Prediction Challenge: Simulating Rydberg photoexcited cyclobutanone with surface hopping dynamics based on different electronic structure methods.

This research examines the nonadiabatic dynamics of cyclobutanone after excitation into the n → 3s Rydberg S2 state. It stems from our contribution to the Special Topic of the Journal of Chemical Physics to test the predictive capability of computational chemistry against unseen experimental data. Decoherence-corrected fewest-switches surface hopping was used to simulate nonadiabatic dynamics with full and approximated nonadiabatic couplings. Several simulation sets were computed with different electronic structure methods, including a multiconfigurational wavefunction [multiconfigurational self-consistent field (MCSCF)] specially built to describe dissociative channels, multireference semiempirical approach, time-dependent density functional theory, algebraic diagrammatic construction, and coupled cluster. MCSCF dynamics predicts a slow deactivation of the S2 state (10 ps), followed by an ultrafast population transfer from S1 to S0 (<100 fs). CO elimination (C3 channel) dominates over C2H4 formation (C2 channel). These findings radically differ from the other methods, which predicted S2 lifetimes 10-250 times shorter and C2 channel predominance. These results suggest that routine electronic structure methods may hold low predictive power for the outcome of nonadiabatic dynamics.

Estimating nitric oxide (NO) from MDSCs by Griess method.

The functional importance of nitric oxide (NO) in the fields of immunology concerning its antimicrobial, anti-tumoral, anti-inflammatory, and immunosuppressive effects have made it inevitable to study its secretion from various cells. Nitrogen oxide synthase (NOS) is the enzyme responsible for synthesizing NO and its three isoforms function in a cell-dependent manner. NO is oxidized rapidly to Reactive nitrogen oxide species (RNOS) through which the roles of NO are being carried out. One of the major immune cells secreting NO is myeloid-derived suppressor cells (MDSCs). The function of these MDSCs in the suppression of T-cell proliferation as well as T-cell differentiation is found to be dependent on NO secretion. Apart from T-cell suppressive activity, NO is also known to interfere with natural killer (NK) cell functions. A convenient method to estimate NO secretion is by using Griess reagent named after Johann Peter Griess. In this method, NO reacts with the reagents to form a colored azo dye detectable using a microplate reader at a wavelength of 548nm. In this chapter, we summarized the detailed method of estimating NO from MDSCs by the Griess method.

Recommendations for Velocity Adjustment in Surface Hopping.

This study investigates velocity adjustment directions after hopping in surface hopping dynamics. Using fulvene and a protonated Schiff base (PSB4) as case studies, we investigate the population decay and reaction yields of different sets of dynamics with the velocity adjusted in either the nonadiabatic coupling, gradient difference, or momentum directions. For the latter, in addition to the conventional algorithm, we investigated the performance of a reduced kinetic energy reservoir approach recently proposed. Our evaluation also considered velocity adjustment in the directions of approximate nonadiabatic coupling vectors. While results for fulvene are susceptible to the adjustment approach, PSB4 is not. We correlated this dependence to the topography near the conical intersections. When nonadiabatic coupling vectors are unavailable, the gradient difference direction is the best adjustment option. If the gradient difference is also unavailable, a semiempirical vector direction or the momentum direction with a reduced kinetic energy reservoir becomes an excellent option to prevent an artificial excess of back hoppings. The precise velocity adjustment direction is less crucial for describing the nonadiabatic dynamics than the kinetic energy reservoir's size.

Temperature effects on the internal conversion of excited adenine and adenosine.

This work aims to elucidate the dependence of the excited-state lifetime of adenine and adenosine on temperature. So far, it has been experimentally shown that while adenine's lifetime is unaffected by temperature, adenosine's lifetime strongly depends on it. However, the non-Arrhenius temperature dependence has posed a challenge in explaining this phenomenon. We used surface hopping to simulate the dynamics of adenine and adenosine in the gas phase at 0 and 400 K. The temperature effects were observed under the initial conditions via Wigner sampling with thermal corrections. Our results confirm that adenine's excited-state lifetime does not depend on temperature, while adenosine's lifetime does. Adenosine's dependency is due to intramolecular vibrational energy transfer from adenine to the ribose group. At 0 K, this transfer reduced the mean kinetic energy of adenine's moiety so much that internal conversion is inhibited, and the lifetime elongated by a factor of 2.3 compared to that at 400 K. The modeling also definitively ruled out the influence of viscosity, which was proposed as an alternative explanation previously.

Quantifying the relationship between spreading depolarization and perivascular cerebrospinal fluid flow.

Recent studies have linked spreading depolarization (SD, an electro-chemical wave in the brain following stroke, migraine, traumatic brain injury, and more) with increase in cerebrospinal fluid (CSF) flow through the perivascular spaces (PVSs, annular channels lining the brain vasculature). We develop a novel computational model that couples SD and CSF flow. We first use high order numerical simulations to solve a system of physiologically realistic reaction-diffusion equations which govern the spatiotemporal dynamics of ions in the extracellular and intracellular spaces of the brain cortex during SD. We then couple the SD wave with a 1D CSF flow model that captures the change in cross-sectional area, pressure, and volume flow rate through the PVSs. The coupling is modelled using an empirical relationship between the excess potassium ion concentration in the extracellular space following SD and the vessel radius. We find that the CSF volumetric flow rate depends intricately on the length and width of the PVS, as well as the vessel radius and the angle of incidence of the SD wave. We derive analytical expressions for pressure and volumetric flow rates of CSF through the PVS for a given SD wave and quantify CSF flow variations when two SD waves collide. Our numerical approach is very general and could be extended in the future to obtain novel, quantitative insights into how CSF flow in the brain couples with slow waves, functional hyperemia, seizures, or externally applied neural stimulations.

Administration of soluble gp130Fc disrupts M-1 macrophage polarization, dendritic cell activation, MDSC expansion and Th-17 induction during experimental cerebral malaria.

Regulatory effect of IL-6 on various immune cells plays a crucial role during experimental cerebral malaria pathogenesis. IL-6 neutralization can restore distorted ratios of myeloid dendritic cells and plasmacytoid dendritic cells as well as the balance between Th-17 and T-regulatory cells. IL-6 can also influence immune cells through classical and trans IL-6 signalling pathways. As trans IL-6 signalling is reportedly involved during malaria pathogenesis, we focused on studying the effects of trans IL-6 signalling blockade on various immune cell populations and how they regulate ECM progression. Results show that administration of sgp130Fc recombinant chimera protein lowers the parasitemia, increases the survivability of Plasmodium berghei ANKA infected mice, and restores the distorted ratios of M1/M2 macrophage, mDC/pDC, and Th-17/Treg. IL-6 trans signalling blockade has been found to affect both expansion of myeloid derived suppressor cells (MDSCs) and expression of inflammatory markers on them during Plasmodium berghei ANKA infection indicating that trans IL-6 signalling might regulate various immune cells and their function during ECM. In this work for the first time, we delineate the effect of sgp130Fc administration on influencing the immunological changes within the host secondary lymphoid organ during ECM induced by Plasmodium berghei ANKA infection.

Application of green synthesized bimetallic nZVI-Cu nanoparticle as a sustainable alternative to chemical fertilizers to enhance growth and photosynthetic efficiency of rice seedlings.

Application of nanomaterials in agriculture has been extensively explored over the past decade leading to a wide ambit of nanoparticle-based agrochemicals. Metallic nanoparticles consisting of plant macro- and micro-nutrients have been used as nutritional supplements for plants through soil amendments, foliar sprays, or seed treatment. However, most of these studies emphasize monometallic nanoparticles which limit the range of usage and effectivity of such nanoparticles (NPs). Hence, we have employed a bimetallic nanoparticle (BNP) consisting of two different micro-nutrients (Cu & Fe) in rice plants to test its efficacy in terms of growth and photosynthesis. Several experiments were designed to assess growth (root-shoot length, relative water content) and photosynthetic parameters (pigment content, relative expression of rbcS, rbcL & ChlGetc.). To determine whether the treatment induced any oxidative stress or structural anomalies within the plant cells, histochemical staining, anti-oxidant enzyme activities, FTIR, and SEM micrographs were undertaken. Results indicated that foliar application of 5 mg L-1 BNP increased vigor and photosynthetic efficiency whereas 10 mg L-1 concentration induced oxidative stress to some extent. Furthermore, the BNP treatment did not perturb the structural integrity of the exposed plant parts and also did not induce any cytotoxicity. Application of BNPs in agriculture has not been explored extensively to date and this study is one of the first reports that not only documents the effectivity of Cu-Fe BNP but also critically explores the safety of its usage on rice plants making it a useful lead to design new BNPs and explore their efficacy.

CD4+IL9+ (Th9) cells as the major source of IL-9, potentially modulate Th17/Treg mediated host immune response during experimental cerebral malaria.

Th9, a new subgroup of CD4+T cells is characterized by its specific cytokine IL-9, is a critical factor in allergic diseases, cancers and parasitic infections. This study aimed to explore the potential roles of Th9 cells in the immunopathogenesis of ECM. In splenocytes sourced from uninfected, PbA and Py infected mice, Th9 cells were characterised by flow cytometry, cell sorting and qPCR. Enhancement of CD4+IL-9+ (Th9) cells were observed in both the infections, which corroborated with increased expression of the differentiating transcription factors. Moreover, crucial cytokine receptors (IL-4R, TGF-ßR, IL-6R) as well as chemokine receptors (CCR3, CCR6 and CCR7) and activation marker (CD96), demonstrated elevation upon PbA infection in splenic Th9 cells. Furthermore, Neutralization of IL-9 along with IL-6 enhanced host survivability, reduced mean neurological score of ECM. However, anti- IL-9 treatment also down regulated frequency of Th17 cells, and its transcription factors pSTAT3, RORγT along with depleted Il-1ß and Il-6 expression. In sum, understanding how IL-9 producing CD4+ T-cells can alter Th17/Treg ratio and by that modulate host's immune response, could pave the way for developing immunomodulatory interventions against cerebral malaria.

Importance of NFκß, IL-10 serum levels and DC-SIGN polymorphic haplotypes in determining dengue disease severity among eastern Indian patients.

OBJECTIVES: Dengue viral (DENV) infection is most prevalent arboviral infection in India resulting in wide-range of symptomatic manifestation from simple (DF) to severe dengue (SD). DENV is internalized by dendritic cell receptor, DC-SIGN, which in turn activates inflammatory cytokines: NFκß, IL-10 as adaptive immune response. Present study focused on role of DC-SIGN polymorphisms and these cytokines in SD development among eastern Indian patients. METHOD: DC-SIGN polymorphisms (rs735239, rs4804803, rs2287886) and NFκß, IL-10 concentrations were analysed among 179 dengue patients and 123 healthy individuals by PCR-RFLP and sandwich ELISA, respectively. DENV copies/ml and serotype in patient-sera were measured by quantitative and qualitative real time PCR, respectively. Statistical and haplotype analysis were performed by GraphPad-Prism and SNPStat, respectively. RESULT: Prevalence of DENV serotypes among infected patients: DENV2>DENV4>DENV3>DENV1; those with DENV3 infection reported significantly increased IL-10 level. NFκß and IL-10 concentrations were significantly elevated among SD patients. ROC curve analysis predicted cut-off values of NFκß>13.46 ng/ml and IL-10 > 490.5 pg/ml to detect SD among infected patients with a good sensitivity and specificity. Patients with rs735239-GG, rs2287886-GG genotypes and GGG, GAG haplotypes were significantly associated with SD development, whereas, those with rs4804803-AG exhibited high DENVcopies/ml. Patients with these haplotypes also demonstrated increased NFκß and IL-10. CONCLUSION: This study emphasised importance of DC-SIGN GGG and GAG haplotypes, NFκß and IL-10 concentrations in WHO-defined severe dengue development among infected patients.

Newton-X Platform: New Software Developments for Surface Hopping and Nuclear Ensembles.

Newton-X is an open-source computational platform to perform nonadiabatic molecular dynamics based on surface hopping and spectrum simulations using the nuclear ensemble approach. Both are among the most common methodologies in computational chemistry for photophysical and photochemical investigations. This paper describes the main features of these methods and how they are implemented in Newton-X. It emphasizes the newest developments, including zero-point-energy leakage correction, dynamics on complex-valued potential energy surfaces, dynamics induced by incoherent light, dynamics based on machine-learning potentials, exciton dynamics of multiple chromophores, and supervised and unsupervised machine learning techniques. Newton-X is interfaced with several third-party quantum-chemistry programs, spanning a broad spectrum of electronic structure methods.

Non-Kasha fluorescence of pyrene emerges from a dynamic equilibrium between excited states.

Pyrene fluorescence after a high-energy electronic excitation exhibits a prominent band shoulder not present after excitation at low energies. The standard assignment of this shoulder as a non-Kasha emission from the second-excited state (S2) has been recently questioned. To elucidate this issue, we simulated the fluorescence of pyrene using two different theoretical approaches based on vertical convolution and nonadiabatic dynamics with nuclear ensembles. To conduct the necessary nonadiabatic dynamics simulations with high-lying electronic states and deal with fluorescence timescales of about 100 ns of this large molecule, we developed new computational protocols. The results from both approaches confirm that the band shoulder is, in fact, due to S2 emission. We show that the non-Kasha behavior is a dynamic-equilibrium effect not caused by a metastable S2 minimum. However, it requires considerable vibrational energy, which can only be achieved in collisionless regimes after transitions into highly excited states. This strict condition explains why the S2 emission was not observed in some experiments.

Correlation of the activities of antioxidant enzymes superoxide dismutase and glutathione reductase with micronuclei counts among areca nut chewers of Manipuri population using exfoliative cytology: A preliminary study.

Context: Areca nut (AN) is a potent cytotoxic and genotoxic agent. Oxidative stress-induced by chewing of AN can cause DNA damage leading to nuclear anomalies such as micronuclei (MN) and also alters antioxidant defense mechanisms, leading to genomic instabilities and the development of oral cancer. Aims: The aim of this study is to study the correlation between the levels of glutathione reductase (GR) and superoxide dismutase (SOD) in exfoliated buccal mucosal cells and the genotoxicity levels (MN count) in chronic AN chewers. Materials and Methods: The present study was conducted with the approval of the Research Ethics Board in 60 individuals; 40 cases (Group I-20 raw AN chewers, Group II-20 dried areca with tobacco chewers), and 20 controls as Group III in the age group of 18-68 years who attended the outpatient department of our college. Estimation of SOD and GR and MN assessment was done using buccal exfoliated cells. Statistical Analysis Used: Statistical analysis was performed using the Student's t-test and one-way ANOVA. Results: Antioxidant levels were found to be significantly reduced in both Group I and Group II in comparison to the control group. Group II showed significantly reduced level of GR in comparison to Group I. The MN count was significantly increased in Group II in comparison to Group I. The MN counts showed an inverse correlation to the activities of the antioxidant enzymes. Greater activities of antioxidant enzymes correlated with decreased MN counts. Conclusions: Detection of MN in AN chewers with or without tobacco can be a useful biomarker for clinical screening procedures that may be used as a risk marker for oral cancer. It is important to increase the awareness programs to educate the public about the deleterious effects of AN chewing, emphasize on early intervention of AN chewing habit and thus prevent the development of oral cancer.

Fungal disease suppression and growth promotion potential of endophytic bacteria from ethnomedicinal plants.

103 bacterial isolates obtained from 8 ethnomedicinal plants in Manipur, India were studied for antifungal and plant growth promoting (PGP) activities. Forty-six (46), out of 62 antifungal isolates, showed potent activities against R. solani. Since R. solani (RS), a sheath blight pathogen, threatens rice yields worldwide, the present study was aimed at discovering promising bioinoculants with anti-RS and PGP potential on rice. Twenty-nine (29) endophytic isolates exhibiting promising anti-RS and PGP activities were subjected to seed vigor assays on rice (var. Jatra) and 16 were found to enhance rice seedling vigour by 70% or more over the control. Four (4) strains, Streptomyces sp. (AcRz21), Alkalihalobacillus sp. (PtL11), Bacillus sp. (TgIb5), and Priestia sp. (TgIb12) with the highest vigor indices were studied for growth promotion of rice in field conditions under pathogen-challenged and pathogen-free conditions. These bioactive strains were able to significantly enhance root and shoot biomass and reduce lesion heights caused by R. solani.

Social evolution of shared biofilm matrix components.

Biofilm formation is an important and ubiquitous mode of growth among bacteria. Central to the evolutionary advantage of biofilm formation is cell-cell and cell-surface adhesion achieved by a variety of factors, some of which are diffusible compounds that may operate as classical public goods-factors that are costly to produce but may benefit other cells. An outstanding question is how diffusible matrix production, in general, can be stable over evolutionary timescales. In this work, using Vibrio cholerae as a model, we show that shared diffusible biofilm matrix proteins are indeed susceptible to cheater exploitation and that the evolutionary stability of producing these matrix components fundamentally depends on biofilm spatial structure, intrinsic sharing mechanisms of these components, and flow conditions in the environment. We further show that exploitation of diffusible adhesion proteins is localized within a well-defined spatial range around cell clusters that produce them. Based on this exploitation range and the spatial distribution of cell clusters, we constructed a model of costly diffusible matrix production and related these length scales to the relatedness coefficient in social evolution theory. Our results show that production of diffusible biofilm matrix components is evolutionarily stable under conditions consistent with natural biofilm habitats and host environments. We expect the mechanisms revealed in this study to be relevant to other secreted factors that operate as cooperative public goods in bacterial communities and the concept of exploitation range and the associated analysis tools to be generally applicable.

A Hessian-Free Method to Prevent Zero-Point Energy Leakage in Classical Trajectories.

The problem associated with the zero-point energy (ZPE) leak in classical trajectory calculations is well known. Since ZPE is a manifestation of the quantum uncertainty principle, there are no restrictions on energy during the classical propagation of nuclei. This phenomenon can lead to unphysical results, such as forming products without the ZPE in the internal vibrational degrees of freedom (DOFs). The ZPE leakage also permits reactions below the quantum threshold for the reaction. We have developed a new Hessian-free method, inspired by the Lowe-Andersen thermostat model, to prevent energy dipping below a threshold in the local-pair (LP) vibrational DOFs. The idea is to pump the leaked energy to the corresponding local vibrational mode taken from the other vibrational DOFs. We have applied the new correction protocol on the ab-initio ground-state molecular dynamics simulation of the water dimer (H2O)2, which dissociates due to unphysical ZPE spilling from high-frequency OH modes. The LP-ZPE method has been able to prevent the ZPE spilling of the OH stretching modes by pumping back the leaked energy into the corresponding modes, while this energy is taken from the other modes of the dimer itself, keeping the system as a microcanonical ensemble.

Pre-Dewar structure modulates protonated azaindole photodynamics.

Recent experimental work revealed that the lifetime of the S3 state of protonated 7-azaindole is about ten times longer than that of protonated 6-azaindole. We simulated the nonradiative decay pathways of these molecules using trajectory surface hopping dynamics after photoexcitation into S3 to elucidate the reason for this difference. Both isomers mainly follow a common ππ* relaxation pathway involving multiple state crossings while coming down from S3 to S1 in the subpicosecond time scale. However, the simulations reveal that the excited-state topographies are such that while the 6-isomer can easily access the region of nonadiabatic transitions, the internal conversion of the 7-isomer is delayed by a pre-Dewar bond formation with a boat conformation.

IL-6 dependent expansion of inflammatory MDSCs (CD11b+ Gr-1+) promote Th-17 mediated immune response during experimental cerebral malaria.

Myeloid derived suppressor cells (MDSCs) are a group of heterogeneous cell populations that can suppress T cell responses. Various aspects of MDSCs in regulating immune responses in several cancer and infectious diseases have been reported till date. But the role and regulation of MDSCs have not been systematically studied in the context of malaria. This study depicts the phenotypic and functional characteristics of splenic MDSCs and how they regulate Th-17 mediated immune response during Experimental Cerebral Malaria (ECM). Flow cytometric analysis reveals that MDSCs in the spleen and bone marrow expand at 8 dpi during ECM. Among subtypes of MDSCs, PMN-MDSCs show significant expansion in the spleen but M-MDSCs remain unaltered. Functional analysis of sorted MDSCs from spleens of Plasmodium berghei ANKA (PbA) infected mice shows suppressive nature of these cells and high production of Nitric oxide (NO). Besides, MDSCs were also found to express various inflammatory markers during ECM suggesting the M1 type phenotype of these cells. In-vivo depletion of MDSCs by the use of Anti Gr-1 increases mice survival but doesn't significantly alter the parasitemia. Previously, it has been reported that Treg/Th-17 balance in the spleen is skewed towards Th-17 during ECM. Depletion of MDSCs was found to regulate Th-17 percentages to homeostatic levels and subvert various inflammatory changes in the spleen. Among different factors, IL-6 was found to play an important role in the expansion of MDSCs and expression of inflammatory markers on MDSCs in a STAT3-dependent manner. These findings provide a unique insight into the role of IL-6 in the expansion of the MDSC population which causes inflammatory changes and increased Th-17 responses during ECM.

Clinical significance of differential serum-signatures for early prediction of severe dengue among Eastern Indian patients.

Dengue infection can result in simple dengue fever or life-threatening severe dengue. Early identification of severe patients is needed for proper disease management. Dengue infection was screened among 168 symptomatic patients by qRT-PCR, anti-dengue IgM, and IgG ELISA. Dengue patients were categorized according to WHO classification. Viral load and dengue serotypes were determined by qRT-PCR. Levels of acute-phase-proteins (SAP, SAA2; CRP and ApoA1), endothelial (Ang2, VEGF), coagulation (fibrinogen) markers were determined by sandwich ELISA/immunoturbidimetry/western-blotting. Hepatic (ALT, AST, ALP) and other blood biochemical parameters were studied by autoanalyzer and haematology cell counter. Statistical analysis and protein-protein-interaction network were performed by GraphPad-Prism and STRINGS database, respectively. Among 87 dengue patients, significantly higher levels of Ang2, VEGF, CRP, SAA2, ApoA1, AST, ALT, and AST/ALT ratio and low level of fibrinogen were detected in severe-dengue cases compared to dengue without warning-signs, with seven of them severely altered during febrile-phase. Higher fold-change of Ang2 and VEGF as well as decreased fibrinogen were observed among patients with haemorrhagic-manifestation, clinical-fluid accumulation and thrombocytopenia. Functional network analysis predicted Ang2, VEGF, and CRP to be functionally and physically connected and SAA2 and ApoA1 to be functioning together. Correlation analyses also validated this connectivity by a strong positive correlation between Ang2, VEGF, and CRP. PCA analysis followed by hierarchical clustering heatmap analysis segregated severe-dengue patients from the rest, with VEGF, Ang2, ApoA1, AST, and ALT clearly distinguishing the severe-dengue group. Thus, serum levels of VEGF, Ang2, ApoA1, AST, and ALT might act as potential biomarkers for predicting dengue severity during the early stage.