Polymer Translocation Dynamics in the Quasi-Static Limit

Monte Carlo (MC) simulations are used to study the dynamics of polymer translocation through a nanopore in the limit where the translocation rate is sufficiently slow that the polymer maintains a state of conformational quasi-equilibrium. The system is modeled as a flexible hard-sphere chain that translocates through a cylindrical hole in a hard flat wall. In some calculations, the nanopore is connected at one end to a spherical cavity. Translocation times are measured directly using MC dynamics simulations. For sufficiently narrow pores, translocation is sufficiently slow that the mean translocation time scales with polymer length N according to \propto (N-N_p)^2, where N_p is the average number of monomers in the nanopore; this scaling is an indication of a quasi-static regime in which polymer-nanopore friction dominates. We use a multiple-histogram method to calculate the variation of the free energy with Q, a coordinate used to quantify the degree of translocation. The free energy functions are used with the Fokker-Planck formalism to calculate translocation time distributions in the quasi-static regime. These calculations also require a friction coefficient, characterized by a quantity N_{eff}, the effective number of monomers whose dynamics are affected by the confinement of the nanopore. This was determined by fixing the mean of the theoretical distribution to that of the distribution obtained from MC dynamics simulations. The theoretical distributions are in excellent quantitative agreement with the distributions obtained directly by the MC dynamics simulations for physically meaningful values of N_{eff}. The free energy functions for narrow-pore systems exhibit oscillations with an amplitude that is sensitive to the nanopore length. Generally, larger oscillation amplitudes correspond to longer translocation times.Comment: 13 pages, 13 figure

Importance of Electronic Relaxation for Inter-Coulombic Decay in Aqueous Systems

Inspired by recent photoelectron spectroscopy experiments on hydroxide solutions, we have examined the conditions necessary for enhanced (and, in the case of solutions, detectable) inter-Coulombic decay (ICD)—Auger emission from an atomic site other than that originally excited. We present general guidelines, based on energetic and spatial overlap of molecular orbitals, for this enhancement of inter-Coulombic decay-based energy transfer in solutions. These guidelines indicate that this decay process should be exhibited by broad classes of biomolecules and suggest a design criterion for targeted radiooncology protocols. Our findings show that photoelectron spectroscopy cannot resolve the current hydroxide coordination controversy

Nuclear quantum effects in the structure and lineshapes of the N2 near-edge x-ray absorption fine structure spectrum

We study the relative ability of several models of x-ray absorption spectra to capture the Franck–Condon structure apparent from an experiment on gaseous nitrogen. In doing so, we adopt the Born–Oppenheimer approximation and a constrained density functional theory method for computing the energies of the x-ray-excited molecule. Starting from an otherwise classical model for the spectrum, we systematically introduce more realistic physics, first by substituting the quantum mechanical nuclear radial density in the bond separation R for the classical radial density, then by adding the effect of zero-point energy and other level shifts, and finally by including explicit rovibrational quantization of both the ground and excited states. The quantization is determined exactly, using a discrete variable representation (DVR). We show that the near-edge x-ray absorption fine structure (NEXAFS) spectrum can be predicted semiquantitatively within this framework. We also address the possibility of non-trivial temperature dependence in the spectrum. By using constrained density functional theory in combination with more accurate potentials, we demonstrate that it is possible to improve the predicted spectrum. Ultimately, we establish the predictive limits of our method with respect to vibrational fine structure in NEXAFS spectra

Predicting future cardiovascular disease. Do we need the oral glucose tolerance test?

WSTĘP. Celem badania było porównanie przydatności doustnego testu tolerancji glukozy (OGTT, oral glucose tolerance test) z wieloczynnikowymi modelami, uwzględniającymi powszechnie dostępne dane kliniczne do przewidywania wystąpienia w przyszłości chorób układu sercowo-naczyniowego (CVD, cardiovascular disease). MATERIAŁ I METODY. Ze spisu ludności w San Antonio losowo wybrano 2662 osoby pochodzenia latynoskiego i 1595 osób rasy białej pochodzenia nielatynoskiego, w wieku 25–64 lat, niechorujących na CVD i cukrzycę w chwili rozpoczęcia badania. Na początku badania zebrano od osób zakwalifikowanych dokładny wywiad medyczny, informacje na temat palenia tytoniu oraz zbadano ich wskaźnik masy ciała (BMI, body mass index), ciśnienie tętnicze, glikemię i insulinemię na czczo i 2 godziny po posiłku, stężenie triglicerydów oraz stężenie cholesterolu całkowitego, frakcji LDL i HDL na czczo. Choroba układu sercowo-naczyniowego pojawiła się u 88 osób pochodzenia latynoskiego i 71 osób pochodzenia nielatynoskiego w czasie 7-8-letniej obserwacji. Stworzono model krokowej, wieloczynnikowej analizy regresji logistycznej w celu przewidywania występowania CVD. Pola pod krzywą operacyjno-charakterystyczną (ROC, receiver operator chracteristic) użyto do oceny mocy przewidywania tych modeli. WYNIKI. Pole powierzchni pod wykresem ROC glikemii w 2. godzinie testu obciążenia glukozą było nieznacznie, nieznamiennie większe niż pod wykresem glikemii na czczo, oba jednak były słabym wskaźnikiem wystąpienia CVD. Pole pod wykresem ROC dla modeli wieloczynnikowych, uwzględniających łatwo dostępne dane kliniczne inne niż glikemia 2 godziny po obciążeniu glukozą, były znacznie i znamiennie większe niż pod krzywymi ROC glikemii. Uwzględnienie OGTT w tych modelach nie zwiększyło ich wartości predykcyjnych. WNIOSKI. Osoby z wysokim ryzykiem wystąpienia CVD można skuteczniej rozpoznać za pomocą prostych modeli predykcyjnych niż na podstawie wyniku OGTT. Uwzględnienie tego ostatniego w modelach prawdopodobnie nieznacznie, jeżeli w ogóle, zwiększa ich siłę predykcyjną.INTRODUCTION. Our objective was to compare the performance of oral glucose tolerance tests (OGTTs) and multivariate models incorporating commonly available clinical variables in their ability to predict future cardiovascular disease (CVD). MATERIAL AND METHODS. We randomly selected 2662 Mexican-Americans and 1595 non-Hispanic whites, 25–64 years of age, who were free of both CVD and known diabetes at baseline from several San Antonio census tracts. Medical history, cigarette smoking history, BMI, blood pressure, fasting and 2-h plasma glucose and serum insulin levels, triglyceride level, and fasting serum total, LDL, and HDL cholesterol levels were obtained at baseline. CVD developed in 88 Mexican-Americans and 71 non-Hispanic whites after 7–8 years of follow-up. Stepwise multiple logistic regression models were developed to predict incident CVD. The areas under receiver operator characteristic (ROC) curves were used to assess the predictive power of these models. RESULTS. The area under the 2-h glucose ROC curve was modestly but not significantly greater than under the fasting glucose curve, but both were relatively weak predictors of CVD. The areas under the ROC curves for the multivariate models incorporating readily available clinical variables other than 2-h glucose were substantially and significantly greater than under the glucose ROC curves. Addition of 2-h glucose to these models did not improve their predicting power. CONCLUSIONS. Better identification of individuals at high risk for CVD can be achieved with simple predicting models than with OGTTs, and the addition of the latter adds little if anything to the predictive power of the model

Saturable Absorption of Free-Electron Laser Radiation by Graphite near the Carbon K-Edge

The interaction of intense light with matter gives rise to competing nonlinear responses that can dynamically change material properties. Prominent examples are saturable absorption (SA) and two-photon absorption (TPA), which dynamically increase and decrease the transmission of a sample depending on pulse intensity, respectively. The availability of intense soft X-ray pulses from free-electron lasers (FELs) has led to observations of SA and TPA in separate experiments, leaving open questions about the possible interplay between and relative strength of the two phenomena. Here, we systematically study both phenomena in one experiment by exposing graphite films to soft X-ray FEL pulses of varying intensity. By applying real-time electronic structure calculations, we find that for lower intensities the nonlinear contribution to the absorption is dominated by SA attributed to ground-state depletion; our model suggests that TPA becomes more dominant for larger intensities (\u3e1014 W/cm2). Our results demonstrate an approach of general utility for interpreting FEL spectroscopies

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

BackgroundThe recent emergence of COVID-19, rapid worldwide spread, and incomplete knowledge of molecular mechanisms underlying SARS-CoV-2 infection have limited development of therapeutic strategies. Our objective was to systematically investigate molecular regulatory mechanisms of COVID-19, using a combination of high throughput RNA-sequencing-based transcriptomics and systems biology approaches. MethodsRNA-Seq data from peripheral blood mononuclear cells (PSPRINGER NATUREs) of healthy persons, mild and severe 17 COVID-19 patients were analyzed to generate a gene expression matrix. Weighted gene co-expression network analysis (WGCNA) was used to identify co-expression modules in healthy samples as a reference set. For differential co-expression network analysis, module preservation and module-trait relationships approaches were used to identify key modules. Then, protein-protein interaction (PPI) networks, based on co-expressed hub genes, were constructed to identify hub genes/TFs with the highest information transfer (hub-high traffic genes) within candidate modules. ResultsBased on differential co-expression network analysis, connectivity patterns and network density, 72% (15 of 21) of modules identified in healthy samples were altered by SARS-CoV-2 infection. Therefore, SARS-CoV-2 caused systemic perturbations in host biological gene networks. In functional enrichment analysis, among 15 non-preserved modules and two significant highly-correlated modules (identified by MTRs), 9 modules were directly related to the host immune response and COVID-19 immunopathogenesis. Intriguingly, systemic investigation of SARS-CoV-2 infection identified signaling pathways and key genes/proteins associated with COVID-19's main hallmarks, e.g., cytokine storm, respiratory distress syndrome (ARDS), acute lung injury (ALI), lymphopenia, coagulation disorders, thrombosis, and pregnancy complications, as well as comorbidities associated with COVID-19, e.g., asthma, diabetic complications, cardiovascular diseases (CVDs), liver disorders and acute kidney injury (AKI). Topological analysis with betweenness centrality (BC) identified 290 hub-high traffic genes, central in both co-expression and PPI networks. We also identified several transcriptional regulatory factors, including NFKB1, HIF1A, AHR, and TP53, with important immunoregulatory roles in SARS-CoV-2 infection. Moreover, several hub-high traffic genes, including IL6, IL1B, IL10, TNF, SOCS1, SOCS3, ICAM1, PTEN, RHOA, GDI2, SUMO1, CASP1, IRAK3, HSPA5, ADRB2, PRF1, GZMB, OASL, CCL5, HSP90AA1, HSPD1, IFNG, MAPK1, RAB5A, and TNFRSF1A had the highest rates of information transfer in 9 candidate modules and central roles in COVID-19 immunopathogenesis. ConclusionThis study provides comprehensive information on molecular mechanisms of SARS-CoV-2-host interactions and identifies several hub-high traffic genes as promising therapeutic targets for the COVID-19 pandemic

Importance of Electronic Relaxation for Inter-Coulombic Decay in Aqueous Systems

Inspired by recent photoelectron spectroscopy (PES) experiments on hydroxide solutions, we have examined the conditions necessary for enhanced (and, in the case of solutions, detectable) intercoulombic decay (ICD)--Auger emission from an atomic site other than that originally excited. We present general guidelines, based on energetic and spatial overlap of molecular orbitals, for this enhancement of ICDbased energy transfer in solutions. These guidelines indicate that this decay process should be exhibited by broad classes of biomolecules and suggest a design criterion for targeted radiooncology protocols. Our findings show that PES cannot resolve the current hydroxide coordination controversy

A comparison of alternative assays to measure DNA damage in stallion spermatozoa: TUNEL test versus ‘Nicoletti assay’

The aberrations of sperm DNA may cause various problems and have negative consequences on fertility. These influence embryonic development or might lead to early embryo loss. Sperm Chromatin Structure Assay (SCSA) is the flow cytometric method most often used for the detection of DNA lesions; however, some studies using that method reached confusing conclusions. The aim of this pilot study was to adjust and compare two alternative tests, namely the TUNEL test and the Nicoletti assay. The above-mentioned two flow cytometric methods capable of detecting the fragmented DNA of sperm were tested on 12 frozen-thawed stallion semen samples. The TUNEL test demonstrated much higher DNA fragmentation ratio than the Nicoletti assay (mean ± SD: 30.77 ± 13.03% vs. 1.93 ± 0.89%, respectively). A fluorescent microscopic check of the samples showed that TUNEL labelled the plasma membrane and the mitochondria in a nonspecific way, rather than detecting only the fragmented DNA, thus eventually resulting in a false positive sign. The Nicoletti assay is simpler, quicker and does not detect nonspecific binding; however, further analyses are required to determine its diagnostic value