films emit narrow-bandwidth emission and high color stability due to efficient energy transfer between nanostructures that sweeps away the unfavorable disorder effects. Based on these materials, efficient LEDs with external quantum efficiencies up to 11.0% are realized. This makes the technologically appealing in situ approach promising for further development of state-of-the-art LED systems and other optoelectronic devices.

Prognostic value of repeated serum kisspeptin measurements in early first trimester pregnancy: a preliminary study.

RESEARCH QUESTION: What is the diagnostic value of maternal kisspeptin in patients with asymptomatic first-trimester pregnancies, and what is the prognostic significance of kisspeptin versus beta-HCG in early pregnancies. DESIGN: Case-control study in academic medical centres. Patients with no confounding co-morbidities who conceived by IVF and intracytoplasmic sperm injection were analysed. Maternal serum samples were assessed at the time of pregnancy testing. Women who achieved a positive pregnancy test were asked to take serum samples 4 days later. According to the follow-up results, patients who experienced biochemical pregnancy loss (n = 24) and early miscarriage (n = 21), and women who achieved a viable pregnancy (n = 28), were included in this study. Serum samples were collected to detect kisspeptin and beta-HCG, respectively. RESULTS: Single serum determinations of kisspeptin and beta-HCG were correlated with the different pregnancy outcomes. Women who experienced biochemical pregnancy loss showed lower kisspeptin levels than those in groups B and C. No significant difference, however, was observed at the time of pregnancy testing in women who had experienced early miscarriage and those who had achieved viable pregnancy. Sequential measurements of serum kisspeptin are not as effective as beta-HCG in determining pregnancy outcome. Increased kisspeptin level was associated with reduced miscarriage risk. CONCLUSION: Single serum measurement of kisspeptin is significantly altered in pregnant and non-pregnant women. However, it failed to discriminate between miscarriage and ongoing pregnancies in first-trimester pregnancy. Neither single nor sequential kisspeptin have higher diagnostic performance for miscarriage than beta-HCG in early stage.

[Quality Assessment of Euglycemic Glucose Clamp Test].

OBJECTIVE: To explorethe quality of euglycemic glucose clamptest performed in the West China Hospital from 2014 to 2017 and to evaluate whether the quality control indexes are suitable for the quality assessment of the clamp test. METHODS: The data collected from 80 euglycemic glucose clamp tests performed between 2014 and2017 were divided into 4 groups according to the coefficient of variation of the blood glucose concentrations (CVBG): group A (CVBG≤4.5%), group B (4.5% < CVBG≤5.0%), group C (5.0% < CVBG≤5.5%) and group D(CVBG > 5.5%).The differences in percentage of glucose excursion from target range (GEFTR), the duration of GEFTR, the area under curve (AUC) of GEFTR, the mean value of excursion from target glucose (GEFT) and the AUC of GEFT were calculated and compared. RESULTS: In group A, the mean value of CVBG was 3.75%. In group B, the mean value of CVBG was 4.76%. In group C, the mean value of CVBG was 5.28%. The median value of CVBG in group D was 6.07%. The percentage of GEFTR, the duration of GEFTR, the AUC of GEFTR, the mean value of GEFT and the AUC of GEFT in group A were all less than those of other groups (P < 0.05).For the same indexes, there were no significant differences between group B and C, while they were higher in group D compared with the other three groups. CVBG was positively correlated with other quality control indexes (correlation coefficient r was 0.770-0.805). Based on the cut-off point 5% of CVBG, the cut-off points of the percentage of GEFTR, the duration of GEFTR, the AUC of GEFTR, the mean value of GEFT and the AUC of GEFT were 5.8%, 14.6 min, 22.82 mg/dL×min, 3.23 mg/dL, 216.25 mg/dL×min/h respectively, with the sensitivity range from 79.3% to 100% and the specificity range from 74.5% to 89.7%.Combined with these indexes, 8.11% of euglycemic clamps were found to havepoor quality in group A, while 66.67% of euglycemic clamps showed acceptable quality in group C. CONCLUSIONS: The investigators should provide an estimation of the quality of the clamps when reporting the results of the insulin analogues' PK/PD characteristics using euglycemic clamps. CVBG less than 4.5% indicates a good quality, and the above-mentioned quality control indexes especially the AUC of GEFT(cut-off point: 216.25 mg·/dL×min/h) should be evaluated when CVBG is more than 4.5%.False high quality and false low quality euglycemic clamps will be detected and a more precise estimation of quality assessment should be made by the combination of these indexes.

Expression of GRIM-19 in unexplained recurrent spontaneous abortion and possible pathogenesis.

STUDY QUESTION: Is aberrant expression of gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) associated with unexplained recurrent spontaneous abortion (URSA)? SUMMARY ANSWER: GRIM-19 deficiency may regulate regulatory T cell/T helper 17 cell (Treg/Th17) balance partly through reactive oxygen species (ROS)-mammalian target of rapamycin (mTOR) signaling axis in URSA. WHAT IS KNOWN ALREADY: Immunological disorders may cause impaired maternal immune tolerance to the fetus and result in fetal rejection. The differentiation of Treg and Th17 cells is controlled by phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway. GRIM-19 participates in the immune response, but its role in URSA is largely unknown. STUDY DESIGN, SIZE, DURATION: The current study included 28 URSA patients and 30 non-pregnant healthy women. PARTICIPANTS/MATERIALS, SETTING, METHODS: The proportion of Treg and Th17 cells in peripheral blood of URSA patients and control subjects were assessed with flow cytometry. The expression of GRIM-19 in peripheral blood lymphocytes (PBLs) was measured with quantitative real-time PCR and western blot analysis. Furthermore, the ROS level in the PBLs of URSA patients and control subjects were assessed by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Then, Akt/mTOR expression in the PBLs was measured. Downregulation of GRIM-19 in Jurkat cells was performed by specific siRNA. Then, intracellular ROS production and the expression of p-mTOR, which is known to enhance Th17 differentiation and decrease Treg cell differentiation, were detected. Finally, N-acetylcysteine (NAC) was used to decrease the intracellular ROS level, and the expression of p-mTOR was measured. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of Treg cells was reduced in URSA patients, whereas the proportion of Th17 cells was increased. The expression of GRIM-19 was significantly lower in PBLs of URSA patients. Furthermore, there is a considerable increase in intracellular ROS production and a high level of p-Akt and p-mTOR expression in the PBLs of URSA patients compared with the control subjects. In parallel to this, downregulation of GRIM-19 in the Jurkat cells by siRNA results in an increased ROS production and an increased expression of p-mTOR. Importantly, the upregulation of p-mTOR resulting from GRIM-19 loss was significantly reversed in the cells treatment with ROS inhibitor N-acetyl-l-cysteine (NAC), indicating that ROS was indeed required for GRIM-19 depletion induced p-mTOR expression. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: A large number of researches have confirmed that the differentiation of Treg and Th17 cells is controlled by PI3K/Akt/mTOR signaling pathway. We have not shown the regulatory role of ROS and PI3K/Akt/mTOR in Treg and Th17 differentiation in this study. WIDER IMPLICATIONS OF THE FINDINGS: Our study has demonstrated that GRIM-19 deficiency may play a role in regulating Treg/Th17 balance partly through ROS-mTOR signaling axis in URSA. The present study offers a new perspective to the roles of GRIM-19 in immunoregulation. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (Grant numbers 81571511, 81701528, 81370711 and 30901603), the Shandong Provincial Natural Science Foundation (Grant numbers ZR2017PH052 and ZR2013HM090) and the Science Foundation of Qilu Hospital of Shandong University, Fundamental Research Funds of Shandong University (Grant numbers 2015QLQN50 and 2015QLMS24). The authors declare that there is no conflict of interest that could prejudice the impartiality of the present research.

Optimal control of orientation and entanglement for two dipole-dipole coupled quantum planar rotors.

Optimal control simulations are performed for orientation and entanglement of two dipole-dipole coupled identical quantum rotors. The rotors at various fixed separations lie on a model non-interacting plane with an applied control field. It is shown that optimal control of orientation or entanglement represents two contrasting control scenarios. In particular, the maximally oriented state (MOS) of the two rotors has a zero entanglement entropy and is readily attainable at all rotor separations. Whereas, the contrasting maximally entangled state (MES) has a zero orientation expectation value and is most conveniently attainable at small separations where the dipole-dipole coupling is strong. It is demonstrated that the peak orientation expectation value attained by the MOS at large separations exhibits a long time revival pattern due to the small energy splittings arising form the extremely weak dipole-dipole coupling between the degenerate product states of the two free rotors. Moreover, it is found that the peak entanglement entropy value attained by the MES remains largely unchanged as the two rotors are transported to large separations after turning off the control field. Finally, optimal control simulations of transition dynamics between the MOS and the MES reveal the intricate interplay between orientation and entanglement.

Multidrug resistance and tumor-initiating capacity of oral cancer stem cells.

PURPOSE: Recent studies in several tumors showed that presence of cancer stem like side population (SP) cells are responsible for chemotherapeutic drugs resistance and tumor relapse. In our present study, we have analyzed the role of SP cells in oral squamous cell carcinoma cell (OSCC) line OSCC-77. METHODS: The oral cancer cell line OSCC-77 was analyzed for the presence of SP cells by FACS using Hoechst 33342 dye exclusion method. Further the FACS-sorted SP and non-SP cells were subjected to drug resistance and sphere formation assays. RESULTS: We identified that the presence of SP cells in OSCC-77 cell line was 3.4%, which was reduced to 0.6% in the presence of verapamil, an inhibitor of ABC transporter. Furthermore, we showed that these SP cells were highly drug-resistant, had increased survival and were highly potent for self-renewal. Also, the clone formation efficiency of SP cells was significantly higher compared to non-SP cells (p<0.01). CONCLUSION: Our data suggest that cancer stem-like SP cells of OSCC-77 cell line contribute to multidrug resistance and are highly involved in tumor relapse. However, further characterization of SP cells at gene expression level and their signaling pathways might provide new insights into the development of novel anticancer drugs.

[Association of nt3434A→G Mutation in Mitochondrial DNA ND1 Gene with Diabetes Mellitus].

OBJECTIVES: To study the association of nt3434 A→G mutation in mitochondrial DNA NADH dehydrogenase 1 subunit (ND1) gene with diabetes mellitus. METHODS: PCR-RFLP was used to detect the nt3434 A→G variant of mtDNA ND1 gene in 216 diabetic patients and 203 healthy control individuals. Characteristics of mutation and clinical indicators in nt3434A→G family were analyzed. RESULTS: nt3434A→G mutation was detected in one diabetic patient but not found in NC group. This patient had low insulin secretion, low BMI, and elevated serum lactate acids. No significant difference was found in the mutation frequencies between these two groups. nt3434 A→G mutation was also detected in this patient's sister and daughter, who were normal glucose tolerance and had slightly elevated serum lactate acids levels. CONCLUSIONS: Further investigation would be helpful to answer whether nt3434A→G mutation of mitochondrial DNA ND1 gene is associated with an increased risk of diabetes.

The protective role of antifreeze protein 3 on the structure and function of mature mouse oocytes in vitrification.

Several studies have reported the oocyte damage in mice during vitrification; however, little has been known about the protective role that antifreeze protein 3 (Afp3) plays on their cellular structure and function during vitrification. In order to observe the extracellular cryo-protective role of Afp3, four groups were divided randomly. The observations were made for changes in cytoskeleton, expression of the related genes before and after vitrification, and also for changes in the in vitro developmental potential of oocytes. The outcomes were as follows: (i) microtubules, actin filaments and chromosomal integrity were more intact in the vitrification group supplemented with additional Afp3 compared to the vitrification group. In the fresh control group and the group with additional cryoprotectant containing ethylene glycol (EG), dimethyl sulfoxide (Me2SO) and sucrose, the organelles were more intact than the other two vitrification groups. (ii) Real-time PCR analysis revealed that the relative quantification of mitotic arrest deficient 2 (Mad2) and centromere protein E (Cenp-e) were significantly higher in the vitrification group with additional Afp3, the fresh control group and the one group with additional cryoprotectant, in comparison to the vitrification group. On the contrary, the expression of cold inducible RNA-binding protein (Cirbp) and kinesin-5 motor protein (Eg5) were up-regulated in the vitrification group compared to the remaining groups. (iii) The fertilization rate and the recovery rate in the fresh control group and the group with additional cryoprotectant were higher than the other two vitrification groups; furthermore, the recovery rate and the fertilization rate in the vitrification group with Afp3 were higher than the vitrification group. However, the blastocyst formation rate in all the four groups showed no statistical significance. In conclusion, Afp3 plays a positive role in the structure and function of mice oocytes in vitrification.

Comparative analysis of chlorine-resistant bacteria after chlorination and chloramination in drinking water treatment plants.

Chlorine-resistant bacteria (CRB) in drinking water treatment plants (DWTPs) jeopardize water quality and pose a potential risk to human health. However, the specific response of CRB to chlorination and chloramination remains uncharacterized. Therefore, we analyzed 16 S rRNA sequencing data from water samples before and after chlorination and chloramination taken between January and December 2020. Proteobacteria and Firmicutes dominated all finished water samples. After chloramination, Acinetobacter, Pseudomonas, Methylobacterium, Ralstonia, and Sphingomonas were the dominant CRB, whereas Ralstonia, Bacillus, Acinetobacter, Pseudomonas, and Enterococcus were prevalent after chlorination. Over 75% of the CRB e.g. Acinetobacter, Pseudomonas, Bacillus, and Enterococcus were shared between the chlorination and chloramination, involving potentially pathogens, such as Acinetobacter baumannii and Pseudomonas aeruginosa. Notably, certain genera such as Faecalibacterium, Geobacter, and Megasphaera were enriched as strong CRB after chloramination, whereas Vogesella, Flavobacterium, Thalassolituus, Pseudoalteromonas, and others were enriched after chlorination according to LEfSe analysis. The shared CRB correlated with temperature, pH, and turbidity, displaying a seasonal pattern with varying sensitivity to chlorination and chloramination in cold and warm seasons. These findings enhance our knowledge of the drinking water microbiome and microbial health risks, thus enabling better infectious disease control through enhanced disinfection strategies in DWTPs.

[Study on positive rate of blocking antibody in women with recurrent spontaneous abortion administered by route and frequency of paternal lymphocyte immunotherapy].

OBJECTIVE: To investigates factors affecting the positive rate of blocking antibody treated by paternal lymphocyte immunotherapy in patients with recurrent spontaneous abortion (RSA). METHODS: From January 2008 to August 2012, 326 RSA cases undergoing treatment in Infertility Center of Qilu Hospital were studied retrospectively. Those patients were divided into 2 groups randomly: 260 cases in intradermal injection group were administered via bilateral forearm intradermal injections for immunotherapy once 21 days, then the blocking antibody was determined after 2 (23 cases) , 3(73 cases), 4 (74 cases) , 5(90 cases) times respectively, while in subcutaneous injection group, the 66 cases were administered via subcutaneous injection once 21 days, the blocking antibody measured after 3 times; In both cases, the blocking antibody was all determined 2 weeks later. The positive rate of blocking antibodies and the rate of successful pregnancy was recorded, and then followed up after the blocking antibody turning positive. RESULTS: (1) Positive rate of blocking antibodies:the positive rate of blocking antibodies were 17% (4/23) , 58% (42/73), 72% (53/74) and 84% (76/90) in the 2, 3, 4, and 5 times of intradermal injection group, respectively (P < 0.05). In subcutaneous injection group, the positive rate of blocking antibodies was 38 % (25/66), which was significantly lower than that in group intradermal injection receiving 3 times immunotherapy (P < 0.05). (2) The rate of pregnancy:the 176 patients out of 200 patients were pregnant when antibody was positive after immunotherapy, with 71.6% (126/176) of patients gained successful pregnancy(the length of pregnancy more than 5 months). CONCLUSIONS: The route and frequency of administration of immunotherapy could influence the positive rate of blocking antibody. The rate of successful pregnancy will be increased after blocking antibody turning positive.

[The changes of gastrointestinal hormones GLP-1, PYY and ghrelin in patients with newly diagnosed type 2 diabetes mellitus].

OBJECTIVE: To study the changes of plasma glucagon-like peptide-1 (GLP-1), serum peptide-YY (PYY) and Ghrelin and their secretion functions in patients with newly diagnosed type 2 diabetes mellitus (T2DM). METHOD: A total of 102 subjects were enrolled, including 32 normal-glucose-tolerance controls (NGT) and 70 patients with newly diagnosed T2DM. Height, body mass, waist circumference (WC) and hip circumference were measured. The plasma lipids and 0 h, 1/2 h, 2 h plasma glucose, insulin (INS), GLP-1, serum PYY and Ghrelin in a standard meal test in each subject were detected, and body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index (ISI), homeostasis model assessment of beta cell function (HOMA-B) and early insulin secretion function index (DeltaI30/DeltaG30) were calculated. All these variables were compared between the two groups. RESULTS: Compared with those in NGT group, the WC, fasting plasma glucose (FPG), postprandial plasma glucose (2 h-PG), triglyceride (TG), HOMA-IR were significantly higher (P 0.05), while INS(30), HOMA-B, ISI, DeltaI30/DeltaG30 were significantly lower in T2DM group (P<0. 05). In addition, in T2DM group, 0 h, 1/2 h, 2 h plasma GLP-1 and serum PYY and the area under the curve (AUC) of GLP-1 (GLP-lAuc ) and PYY (PYYAc) in standard meal test were significantly lower (P<0. 05), but the serum Ghrelin and GhrelinA, were significantly higher (P<0. 05). Meanwhile, the secretory peak of GLP-1 and PYY after standard meal in T2DM patients all disappeared. In T2DM group, PYYAUC and TG were negatively correlated (P<0.05), the fasting serum Ghrelin level was negatively associated with total cholesterol (TC), and GhrelinAuc was positively associated with HOMA-B, but negatively with the low-density lipoprotein cholesterol (LDL-C) and FPG (P(<0. 05). CONCLUSION: Patients with newly diagnosed T2DM have decreased fasting and postprandial GLP-1 and PYY levels, along with changes of their secretion mode and increased levels of Ghrelin.

The evolution of bitter taste receptor gene in primates: Gene duplication and selection.

Bitter taste perception plays an important role in preventing animals from digesting poisonous and harmful substances. In primates, especially the Cercopithecidae species, most species feed on plants; thus, it is reasonable to speculate that most of the bitter taste receptor genes (T2Rs) of primates are under purifying selection to maintain the functional stability of bitter taste perception. Gene duplication has happened in T2Rs frequently, and what will be the fate of T2Rs copies is another question we are concerned about. To answer these questions, we selected the T2Rs of primates reported in another study and conducted corresponding selective pressure analyses to determine what kind of selective pressure was acting on them. Further, we carried out selective pressure analyses on gene copies and their corresponding ancestors by considering several possible situations. The results showed that among the 25 gene groups examined here, 15 groups are subject to purifying selection and others are under relaxed selection, with many positively selected sites detected. Gene copies existed in several groups, but only some groups (clade1_a1-b2, clade1_c-c2, clade1_d1-d3, clade1_f1-f2, T2R10, T2R13, and T2R42) have positively selected sites, inferring that they may have some relation to functional divergence. Taken together, T2Rs in primates are under diverse selective pressures, and most gene copies are subject to the same selective pressures. In such cases, the copies may be just to keep the function conservative, and more copies can increase the quantity of the bitter taste receptor, raise the efficiency of bitter substance recognition, and finally enhance the fitness of feeding during the evolutionary course of primates. This study can improve our understanding of T2Rs evolution in primates.

The Effect of BMI on Pharmacokinetic and Pharmacodynamic Parameters of Insulin Degludec: Results from an Euglycemic Glucose Clamp Study.

PURPOSE: This study evaluated the effect of body mass index (BMI) on pharmacokinetic (PK) and pharmacodynamic (PD) parameters of insulin degludec in healthy Chinese males, depending on an euglycemic glucose clamp study. METHODS: Sixty-five healthy male subjects were divided into four groups according to quartile of BMI value. Group A: BMI ≤ 20.7 kg/m2; group B: 20.7 < BMI ≤ 22.5 kg/m2; group C: 22.5 < BMI ≤ 23.6 kg/m2; group D: BMI > 23.6 kg/m2. Each volunteer received a single subcutaneous dose (0.4 U/kg) of insulin degludec and accepted a 24-h euglycemic glucose clamp study. The primary PK parameters were maximum observed drug concentration (Cmax) and the area under the curve (AUCINS) for the specified time intervals. The primary PD parameters were the time to the start of glucose infusion (Tonset), maximal glucose infusion rate (GIRmax) and area under the curve (AUCGIR) for the specified time intervals. The differences of these PK/PD parameters were compared among groups. RESULTS: Cmax and the AUC of insulin (0-6 h, 6-12 h and 0-24 h) were more than onefold higher in group A than those in groups B, C, D, and the concentration-time curve of group A was significantly shifted to the left compared with the other three groups. The GIRmax, total AUCGIR, and AUCGIR for each time interval were significantly higher in group A than those in other three groups. The proportion of AUCGIR in group A was the lowest proportion among four groups seen in the late stage. Multiple linear regression analysis showed that BMI was negatively correlated with AUCGIR,0-24 h. CONCLUSIONS: Insulin degludec in healthy Chinese male subjects with BMI ≤ 20.7 kg/m2 had a faster absorption, clearance, and a stronger glucose-lowering effect, but a steeper decrease of insulin action in the late stage after dosing.

A phase-I randomized euglycemic clamp study to demonstrate the pharmacokinetic and pharmacodynamic equivalence of an insulin degludec biosimilar (B01411) with the reference product in healthy Chinese volunteers.

BACKGROUND: B01411 is a biosimilar candidate manufactured by Jilin Huisheng Biopharmaceutical Co. Ltd for the reference insulin degludec (Tresiba) (IDeg). This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of the two IDeg products and to assess the PK/PD similarity of B01411 compared with the reference IDeg product. RESEARCH DESIGN & METHODS: A single-center, single-dose, randomized, crossover, open-labeled, phase I, euglycemic clamp study in healthy Chinese subjects to examine the bioequivalence of B01411 (0.4 U/kg) compared with the reference IDeg product. Blood samples were collected at a predefined time for the analysis of blood glucose (BG), IDeg, and C-peptide concentrations. The glucose infusion rate (GIR) was adjusted to maintain the BG at approximately 0.28 mmol/L below baseline throughout the clamp. RESULTS: Thirty-two subjects (20 males and 12 females) were enrolled, 31 of whom received both treatments. The 90% confidence intervals for the ratio of the least-squares geometric means for AUCIDeg,0-24 h, AUCGIR,0-24 h, IDegmax, and GIRmax were all in the range of 0.80-1.25. Only one adverse event of puncture site bruising occurred once in a subject in the B01411 group. CONCLUSION: B01411 exhibited a pharmacokinetic and pharmacodynamic similarity to the reference product. Both IDeg products were well tolerated. CLINICAL TRIAL REGISTRATION: http://www.chinadrugtrials.org.cn/index.html#. Identifier is CTR20192122.

Multifunctional Nanoparticles Codelivering Doxorubicin and Amorphous Calcium Carbonate Preloaded with Indocyanine Green for Enhanced Chemo-Photothermal Cancer Therapy.

Background: Multifunctional stimuli-responsive nanoparticles with photothermal-chemotherapy provided a powerful tool for improving the accuracy and efficiency in the treatment of malignant tumors. Methods: Herein, photosensitizer indocyanine green (ICG)-loaded amorphous calcium-carbonate (ICG@) nanoparticle was prepared by a gas diffusion reaction. Doxorubicin (DOX) and ICG@ were simultaneously encapsulated into poly(lactic-co-glycolic acid)-ss-chondroitin sulfate A (PSC) nanoparticles by a film hydration method. The obtained PSC/ICG@+DOX hybrid nanoparticles were characterized and evaluated by Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), transmission electron microscopy (TEM), and differential scanning calorimetry (DSC). The cellular uptake and cytotoxicity of PSC/ICG@+DOX nanoparticles were analyzed by confocal laser scanning microscopy (CLSM) and MTT assay in 4T1 cells. In vivo antitumor activity of the nanoparticles was evaluated in 4T1-bearing Balb/c mice. Results: PSC/ICG@+DOX nanoparticles were nearly spherical in shape by TEM observation, and the diameter was 407 nm determined by DLS. Owing to calcium carbonate and disulfide bond linked copolymer, PSC/ICG@+DOX nanoparticles exhibited pH and reduction-sensitive drug release. Further, PSC/ICG@+DOX nanoparticles showed an effective photothermal effect under near-infrared (NIR) laser irradiation, and improved cellular uptake and cytotoxicity in breast cancer 4T1 cells. Importantly, PSC/ICG@+DOX nanoparticles demonstrated the most effective suppression of tumor growth in orthotopic 4T1-bearing mice among the treatment groups. In contrast with single chemotherapy or photothermal therapy, chemo-photothermal treatment by PSC/ICG@+DOX nanoparticles synergistically inhibited the growth of 4T1 cells. Conclusion: This study demonstrated that PSC/ICG@+DOX nanoparticles with active targeting and stimuli-sensitivity would be a promising strategy to enhance chemo-photothermal cancer therapy.

Extended chloramination significantly enriched intracellular antibiotic resistance genes in drinking water treatment plants.

Chloramination and chlorination are both strong barriers that prevent the transmission of potential pathogens to humans through drinking water. However, the comparative effects of chloramination and chlorination on the occurrence of antibiotic resistance genes (ARGs) in drinking water treatment plants (DWTPs) remain unknown. Herein, the antibiotic resistome in water before and after chloramination or chlorination was analyzed through metagenomic sequencing and then verified through quantitative real-time polymerase chain reaction (qPCR). After the treatment of 90 min, chloramination led to higher enrichment of the total relative abundance of intracellular ARGs (iARGs) in water than chlorination, whereas chlorination facilitated the release of more extracellular ARGs (eARGs) than chloramination. According to redundancy and Pearson's analyses, the total concentration of the observed iARGs in the finished water exhibited a strong positive correlation with ammonium nitrogen (NH4+-N) concentration, presenting a linear upward trend with an increase in the NH4+-N concentration. This indicated that NH4+-N is a crucial driving factor for iARG accumulation during chloramination. iARG enrichment ceases if the duration of chloramination is shortened to 40 min, suggesting that shortening the duration would be a better strategy for controlling iARG enrichment in drinking water. These findings emphasized the potential risk of antibiotic resistance after extended chloramination, shedding light on the control of transmission of antibiotic-resistant bacteria through water by optimizing disinfection procedures in DWTPs.