ABSTRACT
S = 2 FeIVâO centers generated in the active sites of nonheme iron oxygenases cleave substrate C-H bonds at rates significantly faster than most known synthetic FeIVâO complexes. Unlike the majority of the latter, which are S = 1 complexes, [FeIV(O)(tris(2-quinolylmethyl)amine)(MeCN)]2+ (3) is a rare example of a synthetic S = 2 FeIVâO complex that cleaves C-H bonds 1000-fold faster than the related [FeIV(O)(tris(pyridyl-2-methyl)amine)(MeCN)]2+ complex (0). To rationalize this significant difference, a systematic comparison of properties has been carried out on 0 and 3 as well as related complexes 1 and 2 with mixed pyridine (Py)/quinoline (Q) ligation. Interestingly, 2 with a 2-Q-1-Py donor combination cleaves C-H bonds at 233 K with rates approaching those of 3, even though Mössbauer analysis reveals 2 to be S = 1 at 4 K. At 233 K however, 2 becomes S = 2, as shown by its 1H NMR spectrum. These results demonstrate a unique temperature-dependent spin-state transition from triplet to quintet in oxoiron(IV) chemistry that gives rise to the high C-H bond cleaving reactivity observed for 2.
ABSTRACT
BACKGROUND: Coronavirus disease 2019 (COVID-19) is majorly known to cause mild to moderate disease, but a small fraction of patients may develop respiratory failure due to diffuse lung injury, requiring management in the intensive care unit (ICU). This study attempts to identify factors that can predict unfavorable outcomes in moderate to severe COVID-19 patients. METHODS: Hospital records of 120 COVID-19 patients admitted to the ICU were retrospectively analyzed and data pertaining to demographic, clinical, and laboratory parameters were obtained. These data were then compared with outcome parameters like survival, duration of hospital stay, and various adverse events. RESULTS: Out of 120 patients, 70% were male, with a mean age of 54.44 years [standard deviation (SD) ± 14.24 years]. Presenting symptoms included breathlessness (100%), cough (94.17%), fever (82.5%), and sore throat (10.83%). Diabetes, hypertension, and chronic obstructive pulmonary disease (COPD) were the common comorbidities associated. Increased serum D-dimer, ferritin, interleukin-6 (IL-6) levels, and unvaccinated status were associated with higher mortality. Overall, 25.83% of patients survived, 24.41% of patients developed septic shock, and 10.6% of patients were discharged on oxygen. World Health Organization (WHO) clinical progression scale score ≥ 6 had 57 and 82% sensitivity and 83 and 77% specificity on days 7 and 14 after admission, respectively, for predicting mortality. A baseline National Early Warning Score 2 (NEWS 2) ≥ 9 had 48% sensitivity and 88% specificity for predicting mortality. CONCLUSION: Advanced age and associated comorbidities are linked to adverse outcomes in moderate to severe COVID-19. Persistently high D-dimer levels, despite standard treatment, may also contribute to increased mortality. WHO clinical progression scale and NEWS 2 have high specificity for predicting mortality.
Subject(s)
COVID-19 , Respiratory Insufficiency , Humans , Male , Middle Aged , Female , COVID-19/complications , Retrospective Studies , SARS-CoV-2 , Respiratory Insufficiency/etiology , Disease ProgressionABSTRACT
Defective intracellular trafficking and export of microRNAs (miRNAs) have been observed in growth-retarded mammalian cells having impaired mitochondrial potential and dynamics. Here, we found that uncoupling protein 2 (Ucp2)-mediated depolarization of mitochondrial membrane also results in progressive sequestration of miRNAs within polysomes and lowers their release via extracellular vesicles. Interestingly, the impaired miRNA-trafficking process in growth-retarded human cells could be reversed in the presence of Genipin, an inhibitor of Ucp2. Mitochondrial detethering of endoplasmic reticulum (ER), observed in cells with depolarized mitochondria, was found to be responsible for defective compartmentalization of translation initiation factor eIF4E to polysomes attached to ER. This caused a retarded translation process accompanied by enhanced retention of miRNAs and target mRNAs within ER-attached polysomes to restrict extracellular export of miRNAs. Reduced compartment-specific activity of the mammalian target of rapamycin complex 1 (mTORC1), the master regulator of protein synthesis, in cells with defective mitochondria or detethered ER, caused reduced phosphorylation of eIF4E-BP1 and prevented eIF4E targeting to ER-attached polysomes and miRNA export. These data suggest how mitochondrial membrane potential and dynamics, by affecting mTORC1 activity and compartmentalization, determine the subcellular localization and export of miRNAs.
Subject(s)
Eukaryotic Initiation Factor-4E , MicroRNAs , Eukaryotic Initiation Factor-4E/metabolism , Humans , Mechanistic Target of Rapamycin Complex 1/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Mitochondria/genetics , Mitochondria/metabolism , Phosphorylation , Polyribosomes/metabolismABSTRACT
RasGRP1 is a Ras guanine nucleotide exchange factor, and an essential regulator of lymphocyte receptor signaling. In mice, Rasgrp1 deletion results in defective T lymphocyte development. RASGRP1-deficient patients suffer from immune deficiency, and the RASGRP1 gene has been linked to autoimmunity. However, how RasGRP1 levels are regulated, and if RasGRP1 dosage alterations contribute to autoimmunity remains unknown. We demonstrate that diminished Rasgrp1 expression caused defective T lymphocyte selection in C57BL/6 mice, and that the severity of inflammatory disease inversely correlates with Rasgrp1 expression levels. In patients with autoimmunity, active inflammation correlated with decreased RASGRP1 levels in CD4+ T cells. By analyzing H3K27 acetylation profiles in human T cells, we identified a RASGRP1 enhancer that harbors autoimmunity-associated SNPs. CRISPR-Cas9 disruption of this enhancer caused lower RasGRP1 expression, and decreased binding of RUNX1 and CBFB transcription factors. Analyzing patients with autoimmunity, we detected reduced RUNX1 expression in CD4+ T cells. Lastly, we mechanistically link RUNX1 to transcriptional regulation of RASGRP1 to reveal a key circuit regulating RasGRP1 expression, which is vital to prevent inflammatory disease.
Subject(s)
Autoimmunity/genetics , Core Binding Factor Alpha 2 Subunit/genetics , DNA-Binding Proteins/genetics , Guanine Nucleotide Exchange Factors/genetics , Transcription, Genetic/genetics , Animals , Autoimmunity/immunology , CD4-Positive T-Lymphocytes/immunology , CRISPR-Cas Systems/genetics , CRISPR-Cas Systems/immunology , Core Binding Factor Alpha 2 Subunit/immunology , DNA-Binding Proteins/immunology , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , Guanine Nucleotide Exchange Factors/immunology , Histones/genetics , Histones/immunology , Humans , Inflammation/genetics , Inflammation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Transcription, Genetic/immunologyABSTRACT
Genetic variants in genome-wide association studies (GWAS) are tested for disease association mostly using simple regression, one variant at a time. Standard approaches to improve power in detecting disease-associated SNPs use multiple regression with Bayesian variable selection in which a sparsity-enforcing prior on effect sizes is used to avoid overtraining and all effect sizes are integrated out for posterior inference. For binary traits, the logistic model has not yielded clear improvements over the linear model. For multi-SNP analysis, the logistic model required costly and technically challenging MCMC sampling to perform the integration. Here, we introduce the quasi-Laplace approximation to solve the integral and avoid MCMC sampling. We expect the logistic model to perform much better than multiple linear regression except when predicted disease risks are spread closely around 0.5, because only close to its inflection point can the logistic function be well approximated by a linear function. Indeed, in extensive benchmarks with simulated phenotypes and real genotypes, our Bayesian multiple LOgistic REgression method (B-LORE) showed considerable improvements (1) when regressing on many variants in multiple loci at heritabilities ≥ 0.4 and (2) for unbalanced case-control ratios. B-LORE also enables meta-analysis by approximating the likelihood functions of individual studies by multivariate normal distributions, using their means and covariance matrices as summary statistics. Our work should make sparse multiple logistic regression attractive also for other applications with binary target variables. B-LORE is freely available from: https://github.com/soedinglab/b-lore.
Subject(s)
Bayes Theorem , Genome-Wide Association Study/statistics & numerical data , Logistic Models , Models, Genetic , Case-Control Studies , Computer Simulation , Coronary Artery Disease/genetics , Genetic Variation , Humans , Likelihood Functions , Multifactorial Inheritance , Phenotype , Polymorphism, Single Nucleotide , SoftwareABSTRACT
Soluble methane monooxygenase (sMMO) carries out methane oxidation at 4 °C and under ambient pressure in a catalytic cycle involving the formation of a peroxodiiron(III) intermediate (P) from the oxygenation of the diiron(II) enzyme and its subsequent conversion to Q, the diiron(IV) oxidant that hydroxylates methane. Synthetic diiron(IV) complexes that can serve as models for Q are rare and have not been generated by a reaction sequence analogous to that of sMMO. In this work, we show that [FeII(Me3NTB)(CH3CN)](CF3SO3)2 (Me3NTB = tris((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)amine) (1) reacts with O2 in the presence of base, generating a (µ-1,2-peroxo)diiron(III) adduct with a low O-O stretching frequency of 825 cm-1 and a short Fe···Fe distance of 3.07 Å. Even more interesting is the observation that the peroxodiiron(III) complex undergoes O-O bond cleavage upon treatment with the Lewis acid Sc3+ and transforms into a bis(µ-oxo)diiron(IV) complex, thus providing a synthetic precedent for the analogous conversion of P to Q in the catalytic cycle of sMMO.
Subject(s)
Coordination Complexes/chemistry , Iron/chemistry , Scandium/chemistry , Coordination Complexes/chemical synthesis , Oxidation-Reduction , Oxygen/chemistry , Spectroscopy, Mossbauer , Spectrum Analysis, RamanABSTRACT
This work directly compares the spectroscopic and reactivity properties of an oxoiron(IV) and an oxoiron(V) complex that are supported by the same neutral tetradentate N-based PyNMe3 ligand. A complete spectroscopic characterization of the oxoiron(IV) species (2) reveals that this compound exists as a mixture of two isomers. The reactivity of the thermodynamically more stable oxoiron(IV) isomer (2b) is directly compared to that exhibited by the previously reported 1e--oxidized analogue [FeV(O)(OAc)(PyNMe3)]2+ (3). Our data indicates that 2b is 4 to 5 orders of magnitude slower than 3 in hydrogen atom transfer (HAT) from C-H bonds. The origin of this huge difference lies in the strength of the O-H bond formed after HAT by the oxoiron unit, the O-H bond derived from 3 being about 20 kcal·mol-1 stronger than that from 2b. The estimated bond strength of the FeIVO-H bond of 100 kcal·mol-1 is very close to the reported values for highly active synthetic models of compound I of cytochrome P450. In addition, this comparative study provides direct experimental evidence that the lifetime of the carbon-centered radical that forms after the initial HAT by the high valent oxoiron complex depends on the oxidation state of the nascent Fe-OH complex. Complex 2b generates long-lived carbon-centered radicals that freely diffuse in solution, while 3 generates short-lived caged radicals that rapidly form product C-OH bonds, so only 3 engages in stereoretentive hydroxylation reactions. Thus, the oxidation state of the iron center modulates not only the rate of HAT but also the rate of ligand rebound.
Subject(s)
Iron Compounds/chemistry , Oxygen/chemistry , Iron Compounds/chemical synthesis , Ligands , Molecular Structure , Spectrophotometry, Ultraviolet , Spectroscopy, Near-Infrared , Spectrum Analysis, Raman , X-Ray Absorption SpectroscopyABSTRACT
The [FeIV (O)(Me3 NTB)]2+ (Me3 NTB=tris[(1-methyl-benzimidazol-2-yl)methyl]amine) complex 1 has been shown by Mössbauer spectroscopy to have an S=1 ground state at 4â K, but is proposed to become an S=2 trigonal-bipyramidal species at higher temperatures based on a DFT model to rationalize its very high C-H bond-cleavage reactivity. In this work, 1 Hâ NMR spectroscopy was used to determine that 1 does not have C3 -symmetry in solution and is not an S=2 species. Our results show that 1 is unique among nonheme FeIV =O complexes in retaining its S=1 spin state and high reactivity at 193â K, providing evidence that S=1 FeIV =O complexes can be as reactive as their S=2 counterparts. This result emphasizes the need to identify factors besides the ground spin state of the FeIV =O center to rationalize nonheme oxoiron(IV) reactivity.
ABSTRACT
We examine the separation distance dependence of the hydrophobic force by systematically varying the distance (d) between two walls. The hydrophobic force exhibits a distance mediated crossover from a liquid-like to a gas-like behavior at around d â¼ 12 Å for 1 atm pressure. The distance dependence can be fitted to a bi-exponential form, with the longer distance part displaying a correlation length of 20 Å. In addition, the crossover is found to be accompanied by a divergent-like growth of the local relative number fluctuation of the water molecules confined between the two surfaces. Furthermore, at a fixed separation (d = 20 Å), we observe a pressure induced structural modification of confined water at high pressure. The confined water is found to form an ordered structure at high pressure (10 000 atm) and room temperature, in agreement with the experimental study [G. Algara-Siller et al. Nature 519(7544), 443 (2015)].
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Research on effectiveness of DAA is limited. Existing researches explore impact of DAA only on relationship between drug manufacturers and consumers. However, in reality, pharma marketing revolves around three major stakeholders: the pharmaceutical companies, physicians and consumers. Pharmaceutical professionals on behalf of drug manufacturers have last mile connectivity with end users and they are an important stakeholder in this entire marketing relationship network. So, it is important for marketers to capture views of pharma professionals in addition to physicians and consumers. The current research evaluates views of consumers and pharmaceutical professionals about effectiveness of unbranded DAA for product message communication.
Subject(s)
Awareness , Consumer Health Information , Direct-to-Consumer Advertising/trends , Drug Industry/organization & administration , Health Communication , Hepatitis C, Chronic , Humans , Marketing/methodsABSTRACT
Oxoiron(IV) units are often implicated as intermediates in the catalytic cycles of non-heme iron oxygenases and oxidases. The most reactive synthetic analogues of these intermediates are supported by tetradentate tripodal ligands with N-methylbenzimidazole or quinoline donors, but their instability precludes structural characterization. Herein we report crystal structures of two [FeIV (O)(L)]2+ complexes supported by pentadentate ligands incorporating these heterocycles, which show longer average Fe-N distances than the complex with only pyridine donors. These longer distances correlate linearly with log k2 ' values for O- and H-atom transfer rates, suggesting that weakening the ligand field increases the electrophilicity of the Fe=O center. The sterically bulkier quinoline donors are also found to tilt the Fe=O unit away from a linear N-Fe=O arrangement by 10°.
ABSTRACT
STUDY OBJECTIVE: To compare the effects of the laparoscopic approach versus the vaginal route for the management of vaginal cuff closure during total laparoscopic hysterectomy on female sexual function in premenopausal patients with benign gynecologic conditions. DESIGN: A prospective study with a randomized, double-blind design (Canadian Task Force Classification I). SETTING: A university hospital. PATIENTS: Patients who were scheduled to have total laparoscopic hysterectomy because of benign conditions. INTERVENTIONS: Patients were randomized to vaginal cuff closure via the vaginal route versus the laparoscopic approach. The study included a total of 70 patients; 34 underwent the laparoscopic approach in the management of vaginal cuff closure, and 36 underwent the vaginal route. MEASUREMENTS AND MAIN RESULTS: Female sexual function and vaginal length were measured. The duration of total surgery was significantly shorter in the laparoscopic approach group compared with the vaginal route group (112.2 ± 36.5 vs 122.7 ± 53.6, p < .05). The total Female Sexual Function Index scores preoperatively and 3 months postoperatively were similar between the laparoscopic approach and vaginal route groups (all p > .05). Vaginal lengths 3 months postoperatively were significantly longer in the laparoscopic approach group compared with the vaginal route group (8.39 ± 0.90 vs 7.34 ± 1.17, p < .05). The duration of cuff closure was significantly shorter in the vaginal route group compared with the laparoscopic approach group (8.92 ± 2.23 vs 7.51 ± 2.5, p < .05). Preoperative vaginal lengths were significantly longer in comparison with 3 months postoperatively both in the laparoscopic approach and the vaginal route groups (all p < .05). The preoperative total Female Sexual Function Index scores were significantly higher in comparison with 3 months postoperatively both in the laparoscopic approach and the vaginal route groups (all p < .05). CONCLUSION: The results of this study indicate that the laparoscopic approach for vaginal cuff closure might be preferable because of better postoperative vaginal length and a shorter duration of total surgery time.
Subject(s)
Hysterectomy/methods , Laparoscopy , Sexual Behavior/physiology , Vagina/anatomy & histology , Adult , Double-Blind Method , Female , Humans , Hysterectomy/adverse effects , Hysterectomy, Vaginal/methods , Middle Aged , Operative Time , Prospective Studies , Sexual Dysfunction, Physiological/etiology , Vagina/surgeryABSTRACT
A new BODIPY derivative with 2,2'-(ethane-1,2-diylbis(oxy))bis(N,N-bis(pyridine-2-ylmethyl)aniline unit as the metal receptor has been designed and synthesized. The dye selectively detects either Cd(2+) or Hg(2+) ions in the presence of hosts of other biologically important and environmentally relevant metal ions in aqueous medium at physiological pH. Binding of metal ions causes a change in the emission behavior of the dye from weakly fluorescent to highly fluorescent. Confocal microscopic experiments validate that the dye can be used to identify changes in either Hg(2+) or Cd(2+) levels in living cells.
Subject(s)
Cadmium/analysis , Fluorescent Dyes/chemistry , Mercury/analysis , Cells, Cultured , Fluorescent Dyes/chemical synthesis , HeLa Cells , Humans , Hydrogen-Ion Concentration , Ions/analysis , Models, Molecular , Molecular Structure , Water/chemistryABSTRACT
The long range attractive force between two hydrophobic surfaces immersed in water is observed to decrease exponentially with their separation-this distance-dependence of effective force is known as the hydrophobic force law (HFL). We explore the microscopic origin of HFL by studying distance-dependent attraction between two parallel rods immersed in 2D Mercedes Benz model of water. This model is found to exhibit a well-defined HFL. Although the phenomenon is conventionally explained by density-dependent theories, we identify orientation, rather than density, as the relevant order parameter. The range of density variation is noticeably shorter than that of orientational heterogeneity. The latter is comparable to the observed distances of hydrophobic force. At large separation, attraction between the rods arises primarily from a destructive interference among the inwardly propagating oppositely oriented heterogeneity generated in water by the two rods. As the rods are brought closer, the interference increases leading to a decrease in heterogeneity and concomitant decrease in free energy of the system, giving rise to the effective attraction. We notice formation of hexagonal ice-like structures at the onset of attractive region which suggests that metastable free energy minimum may play a role in the origin of HFL.
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BACKGROUND: We recently reported induction of broadly neutralizing antibodies (bnAbs) against multiple HIV-1 (human immunodeficiency virus type 1) isolates in rabbits, albeit weak against tier 2 viruses, using a monomeric gp120 derived from an M group consensus sequence (MCON6). To better understand the nature of the neutralizing activity, detailed characterization of immunological properties of the protein was performed. Immunogenic linear epitopes were identified during the course of immunization, and spatial distribution of these epitopes was determined. Subdomain antibody target analyses were done using the gp120 outer domain (gp120-OD) and eOD-GT6, a protein based on a heterologous sequence. In addition, refined epitope mapping analyses were done by competition assays using several nAbs with known epitopes. RESULTS: Based on linear epitope mapping analyses, the V3 loop was most immunogenic, followed by C1 and C5 regions. The V1/V2 loop was surprisingly non-immunogenic. Many immunogenic epitopes were clustered together even when they were distantly separated in primary sequence, suggesting the presence of immunogenic hotspots on the protein surface. Although substantial antibody responses were directed against the outer domain, only about 0.1% of the antibodies bound eOD-GT6. Albeit weak, antibodies against peptides that corresponded to a part of the bnAb VRC01 binding site were detected. Although gp120-induced antibodies could not block VRC01 binding to eOD-GT6, they were able to inhibit VRC01 binding to both gp120 and trimeric BG505 SOSIP gp140. The immune sera also efficiently competed with CD4-IgG2, as well as nAbs 447-52D, PGT121 and PGT126, in binding to gp120. CONCLUSIONS: The results suggest that some antibodies that bind at or near known bnAb epitopes could be partly responsible for the breadth of neutralizing activity induced by gp120 in our study. Immunization strategies that enhance induction of these antibodies relative to others (e.g. V3 loop), and increase their affinity, could improve protective efficacy of an HIV-1 vaccine.
Subject(s)
Antibody Formation , HIV Envelope Protein gp120/immunology , HIV-1/immunology , Animals , Antibodies, Neutralizing/blood , Epitope Mapping , Epitopes/immunology , HIV Antibodies/blood , RabbitsABSTRACT
Water-tert-butyl alcohol (TBA) binary mixture exhibits a large number of thermodynamic and dynamic anomalies. These anomalies are observed at surprisingly low TBA mole fraction, with x(TBA) ≈ 0.03-0.07. We demonstrate here that the origin of the anomalies lies in the local structural changes that occur due to self-aggregation of TBA molecules. We observe a percolation transition of the TBA molecules at x(TBA) ≈ 0.05. We note that "islands" of TBA clusters form even below this mole fraction, while a large spanning cluster emerges above that mole fraction. At this percolation threshold, we observe a lambda-type divergence in the fluctuation of the size of the largest TBA cluster, reminiscent of a critical point. Alongside, the structure of water is also perturbed, albeit weakly, by the aggregation of TBA molecules. There is a monotonic decrease in the tetrahedral order parameter of water, while the dipole moment correlation shows a weak nonlinearity. Interestingly, water molecules themselves exhibit a reverse percolation transition at higher TBA concentration, x(TBA) ≈ 0.45, where large spanning water clusters now break-up into small clusters. This is accompanied by significant divergence of the fluctuations in the size of largest water cluster. This second transition gives rise to another set of anomalies around. Both the percolation transitions can be regarded as manifestations of Janus effect at small molecular level.
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Rugged energy landscapes find wide applications in diverse fields ranging from astrophysics to protein folding. We study the dependence of diffusion coefficient (D) of a Brownian particle on the distribution width (É) of randomness in a Gaussian random landscape by simulations and theoretical analysis. We first show that the elegant expression of Zwanzig [Proc. Natl. Acad. Sci. U.S.A. 85, 2029 (1988)] for D(É) can be reproduced exactly by using the Rosenfeld diffusion-entropy scaling relation. Our simulations show that Zwanzig's expression overestimates D in an uncorrelated Gaussian random lattice - differing by almost an order of magnitude at moderately high ruggedness. The disparity originates from the presence of "three-site traps" (TST) on the landscape - which are formed by the presence of deep minima flanked by high barriers on either side. Using mean first passage time formalism, we derive a general expression for the effective diffusion coefficient in the presence of TST, that quantitatively reproduces the simulation results and which reduces to Zwanzig's form only in the limit of infinite spatial correlation. We construct a continuous Gaussian field with inherent correlation to establish the effect of spatial correlation on random walk. The presence of TSTs at large ruggedness (É â« k(B)T) gives rise to an apparent breakdown of ergodicity of the type often encountered in glassy liquids.
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Since the time of Kirkwood, observed deviations in magnitude of the dielectric constant of aqueous protein solution from that of neat water (â¼80) and slower decay of polarization have been subjects of enormous interest, controversy, and debate. Most of the common proteins have large permanent dipole moments (often more than 100 D) that can influence structure and dynamics of even distant water molecules, thereby affecting collective polarization fluctuation of the solution, which in turn can significantly alter solution's dielectric constant. Therefore, distance dependence of polarization fluctuation can provide important insight into the nature of biological water. We explore these aspects by studying aqueous solutions of four different proteins of different characteristics and varying sizes, chicken villin headpiece subdomain (HP-36), immunoglobulin binding domain protein G (GB1), hen-egg white lysozyme (LYS), and Myoglobin (MYO). We simulate fairly large systems consisting of single protein molecule and 20000-30000 water molecules (varied according to the protein size), providing a concentration in the range of â¼2-3 mM. We find that the calculated dielectric constant of the system shows a noticeable increment in all the cases compared to that of neat water. Total dipole moment auto time correlation function of water ⟨δMW(0)δMW(t)⟩ is found to be sensitive to the nature of the protein. Surprisingly, dipole moment of the protein and total dipole moment of the water molecules are found to be only weakly coupled. Shellwise decomposition of water molecules around protein reveals higher density of first layer compared to the succeeding ones. We also calculate heuristic effective dielectric constant of successive layers and find that the layer adjacent to protein has much lower value (â¼50). However, progressive layers exhibit successive increment of dielectric constant, finally reaching a value close to that of bulk 4-5 layers away. We also calculate shellwise orientational correlation function and tetrahedral order parameter to understand the local dynamics and structural re-arrangement of water. Theoretical analysis providing simple method for calculation of shellwise local dielectric constant and implication of these findings are elaborately discussed in the present work.
Subject(s)
Proteins/chemistry , Water/chemistry , Animals , Chickens , Models, Molecular , Muramidase/chemistry , Myoglobin/chemistry , Neurofilament Proteins/chemistry , Peptide Fragments/chemistry , Static ElectricityABSTRACT
Lung cancer is the most common neoplastic disorder associated with paraneoplastic syndromes. The most common paraneoplastic syndromes are the syndrome of inappropriate release of antidiuretic hormone (SIADH), hypercalcemia of malignancy, ectopic Cushing's syndrome, and various other neurological syndromes. A few case reports have reported gynecomastia as a paraneoplastic syndrome. Recognition of this uncommon presentation can aid in the early detection of associated malignancies, thus potentially improving outcomes. In this article, we are presenting the case of a male patient in his late sixties who, on presentation, had gynecomastia and was eventually diagnosed with non-small-cell lung cancer (NSCLC).