Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Topography-driven electrostatic charge models for molecules

A new method has been proposed for the generation of charge models for use in molecular interaction studies. These models have been developed so as to reproduce the essential topographical features of the corresponding ab initio molecular electrostatic potential. This has been achieved via the fitting of variable parameters in the model, such as point charges and their location, as well as the charge on the diffuse "floating" Gaussian, its exponent and center. Test applications to H<SUB>2</SUB>O and NH<SUB>3</SUB> are reported

Shapes and sizes of molecular anions via topographical analysis of electrostatic potential

The theorem proposed by Pathak and Gadre [J. Chem. Phys. 93, 1770 (1990)], that the electrostatic potential (ESP) of negative ions must exhibit a directional negative valued minimum along any arbitrary direction has been verified for some small negative molecular ions, viz., OH<SUP>-</SUP>, CN<SUP>-</SUP>, N<SUP>-</SUP><SUB>3</SUB>, NO<SUP>-</SUP><SUB>3</SUB>, and NH<SUP>-</SUP><SUB>2</SUB>. Also, as predicted by Gadre and Pathak [Proc. Ind. Acad. Sci. (Chem. Sci.) 102, 18 (1989)], the molecular ESP (MESP) maps are found to be devoid of local maxima. As a consequence, these maps reveal rich topographical details in the form of several saddle points as well as point minima. From the location of these critical points, estimates of the sizes and shapes of the negatively charged molecular ions are obtained. For anions, there exists a surface on which V dS=0 and which passes through all the negative valued critical points (&#8711;V=0). The ionic size estimates from the location of the critical points of the MESP are found to be in good agreement with the corresponding (spherically averaged) literature values

Molecular electrostatic charge models: a topographical approach

Electrostatic charge models for molecules have been developed by employing the critical topographical features of the molecular electrostatic potential (MESP) as the "fitting" criterion. These models include one or more spherical Gaussians for incorporating the continuous electron-charge distribution in addition to the positive valued point charges representing the nuclei. The model parameters (point charges, the orbital exponents, and Gaussian centers) are optimized so as to mimic the extremal characteristics of the corresponding quantum chemical MESP. The test cases reported here include methane, ethylene, and methanol molecules. The charge models developed using the present method are seen to satisfactorily reproduce the ab initio MESP and its extremal features

Use of second-moment constraints for the refinement of determinantal wave functions

A constrained least-squares fit procedure wherein the integral F[&#961;(r)-&#961;0(r)]2 dr is minimized [&#961;0(r) is the reference near-Hartree-Fock (NHF) electron density distribution and &#961;(r) is the refined one obtained from a single Slater determinant] has been developed. The constraints applied are the exact theoretical &#961;2 and r2 expectation values. These expectation values are expected to tailor the electron density around the nuclear and tail regions, respectively. The procedure has been applied to lithium and beryllium atoms as test cases. Nearly all the rn and pn (for n=-2, -1, 1, 3, 4, and 5) expectation values have been improved with use of this procedure. The sacrifice in the electronic energy, in comparison to the corresponding NHF one, is about 0.02% in both cases

Application of rigorous bounds for efficient evaluation of molecular electrostatic potentials

Rigorous upper bounds to electrostatic potential integrals over Gaussian basis sets have been exploited for accurate and speedy evaluation of molecular electrostatic potentials (MESP). These bounds are applied to eliminate those pairs of Gaussians which contribute insignificantly to the total MESP. An efficient algorithm for MESP mapping has been developed with the help of these bounds. Further, rigorous inequalities to the auxiliary functions Fm(t), were derived. Some of these bounds are so tight that they are employed as a good approximation to Fm(t). The algorithm developed by incorporation of the above aspects is tested on trans-butadiene, cyclopropane and 1,2,3,4,5,6,7-octa-heptene molecules using 4-31G and 3G basis sets. A factor of six and more in terms of CPU time is obtained for all the test cases studied over the usual straightforward computation. A parallel version of this algorithm has also been developed

Cross-entropy minimization for refinement of Gaussian basis sets

Information theoretic techniques have been applied for the refinement of Gaussian basis sets. A refined distribution has been obtained by cross-entropy minimization starting from a near Hartree-Fock quality density distribution. For this purpose, the Kullback-Leibler cross-entropy, S[<SUP>&#961;</SUP>|<SUP>&#961;</SUP><SUB>0</SUB>]=&#8747;<SUP>&#961;</SUP>(r)ln[<SUP>&#961;</SUP>(r)/<SUP>&#961;</SUP><SUB>0</SUB>(r)] dr, has been minimized subject to exact, theoretical or experimental, second moment constraints in position and momentum spaces. Here, &#961;<SUB>0</SUB> is the starting density distribution and &#961; is the corresponding refined one. The procedure has been applied to hydrogen, helium, lithium and beryllium atoms as test cases. Nearly all moments (-2 through 4), in coordinate as well as momentum spaces have improved over the original ones at an average worsening of the total energy by a mere 0.04%

Deriving chemical parameters from electrostatic potential maps of molecular anions

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Molecular electrostatic potentials: a topographical study

The topography of the molecular electrostatic potential (MESP) is studied for some small neutral molecules and OH- ion. Different kinds of critical points (CP's) of rank 3 are identified and their occurrences are discussed. The correlation of these CP's with the molecular structure is brought out. Bond ellipticities are determined in terms of curvatures of bond CP's. These ellipticities show trends similar to those reported by Bader et al. [J. Am. Chem. Soc. 105, 5061 (1983)]. A typical example of OH- illustrates the existence of a degenerate nonisolated ring of CP's, which is a rather unique feature of the topology of the MESP of linear molecules. Some suggestive arguments with suitable examples, regarding indeterminacy of the nonisolated degenerate CP's, have been made

A "critical" appraisal of electrostatic charge models for molecules

The conventional electrostatic charge models (PD-AC) are constructed so as to reproduce the molecular electrostatic potential (MESP) on and beyond the van der Waals' (vdW) surface. The MESP distribution has recently [S R Gadre, S A Kulkarni and I H Shrivastava (1992)J. Chem. Phys. 96 5253] been shown to exhibit rich topographical features. With this in view, a detailed topographical comparison of the MESP derived from the charge models, with the respectiveab initio (MO) ones is taken up for water, hydrogen sulphide, methane and benzene molecules as test cases. It is shown that the point charge models have a fundamental lacuna, viz. they fail to mimic the essential topographical features of MESP. A new model incorporating a small number of floating spherical Gaussians is shown to restore all the critical features of the molecules under study. A comparative study of the standard deviations of MESP derived from charge models on scaled vdW surfaces further reveals that the present model leads to a better representation ofab initio MESP