Neutron scattering and neural-network quantum molecular dynamics investigation of the vibrations of ammonia along the solid-to-liquid transition.

Vibrational spectroscopy allows us to understand complex physical and chemical interactions of molecular crystals and liquids such as ammonia, which has recently emerged as a strong hydrogen fuel candidate to support a sustainable society. We report inelastic neutron scattering measurement of vibrational properties of ammonia along the solid-to-liquid phase transition with high enough resolution for direct comparisons to ab-initio simulations. Theoretical analysis reveals the essential role of nuclear quantum effects (NQEs) for correctly describing the intermolecular spectrum as well as high energy intramolecular N-H stretching modes. This is achieved by training neural network models using ab-initio path-integral molecular dynamics (PIMD) simulations, thereby encompassing large spatiotemporal trajectories required to resolve low energy dynamics while retaining NQEs. Our results not only establish the role of NQEs in ammonia but also provide general computational frameworks to study complex molecular systems with NQEs.

[Magnetic resonance imaging T2 mapping could reflect disease status in patients with dermatomyositis or polymyositis].

This study aimed to explore the value of magnetic resonance imaging (MRI) T2 mapping in the assessment of dermatomyositis (DM) and polymyositis (PM). Thirty-three confirmed cases (myosin group) and eight healthy volunteers (healthy control group) at the Department of Rheumatology and Immunology, the First Affiliated Hospital of Kunming Medical University, from October 2016 to December 2017, were collected and analyzed. Multiple parameters of the myosin group were quantified, including creatine kinase (CK), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complement C3, and complement C4. Disease status was evaluated using a panel of tools: myositis disease activity assessment tool-muscle (MDAAT-muscle), myositis disease activity assessment tool-whole (MDAAT-all), health assessment questionnaire (HAQ), medical outcomes study health survey short form-36 item (SF-36), hand muscle strength test (MMT-8) score, and MRI T2 mapping of muscle (22 muscles in the pelvis and thighs) T2 values. The results showed that in the myositis group, the measurements for CK, ESR, CRP, complement C3, and complement C4 were 457.2 (165.6, 1 229.2) IU/L, 20 (10, 42) mm/1h, 3.25 (2.38, 10.07) mg/L, 0.90 (0.83, 1.06) g/L, and 0.18 (0.14, 0.23) g/L, respectively. The scores for MMT-8, MDAAT-muscle, MDAAT-all, HAQ, and SF-36 were 57.12±16.23, 5.34 (4.00, 6.00), 34.63±12.62, 1.55 (0.66, 2.59), and 44.66±7.98, respectively. T2 values were significantly higher in all 22 muscles of the pelvis and thighs of patients with DM or PM compared with the healthy controls [(54.99±11.60)ms vs. (36.62±1.66)ms, P<0.001], with the most severe lesions in the satrorius, iliopsoas, piriformis, gluteus minimus, and gluteus medius muscles. The total muscle T2 value in the myositis group was positively correlated with CK, MDAAT-muscle, MDAAT-all, and HAQ (r=0.461, 0.506, 0.347, and 0.510, respectively, all P<0.05). There was a negative correlation between complement C4, SF-36, and MMT-8 scores (r=-0.424, -0.549, and -0.686, respectively, all P<0.05). Collectively, the findings from this study suggest that MRI T2 mapping can objectively reflect the disease status of DM and PM.

Partial cellular reprogramming stably restores the stemness of senescent epidermal stem cells.

OBJECTIVE: Adult stem cell senescence and exhaustion are important drivers of organismal age. Restored stem cell self-renewal has revealed novel therapeutic targets for decreasing the incidence of age-associated diseases (AADs) and prolonging the human health span. Transient ectopic expression of the reprogramming factors Oct3/4, Sox2, Klf4 and c-Myc (collectively known as OSKM) in somatic cells can induce partial cellular reprogramming and effectively ameliorate their age-associated hallmarks. However, how this form of rejuvenation is applied to senescent stem cells remains unknown. MATERIALS AND METHODS: The Integrin-α6highCD71high epidermal stem cells (ESCs) with low self-renewal ability were sorted by flow cytometry and then treated by the interrupted reprogramming induced by transient expression of OSKM. The ability of secondary clones' generation and self-proliferation in vitro, as well as stem cell marker p63, were detected to determine their self-renewal ability. Besides, gene and protein of epidermal cell markers were detected to determine whether their cell identities were retained. Finally, DNA methylation age (eAge) and DNA dehydroxymethylase/methyltransferase were analyzed to explore the alternation of their global DNA methylation pattern during this rejuvenation. RESULTS: The partial reprogramming restored the youthful self-renewal and proliferation in senescent ESCs, including larger secondary clone generation, higher expression of stem cell marker p63 and proliferation marker Ki67, and faster proliferation speed, in each case without abolishing epithelial cellular identity. Moreover, the rejuvenation of adult stem cells could be maintained for 2 weeks after reprogramming factor withdrawal, which was more stable than that of differentiated somatic cells. Additionally, we found that partial reprogramming counteracted the acceleration of eAge in senescent epidermal stem cells and DNA methyltransferase 1 (DNMT1) may play a crucial role in this process. CONCLUSIONS: Partial reprogramming has high therapeutic potential for reversing adult stem cell age, providing an advanced way to treat AADs.

[Analysis of the therapeutic efficacy and factors influencing sequential combination of nucleos(t)ide analogues with pegylated interferon alpha for 48~96 weeks in the treatment of patients with chronic hepatitis B].

Objective: To explore the therapeutic efficacy and factors influencing the sequential combination of nucleos(t)ide analogues (NAs) with pegylated interferon alpha (Peg-IFN-α) in the treatment of patients with chronic hepatitis B (CHB). Methods: 144 CHB cases with NAs treatment for more than 1 year, HBV DNA < 20 IU/ml, hepatitis B surface antigen (HBsAg) quantification < 3 000 IU/ml, treated with a sequential combination of Peg-IFN-α treatment for 48 to 96 weeks, and followed up were selected from the Fifth Medical Center of the PLA General Hospital between May 2018 and May 2020. Intention-to-treat analysis was used to measure the HBsAg clearance rate at 96 weeks. The Kaplan-Meier method was used to compute the cumulative HBsAg clearance rate at 96 weeks. Univariate and multivariate logistic regression were used to analyze the factors influencing HBsAg clearance at 48 weeks of sequential combination therapy. Univariate and multifactorial COX proportional hazard models were used to analyze the factors influencing HBsAg clearance following 96 weeks of prolonged PEG-IFN-α treatment. The receiver operating characteristic curve was used to assess the predictive value of factors influencing HBsAg clearance. A Mann-Whitney U test was used to compare the measurement data between groups. The count data was compared using the χ(2) test between groups. Results: 41 (28.47%) cases achieved HBsAg clearance at 48 weeks of sequential combination therapy. The HBsAg clearance rate at 96 weeks was 40.28% (58/144) by intention-to-treat analysis. The Kaplan-Meier method computed that the cumulative HBsAg clearance rate at 96 weeks was 68.90%. Multivariate logistic regression analysis showed that HBsAg quantification at baseline (OR = 0.090, 95%CI: 0.034-0.240, P < 0.001) and a 24-week drop in HBsAg level (OR = 7.788, 95%CI: 3.408-17.798, P < 0.001) were independent predictors of HBsAg clearance in CHB patients treated sequentially in combination with NAs and Peg-IFN-α for 48 weeks. Receiver operating characteristic curve analysis showed that the baseline HBsAg quantification [area under the receiver operating characteristic curve (AUC), 0.911, 95% CI: 0.852-0.952)] and 24-week drop in HBsAg level (AUC = 0.881, 95%CI: 0.814-0.930) had equally good predictive value for 48-week HBsAg clearance, but there was no statistically significant difference between the two (Z = 0.638, P = 0.523). The value of the combination of baseline HBsAg quantification and 24-week drop in HBsAg level (AUC = 0.981, 95%CI: 0.941-0.997) was superior to that of single baseline HBsAg quantification (Z = 3.017, P = 0.003) and 24-week drop in HBsAg level (Z = 3.214, P = 0.001) in predicting HBsAg clearance rate at 48 weeks. Multivariate COX proportional hazards model analysis showed that HBsAg quantification at 48 weeks (HR = 0.364, 95%CI: 0.176-0.752, P = 0.006) was an independent predictor of HBsAg clearance with a prolonged course to 96 weeks of Peg-IFN-α treatment. Conclusion: The HBsAg clearance rate can be accurately predicted with baseline HBsAg quantification combined with a 24-week drop in HBsAg level in patients with CHB who are treated with a sequential combination of NAs and Peg-IFN-α therapy for 48 weeks. Prolonging the course of Peg-IFN-α treatment can enhance the HBsAg clearance rate's capability. An independent predictor of HBsAg clearance is HBsAg quantification at 48 weeks of sequential combination therapy with a prolonged course of 96 weeks of Peg-IFN-α treatment.

[Early reduction of serum RANTES can predict HBsAg clearance in patients with chronic hepatitis B treated with nucleos(t)ide analogues combined with peginterferon alpha].

Objective: To observe the dynamic changes of serum RANTES during the treatment with nucleos(t)ide analogues combined with pegylated interferon alpha (peginterferon-α), and further analyze the predictive effect of RANTES on HBsAg clearance in patients with chronic hepatitis B. Methods: 98 cases of chronic hepatitis B with quantitative HBsAg < 3 000 IU/ml and HBV DNA < 20 IU/ml after≥1 year NAs treatment were enrolled. Among them, 26 cases continued to receive NAs monotherapy, 72 cases received NAs combined with pegylated interferon alpha therapy. The changes in RANTES during treatment were observed. The receiver operating characteristic curve was used to analyze the early changes of RANTES to predict the HBsAg clearance during 48 weeks. Results: During 48 weeks, 15 cases (20.83%) had achieved HBsAg clearance in combination group, while no patient had achieved HBsAg clearance in NAs group. The overall serum RANTES level had decreased from baseline in NAs and combination group. At week 48, in the combination group, the serum RANTES level was decreased more significantly in patients with HBsAg clearance than patients without. Further analysis showed that, in combination group, HBsAg clearance rate of patients with serum RANTES decreased at week 12 and 24 was higher than patients with elevated (29.17% vs. 4.17%, P = 0.014; 28.00% vs. 4.55%, P = 0.052), and quantitative HBsAg reduction was larger significantly [(1.49 ± 1.26) log(10)IU/ml vs. (0.73 ± 0.81) log(10)IU/ml, P = 0.017; (1.54 ± 1.27) log(10)IU/ml vs. (0.57 ± 0.56) log(10)IU/ml, P = 0.004]. Receiver operating characteristic curve analysis showed that the baseline quantitative HBsAg and the reduction in quantitative HBsAg and serum RANTES during the early period were predictors of HBsAg clearance after 48-week combination therapy. Furthermore, the combination of baseline quantitative HBsAg and 12 - or 24-week reduction of serum RANTES were better predictors of HBsAg clearance than that of baseline quantitative HBsAg combined with HBsAg decrease at week 12 or 24. The area under the receiver operating characteristic curve of the former was 0.925 and 0.939, while that of the latter was 0.909 and 0.929, respectively. Conclusion: Early reduction of serum RANTES at week 12 and 24 can predict HBsAg loss in CHB patients receiving addition of peginterferon-α to ongoing NAs Therapy, so serum RANTES could be one of the key immunological markers for predicting HBsAg clearance.

Simulation of Inelastic Neutron Scattering Spectra Directly from Molecular Dynamics Trajectories.

Inelastic neutron scattering (INS) is a widely used technique to study atomic and molecular vibrations. With the increasing complexity of materials and thus the INS spectra, being able to simulate the spectra from various atomistic models becomes an essential step and also a major bottleneck for INS data analysis. The conventional approach using density functional theory and lattice dynamics often falls short when the materials of interest are complex (e.g., defective, disordered, heterogeneous, amorphous, large-scale), for which molecular dynamics driven by an interatomic force field is a more common approach. In this paper, we demonstrate a method to directly convert molecular dynamics trajectories into simulated INS spectra, including not only fundamental but also higher order excitations. The results are compared with data collected on various representative samples from different neutron spectrometers. This development will open great opportunities by providing the key tool to perform in-depth analysis of INS data and to validate and optimize computer models.

Calculation of the Thermal Neutron Scattering Cross-Section of Solids Using OCLIMAX.

The thermal neutron scattering cross-section of a solid depends on the energy (or wavelength) of the incident neutrons. Devising a method to calculate the energy dependence from first principles, without the approximations built in the scattering theory, has been a major undertaking in nuclear engineering. Here, we demonstrate such a calculation method using the program OCLIMAX. Our approach eliminates various approximations and limitations involved in a regular calculation with the LEAPR module of NJOY code, and the results are compared with available experimental and theoretical data. It is also demonstrated how additional insight can be obtained from the calculated full dynamical structure factor. The results reported here show the great potential and excellent platform provided by OCLIMAX for future development in the study of neutron thermalization in solid materials for different applications.

Simulation of Inelastic Neutron Scattering Spectra Using OCLIMAX.

Studying the vibration of atoms is of fundamental importance and can provide critical insight for the understanding of materials behavior, such as structure and phase transition, thermodynamics, and chemical reactions. The atomic vibration can be probed using vibrational spectroscopy with various incident particles such as photons, neutrons, or electrons. A major challenge when applying these techniques is often how to interpret the vibrational spectra and how to make connections to the theory. To this end, methods that can simulate the spectra from atomistic models are highly desired. In this paper, we present a program developed for the simulation of inelastic neutron scattering spectra. It has many new and useful features that were not previously available and will greatly facilitate the analysis and understanding of inelastic neutron scattering data.

A sample holder for simultaneous Raman and neutron vibrational spectroscopy.

We have built a sample holder (called a center stick or sample stick) for performing simultaneous Raman and neutron vibrational spectroscopy on samples of material at the VISION neutron vibrational spectrometer of the Spallation Neutron Source at Oak Ridge National Laboratory. This equipment holds material samples in the neutron beam within the cryogenic environment of the VISION spectrometer, allowing for samples to be studied at temperatures as low as 5 K. It also provides the capability for gas to be loaded to or evacuated from the sample while it is loaded at VISION. The optical components for directing and filtering light are located within the cryogenic volume, in physical proximity to the sample. We describe the construction of this sample holder and discuss our first measurements of simultaneous Raman and neutron vibrational spectra. The samples that we report on were of 4-nitrophenol at a temperature of 20 K and of cryogenic hydrogen of a number of different orthohydrogen fractions.

[A real-world study of paritaprevir/ritonavir-ombitasvir combined with dasabuvir in the treatment of genotype 1b chronic hepatitis C].

Objective: To recognize the efficacy and safety of paritaprevir/ritonavir-ombitasvir combined with dasabuvir (OBV/PTV/RTV+DSV) in the treatment of genotype 1b chronic hepatitis C. Methods: Patients with genotype 1b chronic hepatitis C who were admitted to the People's Hospital of Henan Province, Huashan Hospital of Shanghai and the Fifth Medical Center of the General Hospital of the People's Liberation Army of China between November 2017 to August 2018 were enlisted. All patients received OBV/PTV/RTV+DSV antiviral therapy. HCV RNA levels were measured at baseline, weeks 1, 2, 3, 4, 8, 12, and 24, then 12 weeks, and 24 weeks after completion of treatment; patients' comorbidity, concomitant medications, and clinical adverse events were recorded. Results: 108 patients were enrolled in the study, with an average age of 49.1 years, 44 patients were male (40.8%), 96.3% (104/108) were newly diagnosed, and four patients had previous treatment history, of whom three were treated with IFN and one with IFN + DAA. Ninety-eight cases completed 12 weeks treatment and 89 cases were in follow up for 12 weeks, after discontinuation of the drug. Overall, 89 cases (100%) achieved SVR12.One patient treated with PR and DAA had HCV RNA level of 869175 IU/mL at 4 weeks of treatment, which was significantly higher than the baseline HCV RNA level (301776IU/ML), and was judged as failure of treatment; and follow-up was discontinued. Of all enrolled patients, 19 (17.6%) had underlying diseases and 15 (13.9%) had combined medications. During treatment, adverse events (AE) occurred in 11 patients (10.1%). The main adverse events were pruritus and elevated bilirubin. Conclusion: Combined antiviral therapy (OBV/PTV/RTV+DSV) of 12 weeks are highly effective with good safety profile in the treatment of Chinese patients with genotype 1b chronic hepatitis C.

Hydrogen release reactions of Al-based complex hydrides enhanced by vibrational dynamics and valences of metal cations.

Hydrogen release from Al-based complex hydrides composed of metal cation(s) and [AlH4]- was investigated using inelastic neutron scattering viewed from vibrational dynamics. The hydrogen release followed the softening of translational and [AlH4]- librational modes, which was enhanced by vibrational dynamics and the valence(s) of the metal cation(s).

Structures, Phase Transitions and Tricritical Behavior of the Hybrid Perovskite Methyl Ammonium Lead Iodide.

We have examined the crystal structures and structural phase transitions of the deuterated, partially deuterated and hydrogenous organic-inorganic hybrid perovskite methyl ammonium lead iodide (MAPbI3) using time-of-flight neutron and synchrotron X-ray powder diffraction. Near 330 K the high temperature cubic phases transformed to a body-centered tetragonal phase. The variation of the order parameter Q for this transition scaled with temperature T as Q ∼ (Tc-T)ß, where Tc is the critical temperature and the exponent ß was close to », as predicted for a tricritical phase transition. However, we also observed coexistence of the cubic and tetragonal phases over a range of temperature in all cases, demonstrating that the phase transition was in fact first-order, although still very close to tricritical. Upon cooling further, all the tetragonal phases transformed into a low temperature orthorhombic phase around 160 K, again via a first-order phase transition. Based upon these results, we discuss the impact of the structural phase transitions upon photovoltaic performance of MAPbI3 based solar cells.

HCV-induced miR146a controls SOCS1/STAT3 and cytokine expression in monocytes to promote regulatory T-cell development.

Host innate and adaptive immune responses must be tightly regulated by an intricate balance between positive and negative signals to ensure their appropriate onset and termination while fighting pathogens and avoiding autoimmunity; persistent pathogens may usurp these regulatory machineries to dampen host immune responses for their persistence in vivo. Here, we demonstrate that miR146a is up-regulated in monocytes from hepatitis C virus (HCV)-infected individuals compared to control subjects. Interestingly, miR146a expression in monocytes without HCV infection increased, whereas its level in monocytes with HCV infection decreased, following Toll-like receptor (TLR) stimulation. This miR146a induction by HCV infection and differential response to TLR stimulation were recapitulated in vitro in monocytes co-cultured with hepatocytes with or without HCV infection. Importantly, inhibition of miR146a in monocytes from HCV-infected patients led to a decrease in IL-23, IL-10 and TGF-ß expressions through the induction of suppressor of cytokine signalling 1 (SOCS1) and the inhibition of signal transducer and activator transcription 3 (STAT3), and this subsequently resulted in a decrease in regulatory T cells (Tregs) accumulated during HCV infection. These results suggest that miR146a may regulate SOCS1/STAT3 and cytokine signalling in monocytes, directing T-cell differentiation and balancing immune clearance and immune injury during chronic viral infection.

Gate-opening effect in ZIF-8: the first experimental proof using inelastic neutron scattering.

The gate-opening phenomenon in ZIFs is of paramount importance to understand their behavior in industrial molecular separations. Here we show for the first time using in situ inelastic neutron scattering (INS) the swinging of the -CH3 groups and the imidazolate linkers in the prototypical ZIF-8 and ZIF-8@AC hybrid materials upon exposure to mild N2 pressure.