Background: The ever-growing emergence of antibiotic resistance associated with tuberculosis (TB) has become a global challenge. In 2012, USFDA has given expedited approval to bedaquiline (BDQ), as a new treatment for drug-resistant TB in adults when no other viable options are available. BDQ is a diarylquinoline derivative and exhibits targeted action on mycobacterium tuberculosis but due to poor solubility desired therapeutic action is not achieved. Objective: To develop a QbD-based self-nanoemulsifying drug delivery system of Bedaquiline using various oils, surfactants, and co-surfactants. Methods: The quality target product profile (QTPP) and critical quality attributes (CQAs) were identified with a patient-centric approach which facilitated the selection of critical material attributes (CMAs) during pre-formulation studies and initial risk assessment. Caprylic acid as a lipid, propylene glycol as a surfactant and Transcutol-P as a co-surfactant were selected as CMAs for the formulation of Bedaquiline fumarate SNEDDS. Pseudo-ternary phase diagrams were constructed to determine the optimal ratio of oil and Smix. To optimize the formulation, a Box-Benkhen design (BBD) was used. The optimized formulation (BDQ-F-SNEDSS) was further evaluated for parameters such as droplet size, polydispersity index (PDI), percentage transmittance, dilution studies, stability studies, and cell toxicity through the A549 cell. Results: Optimized BDQ-F-SNEDDS showed well-formed droplets of 98.88±2.1 nm with a zeta potential of 21.16 mV. In vitro, studies showed enhanced drug release with a high degree of stability at 25 ± 2 ºC & 60 ± 5 % and 40 ± 2 ºC & 75± 5 %. Furthermore, BDQ-F-SNEDDS showed promising cell viability in A549 cells indicating BDQ-F-SNEDDS as a safer formulation for oral delivery. Conclusion: Finally, it was concluded that the utilization of a QbD approach in the development of BDQ-F-loaded SNEDDS offers a promising strategy to improve the biopharmaceutical properties of the drug, resulting in potential cost and time savings.

This study describes all the properties of high T_c cuprates by introducing rotating holes that are created by angular momentum conservations on a 2D CuO₂ surface, and which have a different mass from that of a normal hole because of the magnetic field energy induced by the rotation. This new particle called a macroscopic Boson describes the doping dependences of pseudo-gap temperature and the transition temperature at which an anomaly metal phase appears and describes the origin of the pseudo-gap. Furthermore, this study introduces a new model to handle many-body interactions, which results in a new statistic equation. This statistic equation describing many-body interactions accurately explains why high T_c cuprates have significantly high critical temperatures. Moreover a partition function of macroscopic Bosons describes all the properties of anomaly metal phase, which sufficiently agree with experiments, using the result from our previous study [1] that analytically describes the doping dependence of T_c. By introducing a macroscopic Boson and the new statistical model for many-body interactions, this study uncovered the mystery of high T_c cuprates, which have been a challenge for many researchers. An important point is that, in this study, pure analytical calculations are consistently conducted, which agree with experimental data well (i.e., they do not use numerical calculations or fitting methods but use many actual physical constants).

Can a gravitational lens magnify gravity ? The answer to this question is the subject of this article. Light is deflected as it passes through curved spacetime caused by a mass distribution. This phenomenon, known as "gravitational lensing," has been extensively studied and is well understood. According to the general theory of relativity, the same deflection is expected for gravitational waves, because they also propagate at the speed of light. But this applies to gravitational fields as well. Thus, gravitational fields, which extend through curved spacetime, are also deflected correspondingly. This effect is referred to as "Gravitationally Lensed Gravity". It leads to the fact that the gravitational field strength originating from an object in the background of a gravitational lens is enhanced in the same way as its light intensity. If the background object is visible to an observer several times due to the gravitational lens, each of the images also exerts a corresponding gravitational attraction on her ! For the first time, a proof of the existence of this amazing effect is given. In a simple thought experiment the contraction of a spherically symmetric gravitational lens is discussed. The proof is essentially based on Birkhoff's theorem. According to this theorem, during the contraction additional null geodesics between the background object and the observer come into existence. To these null geodesics also contributions to the gravitational field are to be assigned. In the literature, similar descriptions can be found for the gravitational self-interaction of a particle in a curved spacetime background. The article is organized as follows: In the introduction, the historical origin of the idea of the "Gravitationally Lensed Gravity" is briefly outlined. In the second chapter, the subsequently required basic principles and essential features of general relativity are explained. In the third chapter I analyze different arrangements of masses and describe the observations to be expected. The arrangements show step by step the transition from the classical "Newtonian limit" in a flat spacetime background to the "Gravitationally Lensed Gravity" in a curved spacetime background. Due to its clarity, the simple scenario may also serves as a suitable test case for the mathematical methods of general relativity. The concluding outlook provides references to current questions in astrophysics, especially the question of the existence of Dark Matter. Here, the general theory of relativity offers much simpler explanations with the "Gravitationally Lensed Gravity".

A gravitational lens is mass-curved spacetime. Light that propagates freely, locally always on the fastest way, follows curved paths in it. The same applies to all effects propagating with the speed of light, also to gravity itself. They all have to follow the curvature of spacetime. A gravitational lens not only enhances the light from background objects but concurrently also their gravitational effect ! The "Gravitationally Lensed Gravity" (GLG) is a still scarcely noticed peculiar feature of general relativity. In [1] I presented a thought experiment to make the existence of this effect plausible. Here these considerations are described in terms of future and past light cones or null cones commonly used in relativity theory to illustrate the causal structure of spacetime. In the framework of general relativity, the GLG effect can be understood as a consequence of the folding of the past null cone by a gravitational lens. Starting from the basic ideas of the theory, the terms are introduced and applied. The extensive description on textbook level should be understandable also for beginners. In order not to obstruct the view on the essential physical relations, I avoid a mathematical formalism and use instead diagrams and figures, based on realistic numerical calculations, to reinforce my logical argumentation. Experts will recognize many long-known facts, but may still be surprised by the resulting conclusions. First, I present some particular aspects of the historical evolution of the concept of gravitational lensing and give a brief overview of the work of other authors on the subject GLG. I then explain the limitations of the applicability of the "Newtonian Limit" and move on to the key role of the speed of gravity in understanding GLG. Finally, I use a simple example to illustrate the possible significance of the GLG effect. With this work I intend to elicit greater interest in "Gravitationally Lensed Gravity" and to initiate a broader discussion about it.

This article presents six probability distributions from the Gamma family with three parameters, for the flood frequency analysis in hydrology. The choice of the Gamma family of statistical dis-tributions was driven by its frequent use in hydrology. In the Faculty of Hydrotechnics, the im-provement of the estimation of maximum flows and including the methodological bases for the realization of a regionalization study with the linear moments method with the corrected pa-rameters was researched, being an element of novelty. The linear moments method is better than MOM because it avoids the choice of skewness depending on the origin of the flows, practiced in Romania. The L-moments method conforms to the current trend for estimating the parameters of statistical distributions. Observed data from hydrometric stations are of relatively short length, so the statistical parameters that characterize them are of a sample that requires correction. The correction of the statistical parameters is proposed, using the method of least squares based on the inverse functions of the statistical distributions expressed with the frequency factor for L-moments. All the necessary elements for their use are presented like, quantile functions, the exact and ap-proximate relations for estimating parameters and frequency factors. A flood frequency analysis case study was carried out for the Ialomita river, to verify the proposed methodology. The per-formance of this distributions is evaluated using Kiling-Gupta and Nash-Sutcliff coefficients.

With reference to electromagnetic interaction and Abdus Salam’s strong (nuclear) gravity, 1) Square root of ‘reciprocal’ of the strong coupling constant can be considered as the strength of nuclear elementary charge. 2) ‘Reciprocal’ of the strong coupling constant can be considered as the maximum strength of nuclear binding energy. 3) In deuteron, strength of nuclear binding energy is around unity and there exists no strong interaction in between neutron and proton. $G_s\cong 3.32688\times {10}^{28}{\mathrm{m}}^3{\mathrm{kg}}^{-1}{\sec }^{-2}$ being the nuclear gravitational constant, nuclear charge radius can be shown to be, $R_0\cong \frac{2G_s{m}_p}{c^2}\cong 1.24\mathrm{fm}.$ $e_s\cong \left(\frac{G_s{m}_p^2}{\hslash c}\right)e\cong 4.716785\times {10}^{-19}\mathrm{C}$ being the nuclear elementary charge, proton magnetic moment can be shown to be, ${\mu }_p\cong \frac{e_s\hslash }{2m_p}\cong \frac{e{G}_s{m}_p}{2c}\cong 1.48694\times {10}^{-26}\mathrm{J}{.\mathrm{T}}^{-1}.$ ${\alpha }_s\cong {\left(\frac{\hslash c}{G_s{m}_p^2}\right)}^2\cong 0.1153795$ being the strong coupling constant, strong interaction range can be shown to be proportional to $\exp \left(\frac{1}{{\alpha }_s^2}\right).$ Interesting points to be noted are: An increase in the value of ${\alpha }_s$ helps in decreasing the interaction range indicating a more strongly bound nuclear system. A decrease in the value of ${\alpha }_s$ helps in increasing the interaction range indicating a more weakly bound nuclear system. From $Z\cong 30$ onwards, close to stable mass numbers, nuclear binding energy can be addressed with, ${\left(B\right)}_{A_s}\cong Z\times \left\{\left(\frac{1}{{\alpha }_s}+1\right)+\sqrt{\sqrt{30\times 31}}\right\}\left(m_n-m_p\right)c^2\approx Z\times 19.66\mathrm{MeV}.$ With further study, magnitude of the Newtonian gravitational constant can be estimated with nuclear elementary physical constants. One sample relation is, $\left(\frac{G_N}{G_s}\right)\cong \frac{1}{2}{\left(\frac{m_e}{m_p}\right)}^{10}\left[\sqrt{\frac{G_F}{\hslash c}}/\left(\frac{\hslash }{m_{e}c}\right)\right]$ where $G_N$ represents the Newtonian gravitational constant and $G_F$ represents the Fermi’s weak coupling constant. Two interesting coincidences are, ${\left(m_p/m_e\right)}^{10}\cong \exp \left(1/{\alpha }_s^2\right)$ and $2G_s{m}_e/c^2\cong \sqrt{G_F/\hslash c}.$

Current prenatal genetic evaluation showed a significantly increase in non-invasive screening and the reduction of invasive diagnostic procedures. To evaluate the diagnostic efficacy on detecting common aneuploidies, structural chromosomal rearrangements and pathogenic copy number variants (pCNV), we performed a retrospective analysis on a case series initially analyzed by aneuvysion fluorescence in situ hybridization (FISH) and karyotyping then followed by array comparative genomic hybridization (aCGH). Of the 386 cases retrieved from the past decade, common aneuploidies were detected in 137 cases (35.5%), other chromosomal structural rearrangements were detected in four cases (1%), and pCNV were detected in five cases (1.3%). The relative frequencies for common aneuploidies suggested a under detection of sex chromosome aneuploidies. Approximately 9.5% of cases with common aneuploidies showed a mosaic pattern. Inconsistent results between FISH and karyotyping were noted in cases with pseudo-mosaicism introduced by culture artifact or variable cellular proliferation from cells with mosaic karyotypic complements under in vitro cell culture. Based on findings from this case series, cell-based FISH and karyotyping should be performed to detect common aneuploidies, structural chromosomal abnormalities, and mosaic pattern. DNA-based aCGH and reflex FISH should be performed to detect and confirm genomic imbalances and pCNV. Practice points to ensure the diagnostic accuracy and efficacy were summarized.