Ion mobility calculations of flexible all-atom systems at arbitrary fields using two-temperature theory.

Ion mobility spectrometry (IMS) separates and analyzes ions based on their mobility in a gas under an electric field. When the field is increased, the mobility varies in a complex way that depends on the relative velocity between gas and ion, their electrostatic potential interactions, and the effects from direct impingement. Recently, the two-temperature theory, primarily developed for monoatomic ions in monoatomic gases, has been extended to study mobilities at arbitrary fields using polyatomic ions in polyatomic gases, with some success. However, this extension poses challenges, such as inelastic collisions between gas and ion and structural modifications of ions as they heat up. These challenges become significant when working with diatomic gases and flexible molecules. In a previous study, experimental mobilities of tetraalkylammonium salts were obtained using a FAIMS instrument, showing satisfactory agreement with numerical two-temperature theory predictions. However, deviations occurred at fields greater than 100 Td. To address this issue, this paper introduces a modified high-field calculation method that accounts for the structural changes in ions due to field heating. The study focuses on tetraheptylammonium (THA+), tetradecylammonium (TDA+), and tetradodecylammonium (TDDA+) salts. Molecular structures were generated at various temperatures using MM2 forcefield. The mobility was calculated using IMoS 1.13 with two-temperature trajectory method calculations up to the fourth approximation. Multiple effective temperatures were considered, and a linear weighing system was used to create mobility vs. reduced field strength plots. The results suggest that the structural enlargement due to ion heating plays a significant role in mobility at high fields, aligning better with experimental data. FAIMS' dispersion plots also show improved agreement with experimental results. However, the contribution of inelastic collisions and energy transfer to rotational degrees of freedom in gas molecules remains a complex and challenging aspect.

Investigation of Zero-/High-Field Ion Mobility Orthogonal Separation Using a Hyphenated DMA-FAIMS System and Validation of the Two-Temperature Theory at Arbitrary Field for Tetraalkylammonium Salts in Nitrogen.

Toward greater separation techniques for ions, a differential mobility analyzer (DMA) has been coupled with field asymmetric waveform ion mobility spectrometry (FAIMS) to take advantage of two mobility-related but different methods of separation. The filtering effect of the DMA allows ions to be selected individually based on low-field mobility and studied in FAIMS at variable electric field, yielding mobility separations in two dimensions. Because spectra fully describe ion mobility at variable field strength, results are then compared with a two-temperature theory-predicted mobility up to the fourth-order approximation. The comparison yields excellent results up to at least 100 Td, beyond which the theory deviates from experiments. This is attributed to two effects, the enlargement of the structure due to ion heating and the inelasticity of the collisions with the nitrogen bath gas. The corrected mobility can then be used to predict the dispersion plot through a newly developed implicit equation that circumvents the possible issues related to the more elaborate Buryakov equation. Our results simultaneously show that the DMA-FAIMS coupling yields complete information on ion mobility versus the field-strength to gas-density ratio and works toward predicting such spectra from ion structures and gas properties.

Flow-Optimized Model for Gas Jet Desorption Sampling Mass Spectrometry.

Thermal gas jet probes, including post-plasma desorption/ionization sources, have not been studied using computational fluid dynamics (CFD) models, as have other ambient mass spectrometry sampling techniques. Two systems were constructed: a heated nitrogen jet probe to establish practical bounds for a sampling/transmission experiment and a CFD model to study trajectories of particles desorbed from a surface through optimization of streamlines and temperatures. The physical model configuration as tested using CFD revealed large losses, transmitting less than 10% of desorbed particles. Different distances between the desorption probe and the transport tube and from the sample surface were studied. The transmission improved when the system was very close to the sample, because the gas jet otherwise creates a region of low pressure that guides the streamlines below the inlet. A baffle positioned to increase pressure in the sample region improves collection efficiency. A Lagrangian particle tracking approach confirms the optimal design leading to a transmission of almost 100%.

Enhancing Separation and Constriction of Ion Mobility Distributions in Drift Tubes at Atmospheric Pressure Using Varying Fields.

A linearly decreasing electric field has been previously proven to be effective for diffusional correction of ions in a varying field drift tube (VFDT) system, leading to higher resolving powers compared to a conventional drift tube due to its capacity to narrow distributions midflight. However, the theoretical predictions in resolving power of the VFDT were much higher than what was observed experimentally. The reason behind this discrepancy has been identified as the difference between the theoretically calculated resolving power (spatial) and the experimental one (time). To match the high spatial resolving power experimentally, a secondary high voltage pulse (HVP) at a properly adjusted time is used to provide the ions with enough momentum to increase their drift velocity and hence their time-resolving power. A series of systematic numerical simulations and experimental tests have been designed to corroborate our theoretical findings. The HVP-VFDT atmospheric pressure portable system improves the resolving power from the maximum expected of 60-80 for a regular drift tube to 250 in just 21 cm in length and 7kV, an unprecedent accomplishment.

Measurement and Theory of Gas-Phase Ion Mobility Shifts Resulting from Isotopomer Mass Distribution Changes.

The unanticipated discovery of recent ultra-high-resolution ion mobility spectrometry (IMS) measurements revealing that isotopomers─compounds that differ only in the isotopic substitution sites─can be separated has raised questions as to the physical basis for their separation. A study comparing IMS separations for two isotopomer sets in conjunction with theory and simulations accounting for ion rotational effects provides the first-ever prediction of rotation-mediated shifts. The simulations produce observable mobility shifts due to differences in gas-ion collision frequency and translational-to-rotational energy transfer. These differences can be attributed to distinct changes in the moment of inertia and center of mass between isotopomers. The simulations are in broad agreement with the observed experiments and consistent with relative mobility differences between isotopomers. These results provide a basis for refining IMS theory and a new foundation to obtain additional structural insights through IMS.

Ion Mobility Mass Spectrometry Uncovers Guest-Induced Distortions in a Supramolecular Organometallic Metallosquare.

The encapsulation of the tetracationic palladium metallosquare with four pyrene-bis-imidazolylidene ligands [1]4+ with a series of organic molecules was studied by Electrospray ionization Travelling Wave Ion-Mobility Mass Spectrometry (ESI TWIM-MS). The method allowed to determine the Collision Cross Sections (CCSs), which were used to assess the size changes experienced by the host upon encapsulation of the guest molecules. When fullerenes were used as guests, the host is expanded ΔCCS 13 Å2 and 23 Å2 , for C60 or C70 , respectively. The metallorectangle [1]4+ was also used for the encapsulation of a series of polycyclic aromatic hydrocarbons (PAHs) and naphthalenetetracarboxylic diimide (NTCDI), to form complexes of formula [(NTCDI)2 (PAH)@1]4+ . For these host:guest adducts, the ESI IM-MS studies revealed that [1]4+ is expanded by 47-49 Å2 .. The energy-minimized structures of [1]4+ , [C60 @1]4+ , [C70 @1]4+ , [(NTCDI)2 (corannulene)@1]4+ in the gas phase were obtained by DFT calculations.Introduction.

Elucidating Protein Structures in the Gas Phase: Traversing Configuration Space with Biasing Methods.

Achieving accurate characterization of protein structures in the gas phase continues to be a formidable challenge. To tackle this issue, the present study employs Molecular Dynamics (MD) simulations in tandem with enhanced sampling techniques (methods designed to efficiently explore protein conformations). The objective is to identify suitable structures of proteins by contrasting their calculated Collision Cross-Section (CCS) with those observed experimentally. Significant discrepancies were observed between the initial MD-simulated and experimentally measured CCS values through Ion Mobility-Mass Spectrometry (IMS-MS). To bridge this gap, we employed two distinct enhanced sampling methods, Harmonic Biasing Potential and Adaptive Biasing Force, which help the proteins overcome energy barriers to adopt more compact configurations. These techniques leverage the radius of gyration as a reaction coordinate (guiding parameter), guiding the system toward compressed states that potentially match experimental configurations more closely. The guiding forces are only employed to overcome existing barriers and are removed to allow the protein to naturally arrive at a potential gas phase configuration. The results demonstrated close alignment (within ∼4%) between simulated and experimental CCS values despite using different strengths and/or methods, validating their efficacy. This work lays the groundwork for future studies aimed at optimizing biasing methods and expanding the collective variables used for more accurate gas-phase structural predictions.

Factors and perceptions associated with energy drink consumption among undergraduate students attending a rural university: a descriptive study.

Objectives: This study examined the prevalence, patterns, and knowledge of Energy Drink (ED) consumption among undergraduate students. Participants: Participants included students (n = 373) attending a medium-sized rural university in Texas. Methods: Students were surveyed anonymously using convenience sampling and a cross-sectional design with 15 items structured questionnaire. Results: Nearly 90% of the study participants (N = 373) were between 18-24 years. Among the consumers (n = 165), the majority were females (80%) and Caucasian (73%). About 60% of them lived on campus, 22% were engaged in some type of sports activity, and primarily represented the freshmen (42%) and sophomore (25%) population. Having apriori knowledge of the negative health effects of EDs was associated with their consumption [OR: 0.40, CI: (0.22, 0.72)]. Conclusions: Our findings highlight the need to establish programs and policies on campus to address ED consumption issues and create educational campaigns to inform the undergraduate population attending a rural university.

Identifying Barriers to Basic Needs, Academic Success, and the Vaccination Pattern among College Students during the COVID-19 Pandemic.

College students face significant challenges during large-scale disease outbreaks that potentially compromise their basic needs, vaccine confidence, and academic success. Using a cross-sectional design and convenience sampling, we examined the impact of COVID-19 among college students (N = 828). The survey was administered using the Qualtrics survey platform to collect data on multiple demographic and health behaviors of students in the summer semester (2021). Our study demonstrated that the most common financial shock experienced by the study participants was job loss, with less remarkable changes in food and housing insecurities. Academically, students had the most difficulty learning online compared to other modalities (face-to-face, Hyflex, etc.) and struggled with staying motivated. They also struggled with group work and finding appropriate learning spaces. However, many did not use university support systems such as career and tutoring services. Exploring the COVID-19 vaccination attitudes, we found that only age, ethnicity, classification, and health insurance status were associated with getting vaccinated (p < 0.05). When the learning environment was assessed for various modalities, only college attendance was significantly associated (p < 0.05) with the accessible platforms (online, Hyflex, face-to-face, and others); however, nearly 40% of students reported difficulty learning on an online learning platform compared other categories that had much lower proportions. Our findings underscore an immediate need for universities to take measures to improve their preparedness and response strategies to mitigate the negative effects of future large-scale public health emergencies among students.

Discovery and SAR of orally efficacious tetrahydropyridopyridazinone PARP inhibitors for the treatment of cancer.

PARP-1, the most abundant member of the PARP superfamily of nuclear enzymes, has emerged as a promising molecular target in the past decade particularly for the treatment of cancer. A number of PARP-1 inhibitors, including veliparab discovered at Abbott, have advanced into different stages of clinical trials. Herein we describe the development of a new tetrahydropyridopyridazinone series of PARP-1 inhibitors. Many compounds in this class, such as 20w, displayed excellent potency against the PARP-1 enzyme with a K(i) value of <1nM and an EC(50) value of 1nM in a C41 whole cell assay. The presence of the NH in the tetrahydropyridyl ring of the tetrahydropyridopyridazinone scaffold improved the pharmacokinetic properties over similar carbon based analogs. Compounds 8c and 20u are orally available, and have demonstrated significant efficacy in a B16 murine xenograft model, potentiating the efficacy of temozolomide (TMZ).

Field-Switching Repeller Flowing Atmospheric-Pressure Afterglow Drift Tube Ion Mobility Spectrometry.

In this work, a field-switching (FS) technique is employed with a flowing atmospheric pressure afterglow (FAPA) source in drift tube ion mobility spectrometry (DTIMS). The premise is to incorporate a tip-repeller electrode as a substitute for the Bradbury-Nielsen gate (BNG) so as to overcome corresponding disadvantages of the BNG, including the gate depletion effect (GDE). The DTIMS spectra were optimized in terms of peak shape and full width by inserting an aperture at the DTIMS inlet that was used to control the neutral molecules' penetration into the separation region, thus preventing neutral-ion reactions inside. The FAPA and repeller's experimental operating conditions including drift and plasma gas flow rates, pulse injection times, repeller positioning and voltage, FAPA current, and effluent angle were optimized. Ion mobility spectra of selected compounds were captured, and the corresponding reduced mobility values were calculated and compared with the literature. The 6-fold improvements in limit of detection (LOD) compared with previous work were obtained for 2,6-DTBP and acetaminophen. The enhanced performance of the FS-FAPA-DTIMS was also investigated as a function of the GDE when compared with FAPA-DTIMS containing BNG.

Predicting ion mobility as a function of the electric field for small ions in light gases.

High resolution mobility devices such as Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) and Differential Mobility spectrometers (DMS) use strong electric fields to gas concentration ratios, E/N, to separate ions in the gas phase. While extremely successful, their empirical results show a non-linear, ion-dependent relation between mobility K and E/N that is difficult to characterize. The one-temperature theory Mason-Schamp equation, which is the most widely used ion mobility equation, unfortunately, cannot capture this behavior. When the two-temperature theory is used, it can be shown that the K-E/N behavior can be followed quite closely numerically by equating the effect of increasing the field to an increase in the ion temperature. This is attempted here for small ions in a Helium gas environment showing good agreement over the whole field range. To improve the numerical characterization, the Lennard-Jones (L-J) potentials may be optimized. This is attempted for Carbon, Hydrogen, Oxygen and Nitrogen at different degrees of theory up to the fourth approximation, which is assumed to be exact. The optimization of L-J improves the accuracy yielding errors of about 3% on average. The fact that a constant set of L-J potentials work for the whole range of E/N and for several molecules, also suggests that inelastic collisions can be circumvented in calculations for He. The peculiar K-E/N hump behaviors are studied, and whether mobility increases or decreases with E/N is shown to derive from a competition between relative kinetic energy and the interaction potentials.

Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer.

Through conformational restriction of a benzamide by formation of a seven-membered hydrogen-bond with an oxindole carbonyl group, a series of PARP inhibitors was designed for appropriate orientation for binding to the PARP surface. This series of compounds with a 3-oxoisoindoline-4-carboxamide core structure, displayed modest to good activity against PARP-1 in both intrinsic and cellular assays. SAR studies at the lactam nitrogen of the pharmacophore have suggested that a secondary or tertiary amine is important for cellular potency. An X-ray structure of compound 1e bound to the protein confirmed the formation of a seven-membered intramolecular hydrogen bond. Though revealed previously in peptides, this type of seven-membered intramolecular hydrogen bond is rarely observed in small molecules. Largely due to the formation of the intramolecular hydrogen bond, the 3-oxoisoindoline-4-carboxamide core structure appears to be planar in the X-ray structure. An additional hydrogen bond interaction of the piperidine nitrogen to Gly-888 also contributes to the binding affinity of 1e to PARP-1.

Synthesis and SAR of novel, potent and orally bioavailable benzimidazole inhibitors of poly(ADP-ribose) polymerase (PARP) with a quaternary methylene-amino substituent.

Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. Utilizing a benzimidazole carboxamide scaffold in which the amide forms a key intramolecular hydrogen bond for optimal interaction with the enzyme, we have identified a novel series of PARP inhibitors containing a quaternary methylene-amino substituent at the C-2 position of the benzimidazole. Geminal dimethyl analogs at the methylene-amino substituent were typically more potent than mono-methyl derivatives in both intrinsic and cellular assays. Smaller cycloalkanes such as cyclopropyl or cyclobutyl were tolerated at the quaternary carbon while larger rings were detrimental to potency. In vivo efficacy data in a B16F10 murine flank melanoma model in combination with temozolomide (TMZ) are described for two optimized analogs.

Discovery and SAR of 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide: A potent inhibitor of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer.

We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP-1 enzyme with a K(i) of 8nM and in a whole cell assay with an EC(50) of 3nM. 10b is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast xenograph model in combination with cisplatin.

Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension.

Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

From the cell of Schwann to schwannoma--a century's fruition.

The word "schwannoma" is pervasive throughout the neurosurgical community. However, little is known about the origin of the cell of "Schwann cell," the manifestation of the tumor's nomenclature, or the prominent physicians who studied its etiopathogenesis. Schwann was a founding father of cellular theory and one of the greatest scientists of the 19th century. He not only proposed cell theory but also discovered the "secondary" nerve cell and hypothesized its possible function in myelination. It took a century to confirm Schwann's hypothesis. In 1954, Geren, aided by the electron microscope, demonstrated that the cell of Schwann is responsible for nerve myelination. Concurrently, researchers worked to understand the etiology and pathogenesis of peripheral nerve neoplasms. Several attempts were made; Older, Virchow, and von Recklinghausen were the first pioneers who worked on the classification of these neoplasms. However, Masson first used the word "schwannoma" to describe peripheral nerve neoplasms other than neuromas. His French colleague Nageotte used the term "peripheral-glioma" to denote these tumors. These schwannomas were considered to have a malignant course. In 1932, Penfield attempted to classify peripheral nerve neoplasms into 3 categories: peripheral fibroblastoma, peripheral glioma, and neurofibroma of von Recklinghausen. He classified "Verocay's neurinoma," "Masson's schwannoma," and "cerebellopontine angle" tumors as perineural fibroblastoma. He believed that these tumors have a non-nerve cell, non-Schwann cell origin. He classified the tumors arising from the Schwann cell sheath as peripheral gliomas and articulated, "If any tumors are to be called schwannomas, these should be." The neurofibroma of von Recklinghausen was recognized as a separate entity, as described by von Recklinghausen himself. Murray and Stout proposed that schwannomas are essentially benign in nature clarifying the abstruseness of the benign or malignant nature of schwannoma.

Antonius Balthazar Raymundus Hirsch and the peregrination of "gasserian ganglion".

The anatomical description of the fifth cranial nerve ganglion lacked detail before the work of Antonius Balthazar Raymundus Hirsch (1744-1778). Hirsch used new dissection techniques that resulted in the most meticulous report of the trigeminal ganglion (the gasserian ganglion) to have been reported. In 1765, the 21-year-old published these findings in a thesis, Paris Quinti Nervorum Encephali Disquisitio Anatomica In Quantum Ad Ganglion Sibi Proprium, Semilunare, Et Ad Originem Nervi Intercostalis Pertinet [An anatomical inquiry of the fifth pair of the nerves of the brain, so far as it relates to the ganglion unto itself, the semilunar, and to the source of the intercostal nerve]. Hirsch wrote his thesis as a paean to his ailing teacher, Johann Lorenz Gasser, but Gasser died before Hirsch was able to defend his thesis. Thereafter, Hirsch applied to teach anatomy at his alma mater, the University of Vienna, but the university did not consider his application, deeming him too young for the position. Oddly, Hirsch died at the young age of 35. For the present paper, the library at the University of Vienna (Universität Wien), Austria, was contacted, and Anton Hirsch's thesis was digitized and subsequently translated from Latin into English. The authors here attempt to place the recognition of the fifth cranial nerve ganglion within a historical perspective and trace the trajectory of its anatomical descriptions.

Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor.

We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K(i) of 1 nM and an EC(50) of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.

Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer.

We have developed a series of cyclic amine-containing benzimidazole carboxamide PARP inhibitors with a methyl-substituted quaternary center at the point of attachment to the benzimidazole ring system. These compounds exhibit excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of 3a (2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT-888), currently in human phase I clinical trials. Compound 3a displayed excellent potency against both the PARP-1 and PARP-2 enzymes with a K(i) of 5 nM and in a C41 whole cell assay with an EC(50) of 2 nM. In addition, 3a is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast cancer xenograft model in combination with either carboplatin or cyclophosphamide.