Miracle-dz/UniFAR-FTUs huggingface dataset:
Interplays of electron and nuclear motions along CO dissociation trajectory in myoglobin revealed by ultrafast X-rays and quantum dynamics calculations

Significance In this multidisciplinary study, we investigated local and global structural responses upon carbon monoxide (CO) dissociation from the heme iron(II) in myoglobin in solution using ultrafast X-ray absorption and scattering. CO dissociation was optically triggered and pulsed X-rays probed structural and electronic changes as a function of time, revealing an iron(II) spin state transition and nuclear motions propagating from the active site throughout the entire protein. Quantum mechanical computational results were used to assign the iron K-edge absorption features, and to map out electronic and nuclear trajectories during Fe–CO bond elongation and heme macrocycle doming. The study has important implications for heme–protein function and the interaction of small molecule substrates with the metal active centers in enzymes. Ultrafast structural dynamics with different spatial and temporal scales were investigated during photodissociation of carbon monoxide (CO) from iron(II)–heme in bovine myoglobin during the first 3 ps following laser excitation. We used simultaneous X-ray transient absorption (XTA) spectroscopy and X-ray transient solution scattering (XSS) at an X-ray free electron laser source with a time resolution of 80 fs. Kinetic traces at different characteristic X-ray energies were collected to give a global picture of the multistep pathway in the photodissociation of CO from heme. In order to extract the reaction coordinates along different directions of the CO departure, XTA data were collected with parallel and perpendicular relative polarizations of the laser pump and X-ray probe pulse to isolate the contributions of electronic spin state transition, bond breaking, and heme macrocycle nuclear relaxation. The time evolution of the iron K-edge X-ray absorption near edge structure (XANES) features along the two major photochemical reaction coordinates, i.e., the iron(II)–CO bond elongation and the heme macrocycle doming relaxation were modeled by time-dependent density functional theory calculations. Combined results from the experiments and computations reveal insight into interplays between the nuclear and electronic structural dynamics along the CO photodissociation trajectory. Time-resolved small-angle X-ray scattering data during the same process are also simultaneously collected, which show that the local CO dissociation causes a protein quake propagating on different spatial and temporal scales. These studies are important for understanding gas transport and protein deligation processes and shed light on the interplay of active site conformational changes and large-scale protein reorganization.
Sialic Acid Protects Nontypeable Haemophilus influenzae from Natural IgM and Promotes Survival in Murine Respiratory Tract

Nontypeable Haemophilus influenzae (NTHi), a common inhabitant of the human nasopharynx and upper airways, causes opportunistic respiratory tract infections that are frequently recurring and chronic. NTHi utilizes sialic acid from the host to evade antibacterial defenses and persist in mucosal tissues; however, the role of sialic acid scavenged by NTHi during infection is not fully understood. ABSTRACT Nontypeable Haemophilus influenzae (NTHi), a common inhabitant of the human nasopharynx and upper airways, causes opportunistic respiratory tract infections that are frequently recurring and chronic. NTHi utilizes sialic acid from the host to evade antibacterial defenses and persist in mucosal tissues; however, the role of sialic acid scavenged by NTHi during infection is not fully understood. We previously showed that sialylation protects specific epitopes on NTHi lipooligosaccharide (LOS) targeted by bactericidal IgM in normal human serum. Here, we evaluated the importance of immune evasion mediated by LOS sialylation in the mouse respiratory tract using wild-type H. influenzae and an isogenic siaB mutant incapable of sialylating the LOS. Sialylation protected common NTHi glycan structures recognized by human and murine IgM and protected NTHi from complement-mediated killing directed by IgM against these structures. Protection from IgM binding by sialylated LOS correlated with decreased survival of the siaB mutant versus the wild type in the murine lung. Complement depletion with cobra venom factor increased survival of the siaB mutant in the nasopharynx but not in the lungs, suggesting differing roles of sialylation at these sites. Prior infection increased IgM against H. influenzae but not against sialic acid-protected epitopes, consistent with sialic acid-mediated immune evasion during infection. These results provide mechanistic insight into an NTHi evasive strategy against an immune defense conserved across host species, highlighting the potential of the mouse model for development of anti-infective strategies targeting LOS antigens of NTHi.
Merck molecular force field. II. MMFF94 van der Waals and electrostatic parameters for intermolecular interactions

This article defines the parameterization and performance of MMFF94 for intermolecular interactions. It specifies the novel “buffered” functional forms used for treating van der Waals (vdW) and electrostatic interactions, and describes the use of : (1) high quality ab initio data to parameterize vdW interactions involving aliphatic hydrogens; and (2) HF/6‐31G* calculations on hydrogen‐bonded complexes to parameterize nonbonded interactions in polar systems. Comparisons show that appropriate trends in the HF/6‐31G* data are well reproduced by MMFF94 and that intermolecular interaction energies and geometries closely parallel those given by the highly regarded OPLS force field. A proper balance between solvent–solvent, solvent–solute, and solute–solute interactions, critically important for prospective success in aqueous simulations, thus appears to be attained. Comparison of MMFF94, OPLS, CHELPG electrostatic potential fit, QEq, Gasteiger, and Abraham charges for 20 small molecules and ions also shows the close correspondence between MMFF94 and OPLS. As do OPLS and all current, widely used force fields, MMFF94 employs “effective pair potentials” which incorporate in an averaged way the increases in polarity which occur in high dielectric media. Some limitations of this approach are discussed and suggestions for possible enhancements to MMFF94's functional form are noted. © 1996 John Wiley & Sons, Inc.
Propagating data uncertainty through smoothing spline fits

Smoothing splines have been used extensively in the analysis of gas concentration data from bubbles in ice cores. Since the fit is a linear projection of the data, propagation of data uncertainty through the fitting process is formally straightforward and, as we demonstrate, readily achievable from pre-existing spline-fitting procedures. The uncertainty propagation can be extended to determining both uncertainties in derivatives and uncertainties in quantities that reflect rates of input to the atmosphere. As an example, we apply the technique to 1000 yr of methane data from a Law Dome ice core.
What do patients and dermatologists prefer regarding low-risk basal cell carcinoma follow-up care? A discrete choice experiment

Background Follow-up after low-risk basal cell carcinoma (BCC) is being provided more frequently than recommended by guidelines. To design an acceptable strategy to successfully reduce this ‘low-value’ care, it is important to obtain insights into the preferences of patients and dermatologists. Objective To determine the preferences and needs of patients and dermatologists to reduce low-risk BCC follow-up care, and the trade-offs they are willing to make. Methods A questionnaire including a discrete choice experiment was created, containing attributes regarding amount of follow-up, continuity of care, method of providing addition information, type of healthcare provider, duration of follow-up visits and skin examination. In total, 371 BCC patients and all Dutch dermatologists and dermatology residents (n = 620) were invited to complete the questionnaire. A panel latent class model was used for analysis. Results Eighty-four dermatologists and 266 BCC patients (21% and 72% response rates respectively) completed the discrete choice experiment. If the post-treatment visit was performed by the same person as treatment provider and a hand-out was provided to patients containing personalised information, the acceptance of having no additional follow-up visits (i.e. following the guidelines) would increase from 55% to 77% by patients. Female patients and older dermatologists, however, are less willing to accept the guidelines and prefer additional follow-up visits. Limitations The low response rate of dermatologists. Conclusion This discrete choice experiment revealed a feasible strategy to substantially reduce costs, while maintaining quality of care, based on the preferences and needs of BCC patients, which is supported by dermatologists.
Development and Validation of High-Content Analysis for Screening HDAC6-Selective Inhibitors

Throughout recent decades, histone deacetylase (HDAC) inhibitors have shown encouraging potential in cancer treatment, and several pan-HDAC inhibitors have been approved for treating malignant cancers. Numerous adverse effects of pan-HDAC inhibitors have been reported, however, during preclinical and clinical evaluations. To avoid undesirable responses, an increasing number of investigations are focusing on the development of isotype-selective HDAC inhibitors. In this study, we present an effective and quantitative cellular assay using high-content analysis (HCA) to determine compounds’ inhibition of the activity of HDAC6 and Class I HDAC isoforms, by detecting the acetylation of their corresponding substrates (i.e., α-tubulin and histone H3). Several conditions that are critical for HCA assays, such as cell seeding number, fixation and permeabilization reagent, and antibody dilution, have been fully validated in this study. We used selective HDAC6 inhibitors and inhibitors targeting different HDAC isoforms to optimize and validate the capability of the HCA assay. The results indicated that the HCA assay is a robust assay for quantifying compounds’ selectivity of HDAC6 and Class I HDAC isoforms in cells. Moreover, we screened a panel of compounds for HDAC6 selectivity using this HCA assay, which provided valuable information for the structure–activity relationship (SAR). In summary, our results suggest that the HCA assay is a powerful tool for screening selective HDAC6 inhibitors.
Changes in Chemical Composition within an Internode of Elongating Bamboo

Internodal growth of bamboo was characterized by analyzing chemical composition, X-ray diffraction and CP/MAS solid state 13 C-NMR. When the longest (17th) internode of an 6m-high immature moso-bamboo (Phyllostachys pubescens Mazel), 29.8 cm in length, was sliced into 28 rings and subjected to the analyses, growth of bamboo was concluded to occur upward from the secondary meristem localized at 1.06-2.13 cm above the node. CP/MAS solid state 13 C-NMR proved to be useful in a rapid determination of the exact position of the secondary meristem.
Identification of the 11-lncRNA signatures associated with the prognosis of endometrial carcinoma

Endometrial carcinoma (EC) is the fourth most common cancer in women. Some long non-coding RNAs (lncRNAs) are regarded as potential prognostic biomarkers or targets for treatment of many types of cancers. We aim to screen prognostic-related lncRNAs and build a possible lncRNA signature which can effectively predict the survival of patients with EC. We obtained lncRNA expression profiling from the TCGA database. The patients were classified into training set and verification set. By performing Univariate Cox regression model, Robust likelihood-based survival analysis, and Cox proportional hazards model, we developed a risk score with the Cox co-efﬁcient of individual lncRNAs in the training set. The optimum cut-off point was selected by ROC analysis. Patients were effectively divided into high-risk group and low-risk group according to the risk score. The OS of the low-risk patients was significantly prolonged compared with that of the high-risk group. At last, we validated this 11-lncRNA signature in the verification set and the complete set. We identified an 11-lncRNA expression signature with high stability and feasibility, which can predict the survival of patients with EC. These findings provide new potential biomarkers to improve the accuracy of prognosis prediction of EC.
Adsorption of anionic dyes on a reversibly swelling cationic superabsorbent polymer

A cationic monomer 2-(methacryloyloxy)ethyl]trimethylammonium chloride was polymerized using N,N'-methylenebisacrylamide as the crosslinker to obtain a cationic superabsorbent polymer (SAP). This SAP was characterized by Fourier transform-infrared spectroscopy, and the equilibrium swelling capacity was determined by swelling in water. The SAP was subjected to cyclic swelling/deswelling in water and NaCl solution. The conductivity of the swelling medium was monitored during the swelling/deswelling and was related to the swelling/deswelling characteristics of the SAP. The adsorption of five anionic dyes of different classes on the SAP was carried out and was found to follow the first-order kinetics. The Langmuir adsorption isotherms were found to fit the equilibrium adsorption data. The dye adsorption capacity of the SAP synthesized in this study was higher than that obtained for other hydrogels reported in the literature. (c) 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Combination Adjuvants Affect the Magnitude of Effector-Like Memory CD8 T Cells and Protection against Listeriosis

The development of T cell-based subunit protein vaccines against diseases such as tuberculosis and malaria remains a challenge for immunologists. Here, we have identified a nanoemulsion adjuvant, Adjuplex (ADJ), which enhanced dendritic cell (DC) cross-presentation and elicited effective memory T cell-based immunity to Listeria monocytogenes. ABSTRACT The development of T cell-based subunit protein vaccines against diseases such as tuberculosis and malaria remains a challenge for immunologists. Here, we have identified a nanoemulsion adjuvant, Adjuplex (ADJ), which enhanced dendritic cell (DC) cross-presentation and elicited effective memory T cell-based immunity to Listeria monocytogenes. We further evaluated whether cross-presentation induced by ADJ can be combined with the immunomodulatory effects of Toll-like receptor (TLR) agonists (CpG or glucopyranosyl lipid adjuvant [GLA]) to evoke systemic CD8 T cell-based immunity to L. monocytogenes. Mechanistically, vaccination with ADJ, alone or in combination with CpG or GLA, augmented activation and antigen uptake by CD103+ migratory and CD8α+ resident DCs and upregulated CD69 expression on B and T lymphocytes in vaccine-draining lymph nodes. By engaging basic leucine zipper ATF-like transcription factor 3-dependent cross-presenting DCs, ADJ potently elicited effector CD8 T cells that differentiated into granzyme B-expressing CD27LO effector-like memory CD8 T cells, which provided effective immunity to L. monocytogenes in the spleen and liver. CpG or GLA alone did not elicit effector-like memory CD8 T cells and induced moderate protection in the spleen but not in the liver. Surprisingly, combining CpG or GLA with ADJ reduced the number of ADJ-induced memory CD8 T cells and compromised protective immunity to L. monocytogenes, especially in the liver. Taken together, the data presented in this study provide a glimpse of protective CD8 T cell memory differentiation induced by a nanoemulsion adjuvant and demonstrate the unexpected negative effects of TLR signaling on the magnitude of CD8 T cell memory and protective immunity to L. monocytogenes, a model intracellular pathogen.
Next-Generation Mass Spectrometry Metabolomics Revives the Functional Analysis of Plant Metabolic Diversity.

The remarkable diversity of specialized metabolites produced by plants has inspired several decades of research and nucleated a long list of theories to guide empirical ecological studies. However, analytical constraints and the lack of untargeted processing workflows have long precluded comprehensive metabolite profiling and, consequently, the collection of the critical currencies to test theory predictions for the ecological functions of plant metabolic diversity. Developments in mass spectrometry (MS) metabolomics have revolutionized the large-scale inventory and annotation of chemicals from biospecimens. Hence, the next generation of MS metabolomics propelled by new bioinformatics developments provides a long-awaited framework to revisit metabolism-centered ecological questions, much like the advances in next-generation sequencing of the last two decades impacted all research horizons in genomics. Here, we review advances in plant (computational) metabolomics to foster hypothesis formulation from complex metabolome data. Additionally, we reflect on how next-generation metabolomics could reinvigorate the testing of long-standing theories on plant metabolic diversity. Expected final online publication date for the Annual Review of Plant Biology, Volume 72 is May 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Idiopathic intracranial hypertension and visual function in North Indian population

Background: Idiopathic Intracranial Hypertension (IIH) is a neurological disorder with varied presentation, visual morbidity being the most important one. Literature is sparse as regards the effects of IIH on the visual system in Asians. Objective: Assessment of visual morbidity and change with treatment in IIH patients in North India through a prospective interventional study. Materials and methods: Sixty eyes of newly diagnosed IIH patients were evaluated for functional and structural tests of visual system. Lumbar puncture was performed to establish IIH diagnosis and received oral Carbonic anhydrase inhibitor thereafter. Change in visual function was studied from baseline to 6-month follow-up visit. Results: Mean age of participants at presentation was 33.27 ± 10.68 years and majority were females (73.3%). Seventy percent eyes (n = 42) had visual acuity 20/20 at presentation. Average Pelli Robson contrast sensitivity (CS) improved from 1.86 ± 0.34 to 2.11 ± 0.24 (Friedman Test: X2 = 59.2, p ⩽ 0.001) while number of eyes with detectable visual field deficits reduced from 70% to 43.7%. Retinal nerve fibre layer (RNFL) thickness reduced from 176.27 to 114.97 µ (Friedman Test: X2 = 69.3, p ⩽ 0.001). Conclusions: The socio-demographic profile in our study showed higher male incidence than noted in previous studies. Visual function deficits were present in patients, even in those with 20/20 visual acuity. Significant improvement was seen after lumbar puncture and initiation of medical treatment. CS and RNFL thickness showed significant improvement even after 1 month of treatment and can be used for monitoring IIH patients.
The structure of liquid water at an extended hydrophobic surface

Molecular dynamics simulations have been carried out for liquid water between flat hydrophobic surfaces. The surfaces produce density oscillations that extend at least 10 A into the liquid, and significant molecular orientational preferences that extend at least 7 A into the liquid. The liquid structure nearest the surface is characterized by ‘‘dangling’’ hydrogen bonds; i.e., a typical water molecule at the surface has one potentially hydrogen‐bonding group oriented toward the hydrophobic surface. This surface arrangement represents a balance between the tendencies of the liquid to maximize the number of hydrogen bonds on the one hand, and to maximize the packing density of the molecules on the other. A detailed analysis shows that the structural properties of the liquid farther from the surface can be understood as effects imposed by this surface structure. These results show that the hydration structure of large hydrophobic surfaces can be very different from that of small hydrophobic molecules.
Improvements in Sleep Correlate With Improvements in Clinical Outcomes Among Adolescents Undergoing Intensive Interdisciplinary Pain Treatment

Objectives: Intensive interdisciplinary pain treatment (IIPT) programs have been shown to restore function, improve coping, and reduce pain in adolescents with chronic pain. Yet, little is known about patients’ sleep during IIPT and whether or not improvements in pain treatment outcomes are associated with changes in sleep pre-to-post IIPT treatment. The objectives of the current study were to describe sleep among adolescents entering IIPT and examine associations between sleep parameters and IIPT treatment effects. Materials and Methods: Self-reported sleep measures and clinical outcomes (eg, functional disability, coping, average pain), were collected from 44 adolescents (mean age=14.57, 68.2% female) at admission and discharge from an inpatient IIPT program. Wrist-worn actigraphy data and sleep diaries from participants’ first week and last week in the program were analyzed to characterize sleep parameters. Results: Participants self-reported poor sleep/wake patterns, high levels of insomnia symptoms, and subclinical problems with daytime sleepiness upon admission into IIPT, although actigraphic indices of sleep from the first week of IIPT admission were only just under clinical guidelines for healthy adolescent sleep. Better self-reported sleep quality assessed via aggregated sleep diaries from the first week was associated with improvement in average pain and disability over the course of the program. Furthermore, improvements in insomnia symptoms and daytime sleepiness throughout the program were positively correlated with concurrent improvements in functional disability and coping. Discussion: Taken together, results suggest that sleep may be associated with IIPT treatment effects and pave the way for future research to continue examining these relationships.
Anatomy-guided PET reconstruction using l 1 bowsher prior

Advances in simultaneous positron emission tomography/magnetic resonance imaging (PET/MRI) technology have led to an active investigation of the anatomy-guided regularized PET image reconstruction algorithm based on MR images. Among the various priors proposed for anatomy-guided regularized PET image reconstruction, Bowsher’s method based on second-order smoothing priors sometimes suffers from over-smoothing of detailed structures. Therefore, in this study, we propose a Bowsher prior based on the l1 -norm and an iteratively reweighting scheme to overcome the limitation of the original Bowsher method. In addition, we have derived a closed solution for iterative image reconstruction based on this non-smooth prior. A comparison study between the original l2 and proposed l1 Bowsher priors was conducted using computer simulation and real human data. In the simulation and real data application, small lesions with abnormal PET uptake were better detected by the proposed l1 Bowsher prior methods than the original Bowsher prior. The original l2 Bowsher leads to a decreased PET intensity in small lesions when there is no clear separation between the lesions and surrounding tissue in the anatomical prior. However, the proposed l1 Bowsher prior methods showed better contrast between the tumors and surrounding tissues owing to the intrinsic edge-preserving property of the prior which is attributed to the sparseness induced by l1 -norm, especially in the iterative reweighting scheme. Besides, the proposed methods demonstrated lower bias and less hyper-parameter dependency on PET intensity estimation in the regions with matched anatomical boundaries in PET and MRI. Therefore, these methods will be useful for improving the PET image quality based on the anatomical side information.