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Objective: To analyze the similarity between Mongolian medicine prescriptions included in the 2020 edition of the Pharmacopoeia of the People’s Republic of China(hereinafter referred to as the Chinese Pharmacopoeia) and Tibetan medicinal compounds according to the Drug Standards of the Ministry of Public Health of the People’s Republic of China: Tibetan Medicine (Volume I)(hereinafter referred to as the Ministerial Standards). Methods: A comparative analysis was conducted between Mongolian medicine prescriptions contained in the Chinese Pharmacopoeiaand the corresponding Tibetan medicinal compounds included in the Ministerial Standardsusing Jaccard similarity coefficients and Hellinger distance algorithms across three dimensions: composition, shared drug dosage ratio, and efficacy. Different weights were applied to calculate the comprehensive similarity between the formulas. Simultaneously, we collated and verified the original source literature, and determined the era of composition for each formula. Results: The overall similarity between the Mongolian medicine prescriptions from the Chinese Pharmacopoeiaand the Tibetan medicinal compounds from the Ministerial Standardswas over 50%. Notably, the composite similarity for the pairings Sanwei Jili San and Sanwei Jili Tangsan, as well as Wuwei Qingzhuo San and Shiliu Anzhi Jinghua San, exceeded 90%. Additionally, six sets of formulas achieved a similarity of over 75%. Literature research has revealed that all 13 sets of formulas first appeared in Tibetan medical literature and were long-standing practices in Tibetan medicine clinics, significantly predating their initial documentation in Mongolian medical literature. Conclusion: The 13 sets of Mongolian medicine prescriptions originated from Tibetan medicinal compounds. Throughout their evolution, the sets adhered to the principles of similar origins and/or properties and effects, leading to the emergence of both commonly used and alternative items. Nevertheless, the efficacy of the formulas has remained highly consistent. The phenomenon of ingredient substitution in the formulas could be attributed to various factors, such as resource availability and cognitive differences among inheritance schools. This study has important implications for further comparative research on content quantification and pharmacological activity. Such research could uncover new medicinal varieties, fostering the sustainable development of Tibetan and Mongolian medicine.

Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.

Social interaction and communication are evolutionary conserved behaviours that are developed in mammals to establish partner cognition. Deficit in sociability has been represented in human patients and animal models of neurodevelopmental disorders, which are connected with genetic variants of synaptic glutamate receptors and associated PDZ-binding proteins. However, it remains elusive how these key proteins are specialized in the cellular level for the initial social behaviour during postnatal developmental stage. Here we identify a hippocampal CA3 specifically expressed PDZ scaffold protein Lnx1 required for initial social behaviour. Through gene targeting we find that Lnx1 deficiency led to a hippocampal subregional disorder in neuronal activity and social memory impairments for partner discrimination observed in juvenile mice which also show cognitive defects in adult stage. We further demonstrate that Lnx1 deletion causes NMDA receptor (NMDAR) hypofunction and this is attributable to decreased GluN2B expression in PSD compartment and disruption of the Lnx1–NMDAR–EphB2 complex. Specific restoration of Lnx1 or EphB2 protein in the CA3 area of Lnx1−/−mice rescues the defective synaptic function and social memory. These findings thus reveal crucial roles of postsynaptic NMDAR multiprotein complex that regulates the formation of initial social memory during the adolescent period.

ABSTRACTThe present study was focused on comparison of four typical fungicides in ginseng field to evaluate the impact of the different fungicides on the soil bacterial and fungal communities’ composition and diversity by using high-throughput sequencing. Five treatments were designed comprising carbendazim (D), dimethyl disulfide (E), dazomet (M), calcium cyanamide (S), and control (C). The application of fungicide obviously altered the distribution of dominant fungal and bacterial communities and remarkably decreased the diversity (1099-763 and 6457-2245). The most abundant Proteobacteriaobviously degenerate in fungicide-treated soil and minimum in E (0.09%) compared to control (25.72%). The relative abundance of Acidobacteriawas reduced from 27.76 (C) to 7.14% after applying fungicide and minimum in E. The phylum Actinobacteriaare both decomposers of organic matter and enemies of soil-borne pathogens, elevated from 11.62 to 51.54% and are high in E. The fungi community mainly distributed into Ascomycotathat enriched from 66.09 to 88.21% and highin M and E (88.21 and 85.10%), and Basidiomycotareduced from 21.13 to 3.23% and low in M and E (5.27 and 3.23%). Overall, environmentally related fungicides decreased the diversity and altered the composition of bacterial and fungal communities, highest sensitivity present in dimethyl disulfide-treated soil.

Heavy cycle oil (HCO) is difficult to be converted into gasoline via fluid catalytic cracking (FCC) or hydrotreating. Abundant polycyclic aromatic hydrocarbons in HCO lead to condensation coke and high H2consumption. To efficiently convert HCO, in this work, HCO was selectively hydrogenated first and then cracked in an FCC unit. For the ideal molecular structure of naphthenoaromatics cracking after HCO selective hydrogenation, tetralin-type naphthenoaromatics were the desired products by the FCC test of model compounds. The effect of hydrogenation extent on structural composition was analyzed to confirm the optimal hydrogenation extent of HCO. The catalytic cracking results of hydro-HCO (Hy-HCO) indicated that the research octane number of FCC gasoline from selective hydrogenation is up to 96.5. Compared with HCO, the conversion and gasoline yield increased significantly, and the yields of heavy oil and coke decreased. Finally, the FCC operation conditions of Hy-HCO were investigated to enhance cracking efficiency.

This study aimed to identify the neuroanatomical substrates and white matter connectivity in children with autism spectrum disorder (ASD) and the association between gray matter and structural connectivity. A total of 36 children including patients with ASD and healthy controls between 6 and 15 years of age were enrolled in this study. High-resolution structural MRI and functional MRI were performed and analyzed using voxel-based morphometry and tract-based spatial statistics. The relationship between gray matter volume and structural connectivity was generated using Pearson correlation analysis. Voxel-based morphometry analysis showed significantly reduced areas of gray matter in the left cerebellum. Tract-based spatial statistics analysis showed white matter abnormalities in several distinct clusters within the right inferior frontal gyrus (opercular part), the left inferior parietal lobule, and the right mentary motor area. Neither ASD nor healthy controls showed a significant correlation between gray matter volume and white matter integrity. Our study confirmed the presence of several structural and regional abnormalities in ASD children. These findings suggest that there are significant differences in some brain regions in children with autism relative to healthy children, but no association between them.

Alkali-activated slag materials are known for their high chloride penetration resistance. This makes them potentially applicable as repair systems for damaged steel-reinforced concrete structures, which are exposed to chloride attack. For this purpose, the influence of the activator composition, i.e. the SiO2 and Na2O concentration of the alkaline solution on a) the compressive strength, b) shrinkage and mass change and c) the resistance against chloride penetration of four alkali-activated slag mortars (AASM) were studied. An ordinary Portland cement-based mortar was used as the reference sample. Increasing SiO2 and Na2O concentrations increased the strength, shrinkage and mass loss of the AASMs. The resistance of the mortars against chloride penetration was evaluated using the non-steady-state migration coefficient Dnssm obtained from NT BUILD 492. The results indicate that the Dnssm is related to differences in the pore solution of the AASMs rather than to differences in their microstructure. An upcoming study of the authors is going to evaluate this hypothesis by the accelerated chloride penetration (diffusion) test.

Molecular dynamics modeling of complex biological systems is limited by finite simulation time. The simulations are often trapped close to local energy minima separated by high energy barriers. Here, we introduce Hamiltonian replica exchange (H-REMD) with torsional flattening in the Binding Energy Distribution Analysis Method (BEDAM), to reduce energy barriers along torsional degrees of freedom and accelerate sampling of intramolecular degrees of freedom relevant to protein–ligand binding. The method is tested on a standard benchmark (T4 Lysozyme/L99A/p-xylene complex) and on a library of HIV-1 integrase complexes derived from the SAMPL4 blind challenge. We applied the torsional flattening strategy to 26 of the 53 known binders to the HIV Integrase LEDGF site found to have a binding energy landscape funneled toward the crystal structure. We show that our approach samples the conformational space more efficiently than the original method without flattening when starting from a poorly docked pose with incorrect ligand dihedral angle conformations. In these unfavorable cases convergence to a binding pose within 2–3 Å from the crystallographic pose is obtained within a few nanoseconds of the Hamiltonian replica exchange simulation. We found that torsional flattening is insufficient in cases where trapping is due to factors other than torsional energy, such as the formation of incorrect intramolecular hydrogen bonds and stacking. Work is in progress to generalize the approach to handle these cases and thereby make it more widely applicable.

BACKGROUND:The study aimed to compare the tolerability and efficacy of gefitinib combined with chemotherapy agents versuschemotherapy alone for the treatment of epidermal growth factor receptor (EGFR)–mutated lung adenocarcinoma in heavily pretreated patients. METHODS:The study was designed as a matched-pair case-control investigation to minimize intergroup heterogeneity. Patients were stratified into gefitinib plus chemotherapy and chemotherapy alone groups with matching for sex, age, ECOG performance status, progress-free survival (PFS) from previous EGFR tyrosine kinase inhibitor treatment, EGFR mutation types, and tumor metastasis status. RESULTS:Sixty-six patients were selected from our database using the matched-pair method. The median age was 61 years (95% confidence interval, 57-65 years). During a follow-up period of 14.5 months on average, the overall response rates of the gefitinib-integrated and chemotherapy alone groups were 9.1% and 6.5%, respectively (P> .05), whereas the corresponding disease-control rates were 39.4% and 30.3%, respectively (P> .05). No statistically significant differences in PFS (median, 4.2 vs3.3 months; P= .06) and overall survival (median, 10.4 vs7.9 months; P= .44) were observed between two groups. The 6-month survival rates of the gefitinib-integrated and chemotherapy alone groups were 21.2% and 12.1%, respectively (P< .05). Side effects were mild, and all treatments were well tolerated. CONCLUSIONS:Our results indicated that gefitinib-integrated therapy offered a trend to better PFS and an improved 6-month survival rate in heavily pretreated patients with metastatic EGFR-mutated lung adenocarcinoma. All treatments were well tolerated. Future prospective studies are warranted to confirm our findings.

RNA hairpin loops are one of the most abundant secondary structure elements and participate in RNA folding and protein-RNA recognition. To characterize the free energy surface of RNA hairpin folding at an atomic level, we calculated the potential of mean force (PMF) as a function of the end-to-end distance, by using umbrella sampling simulations in explicit solvent. Two RNA hairpins containing tetraloop cUUCGg and cUUUUg are studied with AMBER ff99 and CHARMM27 force fields. Experimentally, the UUCG hairpin is known to be significantly more stable than UUUU. In this study, the calculations using AMBER force field give a qualitatively correct description for the folding of two RNA hairpins, as the calculated PMF confirms the global stability of the folded structures and the resulting relative folding free energy is in quantitative agreement with the experimental result. The hairpin stabilities are also correctly differentiated by the more rapid molecular mechanics-Poisson Boltzmann-surface area approach, but the relative free energy estimated from this method is overestimated. The free energy profile shows that the native state basin and the unfolded state plateau are separated by a wide shoulder region, which samples a variety of native-like structures with frayed terminal basepair. The calculated PMF lacks major barriers that are expected near the transition regions, and this is attributed to the limitation of the 1-D reaction coordinate. The PMF results are compared with other studies of small RNA hairpins using kinetics method and coarse grained models. The two RNA hairpins described by CHARMM27 are significantly more deformable than those represented by AMBER. Compared with the AMBER results, the CHARMM27 calculated ΔGfoldfor the UUUU tetraloop is in better agreement with the experimental results. However, the CHARMM27 calculation does not confirm the global stability of the experimental UUCG structure; instead, the extended conformations are predicted to be thermodynamically stable in solution. This finding is further supported by separate unrestrained CHARMM27 simulations, in which the UUCG hairpin unfolds spontaneously within 10 ns. The instability of the UUCG hairpin originates from the loop region, and propagates to the stem. The results of this study provide a molecular picture of RNA hairpin unfolding and reveal problems in the force field descriptions for the conformational energy of certain RNA hairpin.

A series of molecular dynamics (MD) simulations was performed to elucidate the thermodynamic basis for the relative stabilities of hairpin, duplex, and single stranded forms of the 5‘-CGC(UUUU)GCG-3‘ oligonucleotide. According to a recent NMR study this sequence exhibits dynamic conformational equilibrium in aqueous solution in the vicinity of room temperature. Free energy calculations using the molecular mechanics-Poisson Boltzmann-surface area (MM-PB/SA) approach support a shift in the conformational equilibrium from duplex to hairpin as the temperature is increased from 276 to 300 K, in agreement with the NMR results. The effect of added salt on the relative stabilities of RNA conformers is also reproduced by our calculations. The calculated H° for the equilibrium between hairpin and single stranded forms is estimated to be −23.4 kcal/mol, in reasonable agreement with experimental values. Our results reveal that the conformational equilibrium strongly depends on the solute entropy and the electrostatic interactions modulated by added salt. Simulations of hairpin loop conducted at two different temperatures converged to the same lowest energy loop conformation. This conformer is stabilized by favorable van der Waals interactions as a result of U5-U6-U7 base stacking, a hydrogen bond between the U4 base and the phosphate linking U6 and U7, and hydrogen bonds involving the 2‘OH groups at U4 and U6. However, the sugar pucker of the four uridines in the lowest energy conformer is different from that reported by a NMR study. While the NMR study found that U5 and U7 adopt the C2‘-endo conformation, the simulation results suggests that overall the structure with the U5 and U7 in the C3‘-endo conformation is thermodynamically more stable than the structure containing the C2‘-endo pucker by approximately 8 kcal/mol. Calculations based on the MM-PB/SA scheme show that although the electrostatic solvation free energy favors the C2‘-endo conformation for the U5 and U7 riboses, it is offset by the less favorable intramolecular electrostatic and van der Waals energies. To enhance the conformational sampling, a replica exchange molecular dynamics (REMD) simulation was conducted in a generalized Born (GB) continuum solvent for the hairpin loop. This simulation indicates that the stable loop structure observed in the explicit solvent simulations corresponds to the free energy minimum. It also reveals that while the U4, U5, and U6 sugar rings are predominantly in the C3‘-endo conformation, there is considerable variation in the sugar pucker of the U7 ribose ring.

According to experimental data, binding of the Cu2+ ions destabilizes the native state of β2-microglobulin (β2m). The partial unfolding of the protein was generally considered an early step toward fibril formation in dialysis-related amyloidosis. Recent NMR studies have suggested that the destabilization of the protein might be achieved through increased flexibility upon Cu2+ binding. However, the molecular mechanism of destabilization due to Cu2+, its role in amyloid formation, and the relative contributions of different potential copper-binding sites remain unclear. To elucidate the effect of ion ligation at atomic detail, a series of molecular dynamics simulations were carried out on apo- and Cu2+-β2m systems in explicit aqueous solutions, with varying numbers of bound ions. Simulations at elevated temperatures (360K) provide detailed pictures for the process of Cu2+-binding-induced destabilization of the native structure at the nanosecond timescale, which are in agreement with experiments. Conformational transitions toward partially unfolded states were observed in protein solutions containing bound copper ions at His-31 and His-51, which is marked by an increase in the protein vibrational entropy, with TΔS(vibr) ranging from 30 to 69 kcal/mol. The binding of Cu2+ perturbs the secondary structure and the hydrogen bonding pattern disrupts the native hydrophobic contacts in the neighboring segments, which include the β-strand D2 and part of the β-strand E, B, and C and results in greater exposure of the D-E loop and the B-C loop to the water environment. Analysis of the MD trajectories suggests that the changes in the hydrophobic environment near the copper-binding sites lower the barrier of conformational transition and stabilize the more disordered conformation. The results also indicate that the binding of Cu2+ at His-13 has little effect on the conformational stability, whereas the copper-binding site His-31, and to a lesser extent His-51, are primarily responsible for the observed changes in the protein conformation and dynamics.

Pseudoginsenoside-F11(PF11), an ocotillol type saponin isolated from Panax quinquefoliumL., has been shown to antagonize the behavioral actions of morphine. Biochemical experiments revealed that PF11could inhibit diprenorphine (DIP) binding with an IC50of ∼6.1 μM and reduced the binding potency of morphine in Chinese hamster ovary (CHO)-μ cells. Furthermore, PF11significantly attenuated morphine-stimulated 35SGTPγS binding in a dose dependent manner, and strongly decreased the efficacy of morphine to inhibit intracellular cAMP production. In addition, PF11pretreatment could also significantly inhibit naloxone induced cAMP overshoot in the morphine-pretreated cells. However, PF11per sehad no effect on either 35SGTPγS binding or intracellular cAMP accumulation. These data suggested that PF11antagonized the morphine stimulated opioid receptor signalling directly at the cellular level.

Synaptic associativity, a feature of Hebbian plasticity wherein coactivation of two inputs onto the same neuron produces synergistic actions on postsynaptic activity, is a primary cellular correlate of associative learning. However, whether and how synaptic associativity are implemented into context-dependent relapse of extinguished memory (i.e. fear renewal) is unknown. Here, using an auditory fear conditioning paradigm in mice, we show that fear renewal is determined by the associativity between convergent inputs from the auditory cortex (ACx) and ventral hippocampus (vHPC) onto the lateral amygdala (LA) that reactivate ensembles engaged during learning. Fear renewal enhances synaptic strengths of both ACx to LA and the previously unknown vHPC to LA monosynaptic inputs. While inactivating either of the afferents abolishes fear renewal, optogenetic activation of their input associativity in the LA recapitulates fear renewal. Thus, input associativity underlies fear memory renewal.

Motor learning and striatal neuronal function in mice are promoted by the acid-sensing channel ASIC1a.

Various types of ultra sharp Si microtips and multitips with carbon-clading films were fabricated by microwave plasma chemical vapor deposition (MPCVD). The radii of these Si tips prepared by bias assisted carburization (BAC) can be reduced below 300 Å under a low deposition temperature (<550°C). Field emission characterization was performed in a high vacuum environment. With an applied anode voltage of 1100 V, emission currents of 169 µA, 198 µA, and 385 µA can be achieved from an array of 50×50 BAC-clad Si monotips, Si multitips via high bias, and Si multitips via the Ar presputtering technique, respectively. Both the auger electron spectroscopy (AES) and X-ray photo-electron spectroscopy (XPS) studies of the C 1 s peak suggest that the BAC-cladding is more likely to be a carbon-rich SiC layer or a SiC layer mixed with a small amount of diamond nuclei. This BAC-carbon can be used as an effective nucleation layer for further diamond nuclei. Due to the low field emission, low temperature, and large area growth capability, the sharp BAC-clad Si multitip field emitter arrays are attractive for flat panel display applications.