Expanding the search for small-molecule antibacterials by multidimensional profiling.

New techniques for systematic profiling of small-molecule effects can enhance traditional growth inhibition screens for antibiotic discovery and change how we search for new antibacterial agents. Computational models that integrate physicochemical compound properties with their phenotypic and molecular downstream effects can not only predict efficacy of molecules yet to be tested, but also reveal unprecedented insights on compound modes of action (MoAs). The unbiased characterization of compounds that themselves are not growth inhibitory but exhibit diverse MoAs, can expand antibacterial strategies beyond direct inhibition of core essential functions. Early and systematic functional annotation of compound libraries thus paves the way to new models in the selection of lead antimicrobial compounds. In this Review, we discuss how multidimensional small-molecule profiling and the ever-increasing computing power are accelerating the discovery of unconventional antibacterials capable of bypassing resistance and exploiting synergies with established antibacterial treatments and with protective host mechanisms.

Electron superhalogens as positronium superhalogens.

Positronium (Ps) exhibits the ability to form energetically stable complexes with atoms and molecules before annihilation occurs. In particular, F, a halogen, shows the highest reported positronium binding energy (2.95 eV) in the periodic table. Superhalogens are defined as molecules with electron affinities exceeding that of Cl (3.61 eV), the atom with the highest electron affinity. Building upon the concept of superhalogens, we can define Ps-superhalogens as molecules with Ps binding energies surpassing that of F. This study explores structural and energetic aspects of positronium and positron binding to neutral and anionic superhalogen molecules of the MXk+1 family (M = Li, Na, Be, Mg, B, Al, Si, P; X = F, Cl, Br), respectively and where k represents the highest formal valence of M. We perform multicomponent MP2 calculations for positron systems, which reveal how positron affinities vary with the type and number of halogen atoms present. The analysis of the results emphasizes the predominant role of electrostatic interactions in determining the positron affinity, with negligible effects of electronic and geometric relaxation upon positron attachment. We predict the energetic stability of 22 of the 24 PsMXk+1 complexes with respect to the chemically relevant dissociation channels: e+ emission, Ps emission and M-X bond breaking. Our findings reveal six MFk+1 systems that qualify as Ps-superhalogens, showing a positronium binding energy exceeding 2.95 eV. Of these, AlF4 stands out by setting a new record for the highest positronium binding energy among neutral molecules, reaching 4.36 eV.

Traumatic Orbital Compression Syndromes: A Comprehensive Study Into Etiologies, Intervention Strategies, and Clinical Outcomes.

Facial fractures and their historical link to potential blindness have been well-documented, often attributed to optic canal injuries or retinal vascular occlusion. This dire consequence can result from both direct and indirect ocular trauma, including retrobulbar hemorrhage. Traumatic orbital compression can manifest in various forms, such as hematomas, fractured bone fragments, and emphysema, all posing a significant threat to vision, necessitating immediate intervention. In this study, 9 clinical cases of traumatic orbital compression are presented, each characterized by distinct etiologies. The study delves into traumatic orbital compressive syndromes, underscoring the critical imperative of early recognition and treatment to prevent vision loss. Orbital compression, whether from edema, hematoma, or emphysema, collectively culminates in elevated intraorbital pressure and the potential for optic nerve ischemia. Through the presentation of these 9 clinical cases, the article emphasizes the pressing need for timely intervention in addressing orbital compressive syndromes to avert vision loss. Various surgical techniques are elucidated, highlighting the pivotal role of expeditious medical intervention. This article offers invaluable insights into the diagnosis, management, and outcomes of traumatic orbital compressive syndromes.

Fitting Multiplet Simulations to L-Edge XAS Spectra of Transition-Metal Complexes Using an Adaptive Grid Algorithm.

A new methodology based on an adaptive grid algorithm followed by an analysis of the ground state from the fit parameters is presented to analyze and interpret experimental XAS L2,3-edge data. The fitting method is tested first in a series of multiplet calculations for d0-d7 systems and for which the solution is known. In most cases, the algorithm is able to find the solution, except for a mixed-spin Co2+ Oh complex, where it instead revealed a correlation between the crystal field and the electron repulsion parameters near spin-crossover transition points. Furthermore, the results for the fitting of previously published experimental data sets on CaO, CaF2, MnO, LiMnO2, and Mn2O3 are presented and their solution discussed. The presented methodology has allowed the evaluation of the Jahn-Teller distortion in LiMnO2, which is consistent with the observed implications in the development of batteries, which use this material. Moreover, a follow-up analysis of the ground state in Mn2O3 has demonstrated an unusual ground state for the highly distorted site which would be impossible to optimize in a perfect octahedral environment. Ultimately, the presented methodology can be used in the analysis of X-ray absorption spectroscopy data measured at the L2,3-edge for a large number of materials and molecular complexes of first-row transition metals and can be expanded to the analysis of other X-ray spectroscopic data in future studies.

On point perforating defects in bilayer structures.

This article deals with the issue of perforating point defects (pores) in a bilayer heterostructure composed of striped borophene and graphene. Three types of non-equivalent vacancies of the minimum size are considered. These include a single vacancy and two double vacancies. The study of the properties and stability of the perforating defects in borophene-graphene heterostructures is important given the increasing role of such structures in membranes for water purification, renewable energy generation, and other osmotic applications. Using the DFT method, the atomic configurations and main energy characteristics of the proposed defects are obtained. The results show that the formation of a single boron vacancy on the borophene side of borophene-graphene requires less energy than the formation of a carbon vacancy in graphene. Comparisons between double vacancies in nanoscale materials are unreliable because different reference systems produce the different chemical potentials. The problem of choosing the reference system for reliable calculation of the vacancy formation energies is posed and discussed. Using borophene-graphene as an example, it is shown that the reference system strongly affects the magnitude and sign of the vacancy formation energy. Hydrogenation is tested to stabilize the proposed defects.

On the energetic and magnetic stability of neutral and charged lithium clusters doped with one and two yttrium atoms.

DFT calculations were performed to study the effect on energetic and magnetic stability when clusters with up to 24 lithium atoms were doped with one and two atoms of yttrium. In this, the effect of the charge was considered. As a result, some stable structures were identified as possible magnetic superatoms, among them, the YLi12+ cluster with an icosahedron geometry with a spin magnetic moment of 4 bohr magnetons. The participation of yttrium in the electron density of the unpaired electrons providing magnetism in clusters was corroborated at the level of a density of states (DOS) calculation and a spin density calculation. In particular, in the Y2Li12+ superatom, it was found that the encapsulated yttrium atom participates with 35.02% and the second yttrium atom with 15.04%. These percentages, with a contribution from p orbitals, but to a greater extent by d orbitals. The complementation to these percentages is due to the participation of the s and p orbitals of the lithium atoms. In general, doping with a second yttrium atom allowed to obtain a greater amount of high magnetic moments, and considering charged clusters allowed to obtain also high magnetic moments.

Semiempirical Approach to the Fukui Function Analysis of Uric Acid under Different pH Conditions.

Analytic Fukui functions calculated at a first-principles level are combined with experimental pKa values and the calculation of tautomerization energies to obtain the effective regioselectivity of uric acid toward electron-transfer reactions under different pH conditions. Second-order electron binding energies are also computed to determine which of the tautomers is more likely to participate in the electron transfer. A comparison of vertical and adiabatic proton detachment energies allows us to conclude that tautomerization is not mediating deprotonation and that two monoanionic species are of comparable relevance. The main difference between these monoanionic species is the ring that has been deprotonated. Both monoanionic species are produced from a single neutral tautomer and mainly produce a single dianionic tautomer. As a method for the analysis of systems affected by pH such as uric acid, we propose to plot condensed Fukui functions versus pH, allowing us to draw the effect of pH on the regioselectivity of electron transfer in a single image.

Clear aligners combined with orthognathic surgery: a case series.

The goal of this study was to describe a series of orthognathic surgery cases in which a clear aligner system was used for orthodontic treatment. A total of 16 cases were undertaken. A majority of the patients were female (68.75%), and the mean age of the patients was 26.78 years (SD 10.85 years). The most frequent malocclusion was Class II (56.25%), mainly caused by mandibular retrognathism (80.00%). Most of the patients were treated with single-jaw surgeries (56.15%). Orthodontic buttons and elastics were used for maxillomandibular fixation in 81.25% of the patients. The mean (SD) treatment period was 19.00 (1.11) months, and the postsurgical follow-up varied from 6 months to 10 years. Good results were achieved with orthognathic surgery and the adjunctive use of clear aligners, and no damage was noted during the orthosurgical treatment. Since clear aligners provide an esthetic, removable appliance and may be more acceptable to patients than conventional orthodontic appliances, the use of clear aligners in orthognathic surgery is a promising alternative to traditional orthodontics.

The non-canonical Wnt-PCP pathway shapes the mouse caudal neural plate.

The last stage of neural tube (NT) formation involves closure of the caudal neural plate (NP), an embryonic structure formed by neuromesodermal progenitors and newly differentiated cells that becomes incorporated into the NT. Here, we show in mouse that, as cell specification progresses, neuromesodermal progenitors and their progeny undergo significant changes in shape prior to their incorporation into the NT. The caudo-rostral progression towards differentiation is coupled to a gradual reliance on a unique combination of complex mechanisms that drive tissue folding, involving pulses of apical actomyosin contraction and planar polarised cell rearrangements, all of which are regulated by the Wnt-PCP pathway. Indeed, when this pathway is disrupted, either chemically or genetically, the polarisation and morphology of cells within the entire caudal NP is disturbed, producing delays in NT closure. The most severe disruptions of this pathway prevent caudal NT closure and result in spina bifida. In addition, a decrease in Vangl2 gene dosage also appears to promote more rapid progression towards a neural fate, but not the specification of more neural cells.

Analytic Alchemical Derivatives for the Analysis of Differential Acidity Assisted by the h Function.

Analytical calculation of alchemical derivatives based on auxiliary density perturbation theory is described, coded, and validated. For the case where the nucleus is a hydrogen atom and the nuclear charge is changed from 1 to 0, it turns out that a good estimate of the proton binding energies can be obtained very efficiently. First-order results correspond exactly to the molecular electrostatic potential evaluated at the hydrogen nucleus location (removing self-repulsion), in agreement with previously reported extensive studies. Therefore, the second-order results reported here are refinements in accuracy that finally allow a quantitative exploration of differential acidity. Furthermore, the recently reported h function is produced in its analytical form as a byproduct and local descriptor associated with the proton binding energy values found with this approach. In an example application, proton binding energies are computed for a family of imidazolium derivatives to demonstrate the capabilities and the stability of the method with respect to changes in basis set or exchange-correlation functional.

Calculation of the EPR g-tensor from auxiliary density functional theory.

The working equations for the calculation of the electron paramagnetic resonance (EPR) g-tensor within the framework of the auxiliary density functional theory (ADFT) are presented. The scheme known as gauge including atomic orbitals (GIAOs) is employed to treat the gauge origin problem. This ADFT-GIAO formulation possesses an inherent high computational performance, allowing for the calculation of the EPR g-tensor of molecules containing some hundreds of atoms in reasonable computational time employing moderate computational resources. The effect of the use of a gauge independent auxiliary density on the quality of the g-tensor calculation for the evaluation of the exchange-correlation contribution is analyzed in this work. The best agreement with the experiment is obtained with the BLYP functional (Becke 1988 exchange and Lee-Yang-Parr correlation) in combination with a double-ζ basis set, in particular aug-cc-pVDZ. Furthermore, models of endohedral fullerenes N@Cn, with n = {60, 70, 100, 180, 240}, were used for benchmarking its computational performance.

Fabrication of a pediatric torso phantom with multiple tissues represented using a dual nozzle thermoplastic 3D printer.

PURPOSE: To demonstrate an on-demand and nearly automatic method for fabricating tissue-equivalent physical anthropomorphic phantoms for imaging and dosimetry applications using a dual nozzle thermoplastic three-dimensional (3D) printer and two types of plastic. METHODS: Two 3D printing plastics were investigated: (a) Normal polylactic acid (PLA) as a soft tissue simulant and (b) Iron PLA (PLA-Fe), a composite of PLA and iron powder, as a bone simulant. The plastics and geometry of a 1-yr-old computational phantom were combined with a dual extrusion 3D printer to fabricate an anthropomorphic imaging phantom. The volumetric fill density of the 3D-printed parts was varied to approximate tissues of different radiographic density using a calibration curve relating the printer infill density setting to measured CT number. As a demonstration of our method we printed a 10 cm axial cross-section of the computational phantom's torso at full scale. We imaged the phantom on a CT scanner and compared HU values to those of a 1-yr-old patient and a commercial 5-yr-old physical phantom. RESULTS: The phantom was printed in six parts over the course of a week. The printed phantom included 30 separate anatomical regions including soft tissue remainder, lungs (left and right), heart, esophagus, rib cage (left and right ribs 1 to 10), clavicles (left and right), scapulae (left and right), thoracic vertebrae (one solid object defining thoracic vertebrae T1 to T9). CT scanning of the phantom showed five distinct radiographic regions (heart, lung, soft tissue remainder, bone, and air cavity) despite using only two types of plastic. The 3D-printed phantom demonstrated excellent similarity to commercially available phantoms, although key limitations in the printer and printing materials leave opportunity for improvement. CONCLUSION: Patient-specific anthropomorphic phantoms can be 3D printed and assembled in sections for imaging and dosimetry applications. Such phantoms will be useful for dose verification purposes when commercial phantoms are unavailable for purchase in the specific anatomies of interest.

T-cell trafficking plays an essential role in tumor immunity.

Distinct populations of effector memory T cells use different homing receptors to traffic to the skin and gut. Whether tissue-selective T cells are needed for early rejection of a neoplasm growing in these tissues remains an open question. We chose to study an allogeneic tumor model because growth of such a fully mismatched tumor would signify a profound immune deficit. We implanted allogeneic tumor cells in the skin or gut of mice deficient in either α(1,3) fucosyltransferases IV and VII, enzymes critical for generating E-selectin ligands on skin-homing T cells, or ß7 integrin, a component of the α4ß7 integrin ligand for the mucosal adressin MAdCAM. During the first 9 days after tumor implantation, FucTVII-/- mice showed a profoundly impaired capacity to reject tumors growing in the skin, but readily rejected tumors implanted in the gut. Rejection of tumors in the skin was even more impaired in mice deficient in both FucTIV and FucTVII. This impairment was corrected by infusion of T cells from normal mice. By contrast, ß7 integrin-/- mice showed profoundly impaired rejection of tumors in the gut, but no defect in the skin tumor rejection. These differences were unrelated to antigen recognition or effector function of T cells, since all strains of mice were capable of generating tumor-specific CTLs in vitro against the tumor cell line used in vivo. These results demonstrate that T-cell homing defects in vivo impair immune surveillance of peripheral epithelial tissues in a specific and selective fashion.

Effect of Ionizing Radiation from Computed Tomography on Differentiation of Human Embryonic Stem Cells into Neural Precursors.

We studied the effect of radiation from computed tomography (CT) scans on differentiation of human embryonic stem cells (hESCs) into neuronal lineage. hESCs were divided into three radiation exposure groups: 0-dose, low-dose, or high-dose exposure. Low dose was accomplished with a single 15 mGy CT dose index (CTDI) CT scan that approximated the dose for abdominal/pelvic CT examinations in adults while the high dose was achieved with several consecutive CT scans yielding a cumulative dose of 500 mGy CTDI. The neural induction was characterized by immunocytochemistry. Quantitative polymerase chain reaction (qPCR) and Western blots were used to measure expression of the neuronal markers PAX6 and NES and pluripotency marker OCT4. We did not find any visible morphological differences between neural precursors from irradiated and non-irradiated cells. However, quantitative analyses of neuronal markers showed that PAX6 expression was reduced following exposure to the high dose compared to 0-dose controls, while no such decrease in PAX6 expression was observed following exposure to the low dose. Similarly, a statistically significant reduction in expression of NES was observed following high-dose exposure, while after low-dose exposure, a modest but statistically significant reduction in NES expression was only observed on Day 8 of differentiation. Further studies are warranted to elucidate how lower or delayed expression of PAX6 and NES can impact human fetal brain development.

Extended source model for diffusive coupling.

Motivated by the prevailing approach to diffusion coupling phenomena which considers point-like diffusing sources, we derived an analogous expression for the concentration rate of change of diffusively coupled extended containers. The proposed equation, together with expressions based on solutions to the diffusion equation, is intended to be applied to the numerical solution of systems exclusively composed of ordinary differential equations, however is able to account for effects due the finite size of the coupled sources.

Role of Defects on Regioselectivity of Nano Pristine Graphene.

Here analytical Fukui functions based on density functional theory are applied to investigate the redox reactivity of pristine and defected graphene lattices. A carbon H-terminated graphene structure (with 96 carbon atoms) and a graphene defected surface with Stone-Wales rearrangement and double vacancy defects are used as models. Pristine sp2-hybridized, hexagonal arranged carbon atoms exhibit a symmetric reactivity. In contrast, common carbon atoms at reconstructed polygons in Stone-Wales and double vacancy graphene display large reactivity variations. The improved reactivity and the regioselectivity at defected graphene is correlated to structural changes that caused carbon-carbon bond length variations at defected zones.

Analytic second derivatives from auxiliary density perturbation theory.

The working equations for the calculation of analytic second energy derivatives in the framework of auxiliary density functional theory (ADFT) are presented. The needed perturbations are calculated with auxiliary density perturbation theory (ADPT) which is extended to perturbation dependent basis and auxiliary functions sets. The obtained ADPT equation systems are solved with the Eirola-Nevanlinna algorithm. The newly developed analytic second ADFT energy derivative approach was implemented in deMon2k and validated with respect to the corresponding finite difference approach by calculating the harmonic frequencies of small molecules. Good agreement between these two methodologies is found. To analyze the scaling of the new analytic second ADFT energy derivatives with respect to the number of processors in parallel runs, the harmonic frequencies of the carbon fullerene C240 are calculated with varying numbers of processors. Fair scaling up to 720 processors was found. As showcase applications, symmetry unrestricted optimization and frequency analyses of icosahedral carbon fullerenes with up to 960 atoms are presented.

18F-fluorodeoxyglucose Positron Emission Tomography in Kaposi Sarcoma Herpesvirus-Associated Multicentric Castleman Disease: Correlation With Activity, Severity, Inflammatory and Virologic Parameters.

BACKGROUND: Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a lymphoproliferative inflammatory disorder commonly associated with human immunodeficiency virus (HIV). Its presentation may be difficult to distinguish from HIV and its complications, including lymphoma. Novel imaging strategies could address these problems. METHODS: We prospectively characterized (18)F-fluorodeoxyglucose positron emission tomography (PET) findings in 27 patients with KSHV-MCD. Patients were imaged with disease activity and at remission with scans evaluated blind to clinical status. Symptoms, C-reactive protein level, and HIV and KSHV loads were assessed in relation to imaging findings. RESULTS: KSHV-MCD activity was associated with hypermetabolic symmetric lymphadenopathy (median maximal standardized uptake value [SUVmax], 6.0; range, 2.0-8.0) and splenomegaly (3.4; 1.2-11.0), with increased metabolism also noted in the marrow (2.1; range, 1.0-3.5) and salivary glands (3.0; range, 2.0-6.0). The (18)F-fluorodeoxyglucose PET abnormalities improved at remission, with significant SUVmax decreases in the lymph nodes (P = .004), spleen (P = .008), marrow (P = .004), and salivary glands (P = .004). Nodal SUVmax correlated with symptom severity (P = .005), C-reactive protein level (R = 0.62; P = .004), and KSHV load (R = 0.54; P = .02) but not HIV load (P = .52). CONCLUSIONS: KSHV-MCD activity is associated with (18)F-FDG PET abnormalities of the lymph nodes, spleen, marrow, and salivary glands. These findings have clinical implications for the diagnosis and monitoring of KSHV-MCD and shed light on its pathobiologic mechanism.

[Gender-based relations and mistreatment in medical schools: A pending agenda in Mexico and the world]. / Las relaciones de género y el maltrato en las escuelas de medicina: una agenda pendiente en México y el mundo.

The purpose of this review is to describe and analyze the status of gender violence in medical schools around the world, and its consequences in undergraduate students' health and academic development, mainly on female students. The different modalities reported in the literature are presented: gender discrimination, sexism, and sexual harassment, among others. The increase of women in medical schools has not transcendentally improved their condition in these institutions, where androcentrism and gender regimes that favor gender violence reproduce. This type of violence is a public health, human rights, and academic problem.

Calculation of positron binding energies using the generalized any particle propagator theory.

We recently extended the electron propagator theory to any type of quantum species based in the framework of the Any-Particle Molecular Orbital (APMO) approach [J. Romero, E. Posada, R. Flores-Moreno, and A. Reyes, J. Chem. Phys. 137, 074105 (2012)]. The generalized any particle molecular orbital propagator theory (APMO/PT) was implemented in its quasiparticle second order version in the LOWDIN code and was applied to calculate nuclear quantum effects in electron binding energies and proton binding energies in molecular systems [M. Díaz-Tinoco, J. Romero, J. V. Ortiz, A. Reyes, and R. Flores-Moreno, J. Chem. Phys. 138, 194108 (2013)]. In this work, we present the derivation of third order quasiparticle APMO/PT methods and we apply them to calculate positron binding energies (PBEs) of atoms and molecules. We calculated the PBEs of anions and some diatomic molecules using the second order, third order, and renormalized third order quasiparticle APMO/PT approaches and compared our results with those previously calculated employing configuration interaction (CI), explicitly correlated and quantum Montecarlo methodologies. We found that renormalized APMO/PT methods can achieve accuracies of ~0.35 eV for anionic systems, compared to Full-CI results, and provide a quantitative description of positron binding to anionic and highly polar species. Third order APMO/PT approaches display considerable potential to study positron binding to large molecules because of the fifth power scaling with respect to the number of basis sets. In this regard, we present additional PBE calculations of some small polar organic molecules, amino acids and DNA nucleobases. We complement our numerical assessment with formal and numerical analyses of the treatment of electron-positron correlation within the quasiparticle propagator approach.