A theory of evolving natural constants embracing Einstein's theory of general relativity and Dirac's large number hypothesis

Taking a hint from Dirac's large number hypothesis, we note the existence of cosmic combined conservation laws that work to cosmologically long time. We thus modify or generalize Einstein's theory of general relativity with fixed gravitation constant $G$ to a theory for varying $G$, which can be applied to cosmology without inconsistency, where a tensor arising from the variation of G takes the place of the cosmological constant term. We then develop on this basis a systematic theory of evolving natural constants $m_{e},m_{p},e,\hslash ,k_{B}$ by finding out their cosmic combined counterparts involving factors of appropriate powers of $G$ that remain truly constant to cosmologically long time. As $G$ varies so little in recent centuries, so we take these natural constants to be constant.Comment: 29 pages, revtex

Extracellular secretion of Carocin S1 in Pectobacterium carotovorum subsp. carotovorum occurs via the type III secretion system integral to the bacterial flagellum

Background: Pectobacterium carotovorum subsp. carotovorum is a phytopathogenic enterobacterium responsible for soft rot, a disease characterized by extensive maceration of the affected plant tissue. This species also produces two or more antibacterial substances called bacteriocins, which enhance its competitiveness against related rival species. However, the secretion mechanism for low-molecular-weight bacteriocin is still unknown. Results: A mutant (flhC::Tn5) that did not secrete the low-molecular-weight bacteriocin (LMWB), Carocin S1, was generated by Tn5 insertional mutagenesis. Sequence analysis indicated that this insertion disrupted open reading frame 2 (ORF2) and ORF3 of this strain. Deletion and rescue experiments indicated that ORF2 and ORF3 were both required for extracellular LMWB secretion. The ORF2 and ORF3 sequences showed high homology with the flhD and flhC gene sequences of Pectobacterium carotovorum subsp. atroseptica, Serratia marcescens, Yersinia enterocolitica, and Escherichia coli, indicating that they likely encoded key regulatory components of the type III flagella secretion system. Conclusion: Thus, the extracellular export of Carocin S1 by Pectobacterium carotovorum subsp. carotovorum appears to utilize the type III secretion system integral to bacterial flagella

Aspisol inhibits tumor growth and induces apoptosis in breast cancer

Nonsteroidal anti-inflammatory drugs inhibit cell proliferation and induce apoptosis in various cancer cell lines, which is considered to be an important mechanism for their anti-tumor activity and cancer prevention. However, the molecular mechanisms through which these compounds induce apoptosis are not well understood. Aim: to determine the effects of nonselective cyclooxygenase-2 (COX-2) inhibitor, aspisol on breast cancer cells in vitro and in vivo. Methods: The cytotoxic activity of aspisol was evaluated by MTT assay. The apoptosis index of cells was measured by flow cytometry. Immunohistochemical staining was used to detect expressions of COX-2 and caspase-3 in MDA-MB-231 cells. The expression of bcl-2 and bax was analyzed by Western blot analysis. The content of prostaglandin E2 (PGE2) in MDA-MB-231 cells was estimated by ELISA. In vivo apoptosis of the tumor cells was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Results: Our results showed that aspisol reduced viability of MDA-MB-231 cells in time- and dose- dependent fashions and induced apoptosis by increase of caspase-3 and bax expressions while decrease of COX-2 and bcl-2 expression in vitro. In addition, exposure to aspisol decreased the basal release of PGE2. In vivo, aspisol also inhibited the proliferation of breast cancer cells and induced their apoptosis. Conclusions: Our in vitro and in vivo data indicated that the antitumor effects of aspisol on breast cancer cells was probably mediated by the induction of apoptosis, and it could be linked to the downregulation of the COX-2 or bcl-2 expression and up-regulation of caspase-3 or bax expression.Нестероидные противовоспалительные препараты ингибируют пролиферацию клеток и вызывают апоптоз во многих опухолевых клеточных линиях, что считается важным механизмом их противоопухолевой активности и профилактики развития рака. Тем не менее молекулярные механизмы апоптотического действия этих препаратов изучены недостаточно. Цель: изучить действие неспецифического ингибитора циклогексиназы-2 (COX-2) — аспизола — на злокачественные клетки рака молочной железы in vitro и in vivo. Методы: выживаемоть клеток MDA-MB-231 определяли с помощью MTT-теста. Апоптотический индекс измеряли с помощью проточной цитометрии и иммуногистохимическим окрашиванием с антителами против COX-2 и каспазы-3. Экспрессию bcl-2 и bax изучали с помощью Вестерн-блот-анализа. Содержание простагландина E2 (PGE2 ) в клетках MDA-MB-231 оценивали методом ELISA. In vivo апоптоз опухолевых клеток определяли путем выявления разрывов ДНК с помощью концевой дезоксинуклеот-идилтранферазы (метод TUNEL). Результаты: показано, что в зависимости от времени инкубации и дозы аспизол угнетал рост клеток MDA-MB-231 in vitro и вызывал их апоптоз на фоне повышения экспрессии каспазы-3 и bax, а также снижения экспрессии COX-2 и bcl-2. В условиях in vivo аспизол также ингибировал пролиферацию злокачественных клеток рака молочной железы и вызывал их апоптоз. Выводы: данные, полученные in vitro и in vivo, свидетельствуют о противоопухолевом эффекте аспизола на клетки рака молочной железы, что скорее всего опосредовано его проапоптотическим действием и может быть связано со снижением экспрессии COX-2 и bcl-2, а также повышением экспрессии каспазы-3 и bax

Non-Markovian dynamics for an open two-level system without rotating wave approximation: Indivisibility versus backflow of information

By use of the two measures presented recently, the indivisibility and the backflow of information, we study the non-Markovianity of the dynamics for a two-level system interacting with a zero-temperature structured environment without using rotating wave approximation (RWA). In the limit of weak coupling between the system and the reservoir, and by expanding the time-convolutionless (TCL) generator to the forth order with respect to the coupling strength, the time-local non-Markovian master equation for the reduced state of the system is derived. Under the secular approximation, the exact analytic solution is obtained and the sufficient and necessary conditions for the indivisibility and the backflow of information for the system dynamics are presented. In the more general case, we investigate numerically the properties of the two measures for the case of Lorentzian reservoir. Our results show the importance of the counter-rotating terms to the short-time-scale non-Markovian behavior of the system dynamics, further expose the relations between the two measures and their rationality as non-Markovian measures. Finally, the complete positivity of the dynamics of the considered system is discussed

Pre- and Postnatal Maturation are Important for Fentanyl Exposure in Preterm and Term Newborns : A Pooled Population Pharmacokinetic Study

Publisher Copyright: © 2021, The Author(s).Background and Objective Fentanyl is an opioid commonly used to prevent and treat severe pain in neonates; however, its use is off label and mostly based on bodyweight. Given the limited pharmacokinetic information across the entire neonatal age range, we characterized the pharmacokinetics of fentanyl across preterm and term neonates to individualize dosing. Methods We pooled data from two previous studies on 164 newborns with a median gestational age of 29.0 weeks (range 23.9-42.3), birthweight of 1055 g (range 390-4245), and postnatal age (PNA) of 1 day (range 0-68). In total, 673 plasma samples upon bolus dosing (69 patients; median dose 2.1 mu g/kg, median 2 boluses per patient) or continuous infusions (95 patients; median dose 1.1 mu g/kg/h for 30 h) with and without boluses were used for population pharmacokinetic modeling in NONMEM(R) 7.4. Results Clearance in neonates with birthweight of 2000 and 3000 g was 2.8- and 5.0-fold the clearance in a neonate with birthweight of 1000 g, respectively. Fentanyl clearance at PNA of 7, 14, and 21 days was 2.7-fold, 3.8-fold, and 4.6-fold the clearance at 1 day, respectively. Bodyweight-based dosing resulted in large differences in fentanyl concentrations. Depending on PNA and birthweight, fentanyl concentrations increased slowly after the start of therapy for both intermittent boluses and continuous infusion and reached a maximum concentration at 12-48 h. Conclusions As both prenatal and postnatal maturation are important for fentanyl exposure, we propose a birthweight- and PNA-based dosage regimen. To provide rapid analgesia in the first 24 h of treatment, additional loading doses need to be considered.Peer reviewe

Electroless Cu deposition process on TiN for ULSI interconnect fabrication via Pd/Sn colloid activation

In this study, (100)-orientation silicon wafer coated with TiN barrier is catalyzed by a Pd/Sn colloid, which serves as, an activator for electroless copper deposition. After activation, electroless deposition of Cu occurs on the catalytic surface. The coverage of the Cu deposit reaches 100% and the adsorptive amount of Pd is greatly increased by the conditioning process. The correlation between deposition rate, resistivity, morphology, crystal structure, and composition of the deposit when varying the temperature of the plating bath is discussed. The deposition rate of Cu is monitored by both the electrochemical method and the profilometer (alpha-step), while the other properties of the deposit are measured by four-point probe, scanning electron microscopy (SEM), x-ray diffraction (XRD), and Auger electron microscopy (AES). Deposition at 70degreesC is favorable due to the higher deposition rate, lower resistivity, less impurities, and more preferred orientation in the crystal structure than that at lower temperature. Problems regarding adhesion and high resistivity can be greatly mitigated via 400degreesC thermal annealing. The resistivity of Cu can be reduced to 2.2 muOmegacm. Moreover, trenches of 1 mum and 0.25 mum on patterned wafer have been successfully filled by electroless deposition of Cu with the aid of surfactant C12

Probing Cosmic Strings with Satellite CMB measurements

We study the problem of searching for cosmic string signal patterns in the present high resolution and high sensitivity observations of the Cosmic Microwave Background (CMB). This article discusses a technique capable of recognizing Kaiser-Stebbins effect signatures in total intensity anisotropy maps, and shows that the biggest factor that produces confusion is represented by the acoustic oscillation features of the scale comparable to the size of horizon at recombination. Simulations show that the distribution of null signals for pure Gaussian maps converges to a $\chi^2$ distribution, with detectability threshold corresponding to a string induced step signal with an amplitude of about 100 \muK which corresponds to a limit of roughly $G\mu < 1.5\times 10^{-6}$. We study the statistics of spurious detections caused by extra-Galactic and Galactic foregrounds. For diffuse Galactic foregrounds, which represents the dominant source of contamination, we derive sky masks outlining the available region of the sky where the Galactic confusion is sub-dominant, specializing our analysis to the case represented by the frequency coverage and nominal sensitivity and resolution of the Planck experiment.Comment: 14 pages, 3 figures, to be published in JCA

Maturation of Paracetamol Elimination Routes in Preterm Neonates Born Below 32 Weeks of Gestation

Purpose: Despite being off-label, intravenous paracetamol (PCM) is increasingly used to control mild-to-moderate pain in preterm neonates. Here we aim to quantify the maturation of paracetamol elimination pathways in preterm neonates born below 32 weeks of gestation. Methods: Datasets after single dose (rich data) or multiple doses (sparse data) of intravenous PCM dose (median (range)) 9 (3–25) mg/kg were pooled, containing 534 plasma and 44 urine samples of PCM and metabolites (PCM–glucuronide, PCM–sulfate, PCM–cysteine, and PCM–mercapturate) from 143 preterm neonates (gestational age 27.7 (24.0–31.9) weeks, birthweight 985 (462–1,925) g, postnatal age (PNA) 5 (0–30) days, current weight 1,012 (462–1,959) g. Population pharmacokinetic analysis was performed using NONMEM® 7.4. Results: For a typical preterm neonate (birthweight 985 g; PNA 5 days), PCM clearance was 0.137 L/h, with glucuronidation, sulfation, oxidation and unchanged renal clearance accounting for 5.3%, 73.7%, 16.3% and 4.6%, respectively. Maturational changes in total PCM clearance and its elimination pathways were best described by birthweight and PNA. Between 500–1,500 g birthweight, total PCM clearance increases by 169%, with glucuronidation, sulfation and oxidation clearance increasing by 347%, 164% and 164%. From 1–30 days PNA for 985 g birthweight neonate, total PCM clearance increases by 167%, with clearance via glucuronidation and oxidation increasing by 551%, and sulfation by 69%. Conclusion: Birthweight and PNA are the most important predictors for maturational changes in paracetamol clearance and its glucuronidation, sulfation and oxidation. As a result, dosing based on bodyweight alone will not lead to consistent paracetamol concentrations among preterm neonates.</p

Algorithm engineering for optimal alignment of protein structure distance matrices

Protein structural alignment is an important problem in computational biology. In this paper, we present first successes on provably optimal pairwise alignment of protein inter-residue distance matrices, using the popular Dali scoring function. We introduce the structural alignment problem formally, which enables us to express a variety of scoring functions used in previous work as special cases in a unified framework. Further, we propose the first mathematical model for computing optimal structural alignments based on dense inter-residue distance matrices. We therefore reformulate the problem as a special graph problem and give a tight integer linear programming model. We then present algorithm engineering techniques to handle the huge integer linear programs of real-life distance matrix alignment problems. Applying these techniques, we can compute provably optimal Dali alignments for the very first time