THERMODYNAIMIC STUDY OF NUCLEIC ACIDS RECOGNITION BY AMINOGLYCOSIDES

ABSTRACT Since the origin of first aminoglycosides antibiotics, streptomycin, isolated by Selman Waksman about 60 years ago, a number of aminoglycosides antibiotics were discovered to treat different infections. Neomycin class aminoglycosides were found to originally target the A site 16S rRNA in the 30S subunit of the ribosome within the Gram-negative bacteria. In addition to its antibacterial effect, aminoglycosides were also found to binding to various other viral RNA structures such as TAR and RRE of HIV, Group I introns and hammerhead ribozyme, implying its potential to be used as antiviral reagent. Furthermore, previous studies in our laboratory discovered a new class of targets, triple helix nucleic acids for aminolgycosides. Aminoglycosides, especially neomycin, shows potent stabilization effect of poly(dA)2poly(dT), poly(rA)2poly(rU), short-mixed-base oligomers, an intramolecular 12-mer triplex, DNA/RNA hybrid duplexes/triplexes and even G-tetraplex. The binding infidelity of aminoglycosides induces a variety of problems such as drug resistance and adverse side effects, thereby diminishing their therapeutic application. Increase of aminoglycoside antibiotics binding selectivity has become imperative. Chemical derivatization, either modifying a specific functional group or conjugating them with other ligands, has developed quickly in the past decade to improve aminoglycosides selectivity and expand them for a new therapeutic application. Aminoglycosides dimer, intercalator-neomycin conjugate and minor groove binder-neomycin conjugate were synthesized and studied by our laboratory. Primary study showed that the binding selectivity was achieved, for example, a neomycin dimer favors an AT-rich duplex at nanomolar scale. However, in order to understand better the aminoglycosides binding selectivity and achieve the different therapeutic applications, a comprehensive picture of aminoglycosides binding to a variety of nucleic acids is a requirement. Unfortunately, this study is still in lack. This work considers the neomycin class aminoglycosides, especially neomycin which has the most amino groups (6) relative to other aminoglycosides. The binding to a broad range of nucleic acids will be considered, and these targets include single strand RNA, AT/GC rich duplexes, TAT DNA triplex oligomer and polymer, AU rich RNA duplex and triplex, hybrid duplexes, G-tetraplex, polydC intercalating tetraplex, and A site 16S rRNA. The common thread of those structures that neomycin favorably binds to lies in their propensity toward an A-type conformation. The more A like the conformation is, the more favorably neomycin binds to it. The complete thermodynamic and kinetic studies of aminoglycosides interaction with various nucleic acids were conducted mainly via techniques including UV thermal denaturation, circular dichroism, fluorescence, differential scanning calorimetry, isothermal titration calorimetry, and surface plasmon resonance

Study on the bearing characteristics of overrun hydraulic support under impact loading

In order to study the effects of stress change and adaptability of the overrun hydraulic stent under impact load, the rigid–flexible coupling numerical model of the stent is established using multi-body dynamics simulation software ADAMS. In the model, the stent is flexibilized using the HyperMesh module, and the column and jack are equivalently replaced with a spring damping system. By applying impact loads to different positions above the front roof beam of the stent, the dynamic response characteristics of the column and the articulation point are obtained at different positions with different strengths. The results show that when the impact load is applied to different positions of the front roof beam, the steady-state response force of the column shows an overall “M" distribution, and along the length direction of the roof beam, the steady-state response force of the column shows an upward trend, and the maximum steady-state response force of the column is 547 kN at point (1, 6); when the impact load is applied to both sides of the front roof beam, the response at the articulation point is greater, resulting in a higher maximum simple harmonic response at that articulation point. When the impact load acts on both sides of the front roof beam, the response of the articulation point is greater, with a maximum simple harmonic response coefficient of 0.75 and a maximum excitation response coefficient of 0.28; when the impact loads of different strengths act on the whole front roof beam, the force acting on the column and pin shaft at the articulation point will produce a large impact, reducing its adaptability. To address this, we can consider changing the top plate stress conditions using methods like high-pressure injection of water and control the gradual and slow release of the top plate stresses. The results of the study provide a reference for the structural strength design and reliability analysis of the hydraulic support, which is of practical significance and value for improving the safe mining of the coal mining face

Brain Activities Responding to Acupuncture at ST36 (zusanli) in Healthy Subjects: A Systematic Review and Meta-Analysis of Task-Based fMRI Studies

PurposeStomach 36 (ST36, zusanli) is one of the important acupoints in acupuncture. Despite clinical functional magnetic resonance imaging (fMRI) studies of ST36 acupuncture, the brain activities and the neural mechanism following acupuncture at ST36 remain unclear.MethodsLiterature searches were conducted on online databases, including MEDLINE, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang database, WeiPu database, and China Biology Medicine, for task-based fMRI studies of acupuncture at ST36 in healthy subjects. Brain regions activated by ST36 acupuncture were systematically evaluated and subjected to seed-based d mapping meta-analysis. Subgroup analysis was conducted on control procedures, manual acupuncture, electrical acupuncture (EA), and acupuncture-specific activations. Meta-regression analysis was performed to explore the effects of needle retention time on brain activities following ST36 acupuncture stimulation. The activated brain regions were further decoded and mapped on large-scale functional networks to further decipher the clinical relevance of acupuncturing at ST36.ResultsA total of sixteen studies, involving a total of 401 right-handed healthy participants, that satisfied the inclusion criteria were included in the present meta-analysis. Meta-analysis showed that acupuncturing on ST36 positively activates the opercular part of the right inferior frontal gyrus (IFG.R), left superior temporal gyrus (STG.L), and right median cingulate/paracingulate gyri (MCG.R) regions. Needle retention time in an acupuncture session positively correlates with the activation of the left olfactory cortex, as shown in meta-regression analysis. Subgroup analysis revealed that EA stimulation may be a source of heterogeneity in the pooled results. Functional network mappings showed that the activated areas were mapped to the auditory network and salience network. Further functional decoding analysis showed that acupuncture on ST36 was associated with pain, secondary somatosensory, sound and language processing, and mood regulation.ConclusionAcupuncture at ST36 in healthy individuals positively activates the opercular part of IFG.R, STG.L, and MCG.R. The left olfactory cortex may exhibit positive needle retention time-dependent activities. Our findings may have clinical implications for acupuncture in analgesia, language processing, and mood disorders.Systematic Review Registrationhttps://inplasy.com/inplasy-2021-12-0035

Prevalence of and risk factors for non-suicidal self-injury in rural China: Results from a nationwide survey in China

Background Non-suicidal self-injury (NSSI) is a highly prevalent and serious public health problem among adolescents worldwide. However, to date there were no studies assessing the prevalence of NSSI defined by suggested DSM-5 criteria among Chinese adolescents. We aimed to conduct a nationwide survey to explore the prevalence of and risk factors for NSSI among school-based adolescents in rural China. Methods A total sample of 15,623 adolescents in rural China were enrolled by using a multistage sampling method. Data was collected by self-report questionnaires including demographic characteristics, neglect, maltreatment, loneliness, resilience, social support and emotional management ability. NSSI was defined by suggested DSM-5 criteria, according to which the engagement in self-injury took place more than 5 times a year. Multinomial logistic regression models were used to estimate the association between risk factors and NSSI. Results There were 12.2% of adolescents (n = 1908) met the suggested DSM-5 criteria. Approximately 29% reported a history of NSSI at least once during the last year. Significant differences were found in several demographic factors including gender, ethnicity, grade, and family structure between adolescents with and without experiencing NSSI. The top three NSSI behaviors among adolescents with NSSI experience were hitting self, pinching, and pulling hair, with a prevalence rate of 16.7%, 14.1% and 11.2%, respectively. Female, Han ethnicity, fathers’ education level, neglect, maltreatment, loneliness, social support, suicidal behaviors and emotional management ability were significantly associated with NSSI by multivariate analysis. No significant relationship was found between resilience and risk of NSSI. Limitation The DSM-5 has proposed 6 groups of criteria for NSSI, we only used criteria on frequency given its more accepted feasibility and pragmatic application. Consequently, it may different from other prevalence that estimated by other criteria. Conclusion To the best of our knowledge, this is the first study reporting prevalence of NSSI defined by suggested DSM-5 criteria among adolescent in rural China. In comparison to finding from the similar samples of adolescents, Chinese rural adolescents seem to have a relative higher prevalence. The potential risk factors for NSSI include female, father's education, Han ethnicity, psychosocial factors and suicide behaviors. More evidence for further understanding of context of the occurrence, improving access to health care utilization, and identifying the role of psychosocial factors and family relationship, is needed for the prevention and management of NSSI.Published versio

Potential of Core-Collapse Supernova Neutrino Detection at JUNO

JUNO is an underground neutrino observatory under construction in Jiangmen, China. It uses 20kton liquid scintillator as target, which enables it to detect supernova burst neutrinos of a large statistics for the next galactic core-collapse supernova (CCSN) and also pre-supernova neutrinos from the nearby CCSN progenitors. All flavors of supernova burst neutrinos can be detected by JUNO via several interaction channels, including inverse beta decay, elastic scattering on electron and proton, interactions on C12 nuclei, etc. This retains the possibility for JUNO to reconstruct the energy spectra of supernova burst neutrinos of all flavors. The real time monitoring systems based on FPGA and DAQ are under development in JUNO, which allow prompt alert and trigger-less data acquisition of CCSN events. The alert performances of both monitoring systems have been thoroughly studied using simulations. Moreover, once a CCSN is tagged, the system can give fast characterizations, such as directionality and light curve

Detection of the Diffuse Supernova Neutrino Background with JUNO

As an underground multi-purpose neutrino detector with 20 kton liquid scintillator, Jiangmen Underground Neutrino Observatory (JUNO) is competitive with and complementary to the water-Cherenkov detectors on the search for the diffuse supernova neutrino background (DSNB). Typical supernova models predict 2-4 events per year within the optimal observation window in the JUNO detector. The dominant background is from the neutral-current (NC) interaction of atmospheric neutrinos with 12C nuclei, which surpasses the DSNB by more than one order of magnitude. We evaluated the systematic uncertainty of NC background from the spread of a variety of data-driven models and further developed a method to determine NC background within 15\% with {\it{in}} {\it{situ}} measurements after ten years of running. Besides, the NC-like backgrounds can be effectively suppressed by the intrinsic pulse-shape discrimination (PSD) capabilities of liquid scintillators. In this talk, I will present in detail the improvements on NC background uncertainty evaluation, PSD discriminator development, and finally, the potential of DSNB sensitivity in JUNO

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Estimation of Activation Energy of Desorption of n-Hexanol from Activated Carbons by the TPD Technique

Activated carbon and five kinds of metal-ion-substituted activated carbons, viz. Ag + -activated carbon, Cu 2+ -activated carbon, Fe 3+ -activated carbon, Ba 2+ -activated carbon and Ca 2+ -activated carbon, were prepared. A model for estimating the activation energy of desorption was established. Temperature-programmed desorption (TPD) experiments were conducted to measure the TPD curves of n-hexanol and hence estimate the activation energy for n-hexanol desorption from the various activated carbons. The results showed that the activation energies for n-hexanol desorption from the Ag + -activated carbon, the Cu 2+ -activated carbon and the Fe 3+ -activated carbon were higher than those from the unsubstituted activated carbon, the Ca 2+ -activated carbon and the Ba 2+ -activated carbon