Analogous Studies Research Articles

Anti-Mycobacterial Activity of Bacterial Topoisomerase Inhibitors with Dioxygenated Linkers.

Developing new classes of drugs that are active against infections caused by Mycobacterium tuberculosis is a priority for treating and managing this deadly disease. Here, we describe screening a small library of 20 DNA gyrase inhibitors and identifying new lead compounds. Three structurally diverse analogues were identified with minimal inhibitory concentrations of 0.125 μg/mL against both drug-susceptible and drug-resistant strains of M. tuberculosis. These lead compounds also demonstrated antitubercular activity in ex vivo studies using infected THP-1 macrophages with minimal cytotoxicity in THP-1, HeLa, and HepG2 cells (IC50 ≥ 128 μg/mL). The molecular target of the lead compounds was validated through biochemical studies of select analogues with purified M. tuberculosis gyrase and the generation of resistant mutants. The lead compounds were assessed in combination with bedaquiline and pretomanid to determine the clinical potential, and the select lead (158) demonstrated in vivo efficacy in an acute model of TB infection in mice, reducing the lung bacterial burden by approximately 3 log10 versus untreated control mice. The advancement of DNA gyrase inhibitors expands the field of innovative therapies for tuberculosis and may offer an alternative to fluoroquinolones in future therapeutic regimens.

Subsea Capping-Stack Usage Evaluated for CO2 Blowouts

_ This article, written by JPT Technology Editor Chris Carpenter, contains highlights of paper OTC 35246, “Evaluating Subsea Capping-Stack Usage for CO2 Blowouts,” by Lei Zhou, SPE, SLB, Eric R. Upchurch, SPE, Chevron, and Yaxin Liu, SPE, SLB, et al. The paper has not been peer reviewed. _ A dynamic multiphase-flow simulator was used to investigate a capping operation for CO2 well blowouts. Following the typical sequence of a capping procedure and applying a soft shut-in, different primary bore sizes and choke-line configurations were considered. Additionally, different reservoir flow rates, fluid types [CO2 and methane (CH4)] and water depths were investigated, with the intention of understanding what differentiates a CO2 blowout from that of CH4 under varying conditions. Introduction In offshore CO2 storage operations targeting saline aquifers, the depth and pressure gradient of such storage zones dictate that stored CO2 will almost always be in a supercritical state. Given that reality, the complexities of supercritical-to-gaseous phase transition, varying compressibilities (of both gas and supercritical fluid), and the formation of hydrates all must be addressed accurately in simulation if a path to using capping stacks in response to subsea CO2 blowouts is to be charted. Blowouts with CO2 have complications that CH4 blowouts may not exhibit, given the phase change of supercritical CO2 with significant volume expansion. Capping stacks have been the oil and gas industry’s chosen first line of response to subsea blowouts. The adaptation of subsea capping stacks for halting CO2 blowouts is a logical next step for their application. The unique properties of CO2, combined with conditions of the subsea environment, however, can lead to the formation of CO2 hydrates, frozen sea water, and dry ice. Thus, a thorough assessment of the design, deployment, and operation of capping stacks in a CO2 environment is required to ensure their effectiveness. To the authors’ knowledge, no analogous well-control modeling or case studies are available in the literature. Capping-Stack Configurations In this study, the authors consider multiple capping stacks with dimensions and ratings summarized as follows: - Stack 1: 18.75 in., two rams, pressure rating of 15,000 psi, temperature rating of 250°F, four chokes, choke inner diameter (ID) of 5.125 in. - Stack 2: 18.75 in., three rams, pressure rating of 15,000 psi, temperature rating of 250°F, two chokes, choke ID of 3.063 in. - Stack 3: 7.063 in., two gate valves, pressure rating of 10,000 psi, temperature rating of 302°F, four chokes, choke ID of 5.125 in. Well and Reservoir Scenarios Fig. 1 shows the well and reservoir scenarios used in this evaluation. The configuration in Fig. 1a is used for shallow water (984 ft), while that in Fig. 1b is used for deep water (2,500 ft). In shallow water, reservoir and mudline temperatures were assumed to be 210 and 59°F, respectively, and reservoir pressure was set at 5,000 psi. In deep water, reservoir and mudline temperatures of 167 and 40°F, respectively, were used and reservoir pressure was set at 5,500 psi. By using these static variables and varying reservoir permeability, various blowout rates were simulated ranging from 150 to 370 MMscf/D. Each scenario’s steady-state blowout condition was used as the starting point for modeling the operational steps that led to full closure of the capping stack’s primary bore and choke lines. For simulation simplicity, it was assumed that the well unloaded and stabilized with the capping stack already installed on the well. This assumption had no effect on the final simulation results that reflected how fluid behaved during the process of shutting in the well.

Permian evaporites strata of the World: a brief review of possible analogs of the Kungurian sediments of the Pre-Caspian mega-basin

Evaporites of the Permian age, except for the Pre-caspian and Chu-Sarysu basins, have been described in many basins: Amazonian (Amazonas and Solimos), Paranaiba, Permian mega-basin (Delaware, Midland), well-studied areas of development of the Zechstein Formation in middle Europe and the Orn Formation in northern Europe, Khuff on the Arabian Peninsula, etc. This article discusses the peculiarities of the formation of the most studied strata, highlighting their similarities and differences, as well as the depth of paleo-basins at the beginning and completion of the evaporite strata formation. Accurate estimation of paleo-basin depths is essential, as it affects the results of prediction of oil and gas occurrence. This is primarily due to its influence on the thermobaric conditions affecting the key components of hydrocarbon systems, particularly, hydrocarbon source strata. The study of analogs allows for a thorough analysis of the results obtained from calculations specific to each basin. The article emphasizes that most of the complexes being examined are of shallow-marine or continental nature, which distinguishes them from the pre-Caspian mega-basin, where salts are situated beneath deep-water sediments. However, these complexes offer valuable insights that can help refine the model and improve subsequent prediction of oil and gas occurrence.

Henry H. Remak. ‘Comparative literature at the crossroads: Diagnosis, therapy, and prognosis’

Henry H. Remak established his reputation as one of the active and productive participants in the comparative literature ‘crisis’ events, and it is no wonder that his extensive contribution prefaced the summing-up issue of the Yearbook of Comparative and General Literature (1960, Vol. 9, pp. 1–28) where the discussion started five years earlier. A Jewish émigré to the USA from the fascist Germany, Remak stood in the position that provided him an opportunity to bring together the approach and ideas advanced by American and European scholars. Ready to acknowledge the former French achievement, he avoided the extremes of its ‘old factualism’ and adopted a broader cultural position supported by analogy studies. He closed his article pinpointing general tendencies and embraced among them some Russian ideas concerning translation (the Russian formalists, Zhirmunsky) and ‘transition in cyclic stages’ (Plekhanov); though not directly, but through Gleb Struve, Remak was introduced to Aleksandr Veselovsky’s poetics of plot and his ‘theory of borrowings.’ Remak closes his article in hopes of growing cooperation in comparative literature, when many new factors would be brought in to provide a multidisciplinary character to this approach.

‘Crisis’ in comparative literature and the perspective to overcome

The article introduces the publication of the three fragmented contributions to the event known in the history of literary studies as the ‘crisis’ of comparative literature. It was memorably initiated by René Wellek in his review (1953) of ‘littérature comparée’ brought out in the Sorbonne according to the principles worked out there and in the first half of the 20th c. universally adopted. Its ‘old factualism’ was rejected by Wellek, who claimed to advance a comparison with a broader cultural perspective, based on deeper analogy studies, as typology was known then. One of the standing issues in the evolution of the comparative method is a changing notion of world literature in its relation to national literatures. Special attention in the article is paid to the ideas found in Russian comparative studies that seemed productive at the time of the crisis though did not enjoy expansion when the ‘crisis’ seemed over. Thus, the name of Aleksandr Veselovsky and his historical poetics are in demand only now, when a new search for ideas in the field of comparative studies seems to be launched.

Supervisor responsiveness from the inside out

ABSTRACT Despite the recognized importance of close attunement to the shifting needs of supervisees and their clients, empirical study of responsiveness – what-to-do-when – is lacking. To begin filling this gap, we conducted an analogue study of an IPR simulation by asking 12 experienced supervisors to view videoclips of two differentially skilled trainees who responded to the same dissatisfied client and then reflected on this alliance rupture as if speaking directly to a supervisor. In-depth interviews revealed that, despite having different cognitive-emotional reactions to and evaluations of the two therapist/trainees, participants envisioned a similar approach to supervising each of them.

Sea Anemone Kunitz Peptide HCIQ2c1: Structure, Modulation of TRPA1 Channel, and Suppression of Nociceptive Reaction In Vivo.

TRPA1 is a homotetrameric non-selective calcium-permeable channel. It contributes to chemical and temperature sensitivity, acute pain sensation, and development of inflammation. HCIQ2c1 is a peptide from the sea anemone Heteractis magnifica that inhibits serine proteases. Here, we showed that HCIQ2c1 significantly reduces AITC- and capsaicin-induced pain and inflammation in mice. Electrophysiology recordings in Xenopus oocytes expressing rat TRPA1 channel revealed that HCIQ2c1 binds to open TRPA1 and prevents its transition to closed and inhibitor-insensitive 'hyperactivated' states. NMR study of the 15N-labeled recombinant HCIQ2c1 analog described a classical Kunitz-type structure and revealed two dynamic hot-spots (loops responsible for protease binding and regions near the N- and C-termini) that exhibit simultaneous mobility on two timescales (ps-ns and μs-ms). In modelled HCIQ2c1/TRPA1 complex, the peptide interacts simultaneously with one voltage-sensing-like domain and two pore domain fragments from different channel's subunits, and with lipid molecules. The model explains stabilization of the channel in the open conformation and the restriction of 'hyperactivation', which are probably responsible for the observed analgetic activity. HCIQ2c1 is the third peptide ligand of TRPA1 from sea anemones and the first Kunitz-type ligand of this channel. HCIQ2c1 is a prototype of efficient analgesic and anti-inflammatory drugs.

Exploring meaning in life as a potential target for early intervention – results from a randomized trauma analogue study

ABSTRACT Background: Previous studies in individuals exposed to stressors, including traumatic ones, have shown inverse relations between life meaning and distress. Furthermore, meaning-related treatments can benefit (traumatic) stressor-exposed individuals. However, the evidence regarding the effect of life meaning interventions on PTSD symptoms is limited. Moreover, early post-stressor interventions preventing distress are needed. This study investigated the effects of a short, online life meaning intervention after an analogue traumatic stressor on intrusions and anxiety following the intervention, intrusions over a week, and explored distress and life meaning differences after a week. Method: Following an analogue traumatic stressor (i.e. an aversive film), N = 237 participants were randomized to a life meaning intervention, an active or inactive control condition. Participants completed questionnaires in the laboratory, in an online seven-day diary, and at one-week follow-up. Results: The intervention resulted in significantly lower post-intervention state anxiety and higher life meaning, but not significantly less severe wait-period intrusions than the control conditions. Intrusions in the subsequent week as well as depression, anxiety, PTSD, and life meaning after a week did not significantly differ between the conditions. Conclusion: This intervention showed promising temporary effects on anxiety and life meaning after a trauma analogue, but no significant longer-term effects and no effects on PTSD symptoms including intrusions. Meaning-related interventions for PTSD target stressor-related meaning-making rather than life meaning. Thus, future studies may benefit from implementing more intense interventions to extend effects on general distress, as well as stressor-addressing meaning interventions to elicit stressor-related meaning-making.

Facial Expression Perception and Psychological Changes During Space Analogs.

Facial expression perception is the process by which someone can interpret the emotion of another individual using their facial cues. Below-average scores on tests designed to measure facial expression recognition (FER) accuracies are associated with inappropriate behavioral responses and are often linked to mental or neurological disorders. Head-down bed rest microgravity analog studies show changes in facial emotion processing that may indicate a behavioral health risk during spaceflight. During short-duration space analog missions at two separate facilities, 15 subjects took daily FER tests before, during, and after the mission. Each test was accompanied by questionnaires measuring either potential causal or impacted variables: stress, depression, loneliness, irritability, risk-taking, empathy, and intrinsic motivation. Analysis of variance and post hoc t-tests showed that during the mission, the subjects were less likely to identify angry, sad, or fearful faces as disgusted compared to the baseline. Also, interest/enjoyment and perceived competence increased throughout the mission lifecycle. Multiple regression analyses were able to account for greater than 20% of the variance for depression and health/safety risk-taking using the FER data. Changes in FER during space mission simulations show that perception changes are not limited to microgravity analogs. A perceptual change was observed during the short-duration missions, but there is not sufficient evidence to show behavioral health impacts. However, associations between FER and the questionnaires show a potential to develop predictive models, countermeasures, or psychological monitoring tools using FER. Additional research is required to determine the efficacy of such tools during long-duration spaceflight. Van Hoy S. Facial expression perception and psychological changes during space analogs. Aerosp Med Hum Perform. 2024; 95(12):913-918.

Karst geomorphology analysis for geohazard assessment via seismic relief and dip attributes in Jx carbonate field, Central Luconia Province, Malaysia

Carbonate reservoirs in the Central Luconia Province of Malaysia underwent significant karstification during the Miocene. Such features have a detrimental impact on drilling operations, as has been reported for over 40 years in this province. This implies that the karst architecture and geometry may exhibit potentially high-risk behaviours during drilling activities, necessitating a thorough investigation of the features. This study aims to achieve several objectives using Jx field subsurface data, i.e., 3D seismic data and well data, including (1) analysing the interrelationship between karsts and faults, (2) examining the appropriate and effective attributes for analysing the geomorphology of the karst surfaces, and (3) conducting comparative and analog studies to gain a comprehensive understanding of karst formation and characteristics. This research attempted to determine the dimensions and extent of the faults and karsts, which were discovered to be highly connected, and this endeavor is critical for assessing the potential hazardous risk features within the platform. The major fault lineaments that bound the study field were interpreted using the Automatic Fault Extraction (AFE) module application combined with the manual fault-picking technique in the PaleoScan 2022 software. Four main horizon surfaces within the carbonate interval were selected for evaluating karst geomorphology using appropriate seismic attributes, as geomorphology is an important subject that requires serious attention, particularly when determining low-risk regions for drilling programs. Two attributes were extracted from the horizon surfaces: seismic relief and dip attributes, which efficiently distinguish the karst features and define the structural morphology of karsts. Dendritic karst networks, as well as karst collapses or sinkholes, are the most common karst features observed. These features exhibit discontinuity form and synclinal expression (high dip magnitude) when viewed in seismic and using the applied attributes. The comparative and analog study was conducted in Niah Caves, Miri, Sarawak, Malaysia, using karst interpretation employing digital elevation model (DEM) maps and fieldwork. Most of the delineated karst features observed on the DEM map of the Niah Caves are similar to those discovered in the Jx field; however, their dimensions vary between the two carbonate buildups.

Once is enough! An analogue study on repeated validity assessment in adults with ADHD

Performance validity tests (PVTs) can be seen as gatekeepers for valid neuropsychological assessment, by marking cognitive test scores that may not reflect true ability levels. The present study explored the significance of repeated validity testing of adults with attention-deficit/hyperactivity disorder (ADHD), by exploring the potential value of performance consistency across assessments. The operational definition of performance consistency was determined by calculating the mean variation in a participant’s PVT scores across three separate assessments. Neuropsychological test data of 24 individuals diagnosed with ADHD were complemented by an analogue study involving 69 typically developing individuals who were allocated to either a control group or a simulation group instructed to feign ADHD. All individuals were assessed with embedded and stand-alone PVTs three times with one-month intervals between each assessment. The rate of failed validity testing remained rather stable across assessments. Significant differences in neuropsychological performance scores occurred between individuals with ADHD and experimental simulators, however, mostly nonsignificant effects of small size emerged when considering performance consistency. Our data demonstrate that the consistency of cognitive performance over repeated assessments may be no effective approach to complement validity assessment. Replication is needed in independent research on larger samples.

No Evidence for a Metallicity-dependent Enhancement of Distant Giant Companions to Close-in Small Planets in the California Legacy Survey

Understanding the relationship between close-in small (CS) planets and distant giants (DGs) is central to understanding the formation of planetary systems like our own. Most studies of this connection have found evidence for a positive correlation, though significant statistical and systematic uncertainties remain due to differences in sample size, target selection bias, and even the definitions of CS and DG planets. Recently, M. L. Bryan & E. J. Lee conducted a study of 184 stars hosting super-Earths ( Msini=1−20M⊕ or R = 1 − 4 R ⊕) to determine the effect of stellar metallicity on the prevalence of DG companions ( Msini=0.5−20MJ , a = 1−10 au). They found that such giants are twice as common in the presence of inner planets, but only in metal-rich systems: P(DG∣CS, [Fe/H] > 0) = 28.0−4.6+4.9% versus P(DG∣[Fe/H] > 0) = 14.3−1.8+2.0% . Further, they found that this correlation disappears for metal-poor stars: P(DG∣CS, [Fe/H] ≤ 0) = 4.5−1.9+2.6% versus P(DG∣[Fe/H] ≤ 0) = 5.0−1.3+1.6% . We conducted an analogous study to test whether this effect was present in the California Legacy Survey sample. Using the same planet definitions, we did not find evidence for an enhancement in metal-rich systems: P(DG∣CS, [Fe/H] > 0) = 14−8+11% versus P(DG∣[Fe/H] > 0) = 17.9−2.4+2.5% . We also found a 2σ tension between our conditional rate and a 2x enhancement. We brought our results into closer agreement with M. L. Bryan & E. J. Lee by repeating our analysis with different planet definitions. For example, considering only CS planets with 1≤Msini≤10M⊕ and DG planets with 0.5≤Msini≤20MJ gives P(DG∣CS, [Fe/H] > 0) = 48−17+17% and P(DG∣[Fe/H] > 0) = 21.8−2.7+2.9% , consistent with a 2x enhancement. However, we find that this 2x enhancement is also present when we apply the same planet definitions to the overall sample, challenging the idea that metallicity is responsible. Our sample, though only ∼1/6 the size of M. L. Bryan & E. J. Lee, was assembled and analyzed self-consistently. The discrepancy between our findings and theirs may arise from a variety of sources, underscoring the need for large exoplanet surveys to overcome both small number statistics and sample inhomogeneities.

Impact of a free normal velocity boundary on the modelling of external MHD modes

Free normal-flow (NF) conditions at the plasma boundary are shown to be essential for three-dimensional magnetohydrodynamic (MHD) simulations to agree with linear stability theory. A comparative verification study is presented between two different formulations of the boundary conditions (BCs) for velocity perturbations: (i) fully consistent free NF implementation and (ii) fixed NF formulation, neglecting flow perturbations at the numerical boundary. Numerical results are compared with consolidated figures of merit from the linear theory of external kink modes. We consider two classes of initial equilibria presenting different numerical challenges: a uniform current channel surrounded by pure vacuum and a shaped Wesson-like equilibrium, with smooth (polynomial) radial dependency. Only the fully consistent free NF formulation is invariably accurate in modelling the plasma interface at the numerical boundary, without the need of enforcing a pseudovacuum region at the edge of the simulation domain, as in most analogous past studies. This study employs the cylindrical code SPECYL (Cappello & Biskamp, Nucl. Fusion, vol. 36, no. 5, 1996, p. 571) that solves a full-MHD model without pressure gradients, whose fully consistent resistive wall module with free NF BCs was recently successfully verified against the independent code PIXIE3D (Spinicci et al., AIP Adv., vol. 13, no. 9, 2023, p. 095111).

In silico ADMET and Molecular Docking Studies of Natural Analogues as AKT Inhibitors

Background: AKT inhibition presents a promising avenue for cancer treatment strategies. By exploring natural analogues using in-silico docking and ADMET profiles, this work aims to design effective anti-cancer therapies shown by binding affinities and pharmacokinetic assessments. Aims and Objectives: The aim of this research paper is to utilize in-silico ADMET profiling and molecular docking studies to investigate the potential of natural analogues as inhibitors of the AKT enzyme. By leveraging computational techniques, including Molegro Virtual Docker (MVD) 6.0 and computational techniques like pkCSM, we aim to identify promising compounds with strong binding affinities to the target protein (PDB ID: 3OCB) and favorable pharmacokinetic properties. Our objectives include identifying key molecular interactions, evaluating optimal molecular weight ranges, and prioritizing compounds based on their MolDock scores for cancer treatment. Through this approach, our goal is to contribute to the design and development of effective anti-cancer therapies targeting the AKT signaling pathway. Method: The Protein Data Bank provided the target protein (PDB ID: 3OCB) for the molecular docking study, which was conducted using Molegro Virtual Docker (MVD) 6.0. The selection of ligands from PubChem was focused on natural analogues. ADMET profiling benefited from the use of computational techniques such as pkCSM. method: The Protein Data Bank provided the target protein (PDB ID: 3OCB) for the molecular docking study, which was conducted using Molegro Virtual Docker (MVD) 6.0. The selection of ligands from PubChem was focused on natural analogues. ADMET profiling benefited from the use of computational techniques such as pkCSM. Result: A molecular docking study of selected natural compounds was performed, and the top three compounds with higher MolDock scores were considered to be the best among all sixteen natural analogues. The compounds [00]UNX_16, [01]UNX_13, and [00]UNX_11 showed the highest MolDock score of -111.09, -98.31, and -96.37, respectively, and can show great potential in treating cancer. Conclusion: The analysis primarily focuses on a docking study investigating the potential inhibition of the AKT enzyme by natural analogs. The study explores molecular interactions and ADMET properties, offering insights into their role in drug discovery. Key findings include strong binding affinities of selected analogs against the target 3OCB, with specific amino acid residues and steric/hydrogen bond interactions influencing binding success. Compounds within the 400-500 Da molecular weight range show favorable interactions, suggesting implications for future drug design. Additionally, ADMET analysis identifies compounds like [00]UNX_16, [01]UNX_13, and [00]UNX_11 with high MolDock scores, indicating potential as AKT inhibitors for cancer treatment.

Scaffold transforming and in-silico design of potential androgen receptor antagonists in prostate cancer therapy.

Androgens like testosterone and dihydrotestosterone are essential for the growth and development of the prostate gland. Androgenic receptors are overexpressed, which promotes the progression of prostate cancer; therefore, androgenic receptors are a key target in the therapy of prostate cancer. Enzalutamide is used to treat prostate cancer; however, it also causes toxicities such as cardiovascular toxicity, acute myocarditis, hypertension, and seizures. The objective of this research was to create novel and safer analogues of enzalutamide, followed by the prediction of the pharmacokinetic and toxicity characteristics of these enzalutamide analogues. Molecular docking studies of analogues were also done to guess how ligands will work biologically in treating prostate cancer. A total of 195 analogues were generated, and among them, 23 bioisosteres were selected for further pharmacokinetic, toxicological screening and docking studies. The predicted physical-chemical, medicinal, and ADMET characteristics of the designed bioisosteres were optimal to good compared to enzalutamide. Additionally, the drug likeness and drug score of analogues were superior to enzalutamide. According to docking studies of analogues, EZ12, EZ8, and EZ10 formed hydrogen bonds of SER778 with replaceable amide groups in enzalutamide molecules. SER778 residue may be responsible for antagonistic activity towards androgen receptors. Based on the results of the ADMET, drug likeness, drug score, and docking study of designed enzalutamide analogues, the ligands EZ12, EZ8, and EZ10 could be used to find more possible antiandrogen drugs that could be used to treat prostate cancer.

Dynamics of ionic liquid-polymer gel membranes-Insight from NMR relaxometry for [BMIM][BF4]-PVDF-HFP systems.

1H spin-lattice relaxation experiments have been performed for ionic liquid-polymer gel membranes, including 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]) and poly(vinylidene fluoride-co-hexafluoropropylene) (PVdF-HFP) with different proportions. The experiments have been performed in a broad range of resonance frequencies (from about 5Hz to 40MHz) vs temperature and complemented with analogous studies for [BMIM][BF4] in bulk as a reference. A model of the relaxation processes in the membranes has been proposed. The model includes two relaxation contributions. One of them corresponds to the concept of restricted, two-dimensional translation diffusion with a residence lifetime, while the second one has the form characteristic of polymers (mathematically similar to the limiting behavior of two-dimensional translation diffusion with a very long residence lifetime). The extensive dataset has been consistently interpreted in terms of the model, revealing two dynamical processes on the time scales of 10-7s (for the second relaxation contribution) and 10-9s (for the first one). The relationship of these relaxation contributions to the motion of the polymer or ionic liquid-polymer complexes and to the translation diffusion of BMIM cations in the matrix has been discussed.

Anti colorectal cancer activity and in silico studies of novel pyridine nortopsentin analog as cyclin dependent kinase 6 inhibitor

Nortopsentins are a vital class of deep-sea sponge metabolites which can be used as leads for antitumor agents. Although their action has been studied in several diseases’ contexts, their cytotoxic activity against colorectal carcinoma has not yet been fully investigated. Therefore, a series of 2,6-bis(1H-indol-3-yl)-4-(substituted-phenyl)pyridin-5-carbonitriles 4a–j (nortopsentin analogs) was investigated for their cytotoxic activity against colorectal carcinoma. The analog 4i showed the highest antitumor activity via inducing cell cycle arrest at G1 phase. Cell cycle arrest was induced due to expression downregulation of CDK2, CDK4, and CDK6. In addition, 4i suppressed the enzymatic activity of CDK6. The theoretical study of some basic quantum factors and the geometric shape of compound 4i proved that the compound is stable and a soft molecule, in which the EHOMO and ELUMO energies were negative and had a small ∆E gap. 4i also demonstrated a high potential for oral bioavailability due to its adherence to Lipinski’s rule of five. The molecular docking studies of 4i analog showed good binding mode with CDK6 active pocket through the formation of multiple interactions with its key amino acids.

Real-world experience with glucagon-like peptide 2 analogues in patients with short bowel syndrome and chronic intestinal failure: Results from an international survey in expert intestinal failure centers

Background and AimsGlucagon-like peptide 2 (GLP-2) analogues are the first available disease-modifying treatments for patients with intestinal failure (IF) due to short bowel syndrome (SBS). Efficacy in terms of reduction of parenteral support (PS) has been demonstrated in multiple studies and real-world reports. However, it remains unclear how many patients are eligible to receive the treatment, when treatment is started after intestinal resection, how treatment efficacy is assessed outside of clinical trials, and how the treatment is modified in case of non-response or adverse events. The aim of this study was to investigate the real-world management of patients treated with GLP-2 analogues in expert centers around the world. MethodsA survey questionnaire was developed by a multidisciplinary working group consisting of 52 questions related to various aspects of multidisciplinary care of SBS-IF patients. The 17 questions related to the use of GLP-2 analogues in clinical practice were analyzed for this study. The online survey was sent to 33 participating centers in a phase 3 study of a long-acting GLP-2 analogue. Only responses from countries with access to commercially available GLP-2 analogues were included in the study. A descriptive analysis was performed for each question. Results are presented as median (interquartile range). ResultsThe responses from the 19 expert IF centers with access to GLP-2 analogues indicated that 10 (10-20) % of patients with SBS-IF were treated with a GLP-2 analogue, which was less than the number of eligible patients (30 (25-40) %). In most centers (10 centers, 53%), GLP-2 therapy was started 6-12 months after the last intestinal resection, with 5 centers (26%) starting later (12-24 months). Multiple parameters were used in combination to determine the response to GLP-2 analogues of which the three most common were >20% decrease in PS (95%), at least 1 day of PS reduction per week (84%) and increased urinary output (68%). In non-responders GLP-2 therapy was stopped within the first year by 67% of the centers. Finally, strategies in case of significant adverse events include stopping the GLP-2 analogue (used by 79% of experts), dose reduction (67%) and temporary treatment interruption (62%). ConclusionThe results of this survey completed by expert IF centers show the real-life use of GLP-2 analogues in clinical practice. Key learning points identified include the accounting for a period of intestinal adaptation before starting GLP-2 analogues and not stopping the treatment too early in case of non-response. The best strategy in case of adverse effects should be studied further.

Synthesis, Biological Evaluation and Molecular Modeling Studies of Novel Tribromo-substituted Imidazole Analogs

IntroductionWith the increasing rate of antimicrobial resistance, there is an urgent demand of developing newer antimicrobial agents. In the present study we report a novel series of eighteen 1-(aryl)-2-(2,4,5-tribromo-1H-imidazol-1-yl)ethan-1-ones, which were synthesized and their spectral characterization was performed. The in-vitro studies of the compounds were carried out. Molecular modeling studies were performed on the most promising compound. The results obtained would help develop new compounds that may have broad-spectrum therapeutic effects. MethodsThe compounds were synthesized by reacting the corresponding bromo-imidazoles with substituted phenacyl bromides. The predictive ADME studies, MM-GBSA studies, and In-vitro studies were carried out for all the compounds. Binding mode analysis of the most active compounds was carried out. DFT investigations were also performed. Results and discussionsAll the synthesized compounds were found to be active against the different strains of microorganisms used in the in-vitro analysis. Binding mode analysis of the most active compounds were carried out in the active site of glucosamine-6-phosphate synthase (2VF5) and crystal structure of Mycobacterium tuberculosis InhA inhibited by PT70 (2X22). With the increasing global challenge of multi-drug resistance and the urgent need for new antimicrobial agents, these compounds show promising potential to meet emerging therapeutic demands in treating infectious diseases.

DMRG-Tailored Coupled Cluster Method in the 4c-Relativistic Domain: General Implementation and Application to the NUHFI and NUF3 Molecules.

Heavy atom compounds represent a challenge for computational chemistry due to the need for simultaneous treatment of relativistic and correlation effects. Often such systems also exhibit strong correlation, which hampers the application of perturbation theory or single-reference coupled cluster (CC) methods. As a viable alternative, we have proposed externally correcting the CC method using the density matrix renormalization group (DMRG) wave functions, yielding the DMRG-tailored CC method. In a previous paper [J. Chem. Phys. 2020, 152, 174107], we reported a first implementation of this method in the relativistic context, which was restricted to molecules with real double group symmetry. In this work, we present a fully general implementation of the method, covering complex and quaternion double groups as well. The 4c-TCC method thus becomes applicable to polyatomic molecules, including heavy atoms. For the assessment of the method, we performed calculations of the chiral uranium compound NUHFI, which was previously studied in the context of the enhancement of parity violation effects. In particular, we performed calculations of a cut of the potential energy surface of this molecule along the stretching of the N-U bond, where the system exhibits strong multireference character. Since there are no experimental data for NUHFI, we have performed also an analogous study of the (more symmetric) NUF3 molecule, where the vibrational frequency of the N-U bond can be compared with spectroscopic data.