Bifunctional Mesoporous Zirconium Phosphonates for Delivery of Nucleic Acids

The bifunctional mesoporous zirconium phosphonates (ZrBFs) were synthesized through surfactant-assisted co-condensation of ZrCl₄ with two different phosphonic acids, both 1-phosphomethylproline (H₃PMP) and 1,4-bis­(phosphomethyl)­piperazine (BPMP), in a one-pot procedure. The l-proline group of H₃PMP and piperazine group of BPMP in the frameworks endow ZrBFs with pH-controllable release function and high cell penetration capability, which was derived from the reversible protonation–deprotonation of l-proline groups and piperazine groups on the mesoporous walls under different pH values (pH sensitivity) as well as further functionalization with biological modifiers via the carboxyls in l-proline groups on the outer surface (functionalizability), respectively. ZrBFs, possessing cationic frameworks once formed, exhibit high payload for salmon sperm DNA as model nucleic acid owing to strong electrostatic attraction between them. On the basis of pH-sensitive ZrBFs carriers and assisted by lag-time films coating, the time- and pH-controlled oral colon-targeted nucleic acid delivery systems have been developed, which can carry most of the loaded salmon sperm DNA to the colon under dual control, time control and pH value control. Furthermore, salmon sperm DNA can remain intact during delivery, as evidenced by the fact that the released salmon sperm DNA in the pH transition release experiment still retain its structural integrity and native conformation. Also, fluorescence spectra demonstrate that ZrBFs can be further functionalized with a cell-penetrating peptide of octaarginine (R8) via the carboxyls in l-proline groups of H₃PMP on the outer surface using a coupling agent, which will enhance the penetration capability of ZrBFs through biomembranes. ZrBFs have a potential application as a new kind of carrier in oral delivery of nucleic acids targeting the colon for gene therapy of colon-related diseases due to their unique bifunctionality

DataSheet1_Efficacy and safety of tirzepatide in patients with type 2 diabetes: A systematic review and meta-analysis.DOCX

Purpose: A systematic review and meta-analysis was conducted to combine the data available from clinical trials and evaluate the clinical efficacy and safety of tirzepatide in people with type 2 diabetes (T2D).Methods: We systematically searched the MEDLINE, Embase, Cochrane Library, and clinical trials registries (https://clinicaltrials.gov) up to 25 March 2022 for randomized controlled trials (RCTs) that compared tirzepatide with placebo or active hypoglycemic drugs in subjects with T2D. Heterogeneity was judged by the I2 value and Cochran’s Q test. The randomized effects model was adopted to calculate risk ratios and weighted mean differences (WMDs). The primary outcome was the change from baseline in HbA1c levels. Secondary efficacy endpoints were fasting serum glucose (FSG), change of body weight, blood pressure, fasting lipid profiles, and safety indexes.Results: Six trials comprising 6,579 subjects (4,410 in the tirzepatide group and 2,054 in the control group) fulfilled the pre-specified criteria and were included in the study. Tirzepatide treatment resulted in reducing HbA1c (WMD: -1.07%; 95% confidence intervals [CIs]: −1.44, −0.56), FSG (WMD, −21.50 mg/dl; 95% CI: −34.44, −8.56), body weight (WMD: −7.99 kg; 95% CI −11.36, −4.62), and blood pressure and ameliorated fasting lipid profiles, without increasing hypoglycemia, either as monotherapy or an add-on therapy. Tirzepatide increased the risk of gastrointestinal adverse events mainly in add-on therapy but not in terms of pancreatitis or cholelithiasis. Furthermore, tirzepatide presented a dose–response effect on the reduction in HbA1c and body weight and increase in nausea and vomiting.Conclusion: In patients with type 2 diabetes, tirzepatide shows superior blood glucose control and weight loss performance, without an increased risk of hypoglycemia.Systematic Review Registration: (https://www.crd.york.ac.uk/PROSPERO), identifier (CRD42022319442).</p

Table1_Efficacy and safety of tirzepatide in patients with type 2 diabetes: A systematic review and meta-analysis.DOC

Purpose: A systematic review and meta-analysis was conducted to combine the data available from clinical trials and evaluate the clinical efficacy and safety of tirzepatide in people with type 2 diabetes (T2D).Methods: We systematically searched the MEDLINE, Embase, Cochrane Library, and clinical trials registries (https://clinicaltrials.gov) up to 25 March 2022 for randomized controlled trials (RCTs) that compared tirzepatide with placebo or active hypoglycemic drugs in subjects with T2D. Heterogeneity was judged by the I2 value and Cochran’s Q test. The randomized effects model was adopted to calculate risk ratios and weighted mean differences (WMDs). The primary outcome was the change from baseline in HbA1c levels. Secondary efficacy endpoints were fasting serum glucose (FSG), change of body weight, blood pressure, fasting lipid profiles, and safety indexes.Results: Six trials comprising 6,579 subjects (4,410 in the tirzepatide group and 2,054 in the control group) fulfilled the pre-specified criteria and were included in the study. Tirzepatide treatment resulted in reducing HbA1c (WMD: -1.07%; 95% confidence intervals [CIs]: −1.44, −0.56), FSG (WMD, −21.50 mg/dl; 95% CI: −34.44, −8.56), body weight (WMD: −7.99 kg; 95% CI −11.36, −4.62), and blood pressure and ameliorated fasting lipid profiles, without increasing hypoglycemia, either as monotherapy or an add-on therapy. Tirzepatide increased the risk of gastrointestinal adverse events mainly in add-on therapy but not in terms of pancreatitis or cholelithiasis. Furthermore, tirzepatide presented a dose–response effect on the reduction in HbA1c and body weight and increase in nausea and vomiting.Conclusion: In patients with type 2 diabetes, tirzepatide shows superior blood glucose control and weight loss performance, without an increased risk of hypoglycemia.Systematic Review Registration: (https://www.crd.york.ac.uk/PROSPERO), identifier (CRD42022319442).</p

Identifying Individuals with Antisocial Personality Disorder Using Resting-State fMRI

<div><p>Antisocial personality disorder (ASPD) is closely connected to criminal behavior. A better understanding of functional connectivity in the brains of ASPD patients will help to explain abnormal behavioral syndromes and to perform objective diagnoses of ASPD. In this study we designed an exploratory data-driven classifier based on machine learning to investigate changes in functional connectivity in the brains of patients with ASPD using resting state functional magnetic resonance imaging (fMRI) data in 32 subjects with ASPD and 35 controls. The results showed that the classifier achieved satisfactory performance (86.57% accuracy, 77.14% sensitivity and 96.88% specificity) and could extract stabile information regarding functional connectivity that could be used to discriminate ASPD individuals from normal controls. More importantly, we found that the greatest change in the ASPD subjects was uncoupling between the default mode network and the attention network. Moreover, the precuneus, superior parietal gyrus and cerebellum exhibited high discriminative power in classification. A voxel-based morphometry analysis was performed and showed that the gray matter volumes in the parietal lobule and white matter volumes in the precuneus were abnormal in ASPD compared to controls. To our knowledge, this study was the first to use resting-state fMRI to identify abnormal functional connectivity in ASPD patients. These results not only demonstrated good performance of the proposed classifier, which can be used to improve the diagnosis of ASPD, but also elucidate the pathological mechanism of ASPD from a resting-state functional integration viewpoint.</p></div

Altered resting-state functional connectivity and networks in individuals with antisocial personality disorder.

<p>Altered resting-state functional connectivity and networks in individuals with antisocial personality disorder.</p

Brain regions with high discriminative power.

<p>Brain regions with high discriminative power.</p

Flow chart of the LDA+SVM classifier.

<p>Flow chart of the LDA+SVM classifier.</p

Photosynthetic and ascorbate-glutathione metabolism in the flag leaves as compared to spikes under drought stress of winter wheat (<i>Triticum aestivum</i> L.)

<div><p>Ascorbate-glutathione (ASA-GSH) cycle is a major pathway of H₂O₂ scavenging and an effective mechanism of detoxification in plants. The differences in photosynthesis, chlorophyll content (Chl), relative water content (RWC), antioxidants and antioxidative enzyme activities involved in ASA-GSH metabolism were measured between the flag leaves and spike bracts (glumes and lemmas) during grain filling under drought stress. The expression of <i>APX1</i>, <i>GRC1</i>, <i>DHAR</i>, <i>MDHAR</i>, <i>GPX1</i>, and <i>GS3</i> in ASA-GSH cycle was also measured. Compared with the flag leaves, the spike bracts exhibited stable net photosynthetic rate (<i>P</i>_<i>N</i>) and chlorophyll content (Chl), a lower accumulation of reactive oxygen species (ROS), and more enhanced percentages of antioxidant enzyme activities and key enzymes gene transcription levels involved in ASA-GSH metabolism during the grain-filling stage under drought conditions. This could be the reasonable explanation for the more stable photosynthetic capacity in spikes, and the glumes and lemmas senesced later than the flag leaves at the late grain-filling stage. Also, the function of ASA-GSH cycle could not be ignored in alleviating oxidative damage by scavenging more excess ROS in spikes under drought stress.</p></div

On the Nature of Support Effects of Metal Dioxides MO₂ (M = Ti, Zr, Hf, Ce, Th) in Single-Atom Gold Catalysts: Importance of Quantum Primogenic Effect

Fundamental understanding of support effects and metal–support interaction is critical in heterogeneous catalysis. In this work, theoretical investigations are carried out to study the nature of support effects of different tetravalent-metal dioxides of MO₂ (M = Ti, Zr, Ce, Hf, Th) in single-atom gold catalysts using density functional theory with on-site Coulomb interactions (DFT+U). The properties of gold adatom on the stoichiometric (MO₂) and reduced (MO_2–<i>x</i>) surfaces as well as CO adsorption on Au₁/MO₂ and Au₁/MO_2–<i>x</i> have been investigated systematically. Our calculations indicate that the fundamental <i>quantum primogenic effect</i> that causes the radial contraction and low orbital energies of 3d and 4f orbitals in these MO₂ oxides plays a vital role in determining the valence states and charge distribution of single-atom gold as well as the adsorption modes of CO on various MO₂ supports. We find that gold atoms supported on different surfaces exhibit oxidation states from Au­(−I) to Au(0) to Au­(I), depending on the nature of the metal oxide supports. The support-dependent oxidation states and charge distribution of Au can further influence the adsorption mode of CO. While CO adsorbs strongly on Au­(I) in Au₁/MO₂ (M = Ti, Ce) via Au–C σ-bonding, weaker adsorption occurs on Au(0) in Au₁/MO₂ (M = Zr, Hf, Th) with charge back-donation to CO 2π* antibonding orbitals. In contrast, at Au₁/MO_2–<i>x</i> of reduced support, CO adsorption is stronger for M = Zr, Hf, and Th than for M = Ce. These results provide essential understanding on the nature of support effects of metal oxides in heterogeneous catalysis