Set Of Analogues Research Articles

Ribonuclease T2 represents a distinct circularly permutated version of the BECR RNases.

Detection of homologous relationships among proteins and understanding their mechanisms of diversification are major topics in the fields of protein science, bioinformatics, and phylogenetics. Recent developments in sequence/profile-based and structural similarity-based methods have greatly facilitated the unification and classification of many protein families into superfamilies or folds, yet many proteins remain unclassified in current protein databases. As one of the three earliest identified RNases in biology, ribonuclease T2, also known as RNase I in Escherichia coli, RNase Rh in fungi, or S-RNase in plant, is thought to be an ancient RNase family due to its widespread distribution and distinct structure. In this study, we present evidence that RNase T2 represents a circularly permutated version of the BECR (Barnase-EndoU-Colicin E5/D-RelE) fold RNases. This subtle relationship cannot be detected by traditional methods such as sequence/profile-based comparisons, structure-similarity searches, and circular permutation detections. However, we were able to identify the structural similarity using rational reconstruction of a theoretical RNase T2 ancestor via a reverse circular permutation process, followed by structural modeling using AlphaFold2, and structural comparisons. This relationship is further supported by the fact that RNase T2 and other typical BECR RNases, namely Colicin D, RNase A, and BrnT, share similar catalytic site configurations, all involving an analogous set of conserved residues on the α0 helix and the β4 strand of the BECR fold. This study revealed a hidden root of RNase T2 in bacterial toxin systems and demonstrated that reconstruction and modeling of ancestral topology is an effective strategy to identify remote relationship between proteins.

Synthesis of Novel Bis-imino and Bis-amino Curcuminoids for Evaluation of Their Anticancer and Antibacterial Activity.

A new set of curcumin analogues with a Schiff base moiety were synthesized from a bis-aldehyde derivative of hydroxybenzylidene cyclohexanone and various alicyclic and aromatic amines. The single crystals of compound 2 (bis-aldehyde), compound 3b (bis-cyclohexylimino derivative), and compound 3c (bis-1-imino piperidyl derivative) were developed. The said bis-imino and bis-amino curcuminoids were tested for anticancer activity against MCF-7 utilizing the conventional MTT assay. These Schiff bases had significantly higher anticancer efficacy than curcumin and methotrexate against MCF-7 cell lines. Compounds 3k, 3b, and 3l have the highest efficacy among all synthesized curcuminoids. The MTT results are in accordance with the binding affinities found by docking the said molecules with HER2 Tyrosine Kinase (HER2-TK). Compound 3b is identified as a promising HER2-TK inhibitor and also shows effective inhibition against Gram-positive bacteria Staphylococcus aureus.

Differences between remote and analog design thinking through the lens of distributed cognition.

Due to the huge surge in remote work all over the world caused by the COVID-19 pandemic, today's work is largely defined by tools for information exchange as well as new complex problems that must be solved. Design Thinking offers a well-known and established methodological approach for iterative, collaborative and interdisciplinary problem solving. Still, recent circumstances shed a new light on how to facilitate Design Thinking activities in a remote rather than an analog way. Due to Design Thinking's high production of artifacts and its focus on communication and interaction between team members, the theory of Distributed Cognition, specifically the Distributed Cognition for Teamwork (DiCoT) framework, provides an interesting perspective on the recent going-remote of Design Thinking activities. For this, we first highlight differences of analog vs. remote Design Thinking by analyzing corresponding literature from the recent years. Next, we apply the DiCoT framework to those findings, pointing out implications for practical facilitation of Design Thinking activities in an analog and remote setting. Finally, we discuss opportunities through artificial intelligence-based technologies and methods.

IMMU-30. THE ROLE OF CD4 T CELLS IN ANTITUMOR IMMUNITY AGAINST BRAIN TUMORS

Abstract Glioblastoma is a primary brain tumor with a dismal prognosis. CD4 T cell responses to neoantigen vaccines or checkpoint blockade immunotherapy impact the tumor microenvironment. However, the function of CD4 T cells in glioblastoma remains understudied. Here we further characterize the role of CD4 T cells in antitumor immunity against the GL261 orthotopic model of glioblastoma. We studied the memory response generated during high-dose PD-L1 blockade mediated clearance of intracranial tumors. Mice that previously rejected GL261 retained protection against intracranial rechallenge after depletion of CD4 or CD8 T cells, but not both. Thus, these memory CD4 T cells are sufficient but not necessary for protection. Interestingly, in mice with a memory response generated during clearance of extracranial GL261, depletion of CD4 T cells abrogates protection against intracranial rechallenge, but depletion of CD8 T cells alone does not affect protection. Therefore, memory CD4 T cells generated with extracranial antigen challenge are necessary and sufficient for protection against intracranial rechallenge. In an analogous setting, we vaccinated mice against MHC class I neoantigens with concurrent checkpoint blockade immunotherapy to generate memory responses. Similar to the challenge-rechallenge model, mice challenged with GL261 and depleted of CD4 T cells lost protection from neoantigen vaccination and PD-L1 blockade. We then modified GL261 to express the C-terminal end of ovalbumin (GL261-OVAII), which contains the MHC class II immunodominant antigen (OVA323-339) but not the class I antigen (OVA257-264). Mice challenged intracranially with GL261-OVAII have a minimal survival benefit from PD-L1 blockade therapy. However, vaccination against OVA323-339 greatly enhances the protection from PD-L1 blockade. We determined by ELISPOT that CD4 T cells do not directly recognize GL261. Our data show the importance of the CD4 T cell subset in glioblastoma and the importance of targeting class II neoantigens to generate strong antitumor immunity.

Expanding the knowledge around antitubercular 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides: Hit–to–lead optimization and release of a novel antitubercular chemotype via scaffold derivatization

Tuberculosis is one of the deadliest infectious diseases in the world, and the increased number of multidrug-resistant and extensively drug-resistant strains is a reason for concern. We have previously reported a series of substituted 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides with growth inhibitory activity against Mycobacterium tuberculosis strains and low propensity to be substrate of efflux pumps. Encouraged by these preliminary results, we have undertaken a medicinal chemistry campaign to determine the metabolic fate of these compounds and to delineate a reliable body of Structure–Activity Relationships. Keeping intact the (thiazol-4-yl)isoxazole-3-carboxamide core, as it is deemed to be the pharmacophore of the molecule, we have extensively explored the structural modifications able to confer good activity and avoid rapid clearance. Also, a small set of analogues based on isostere manipulation of the 2-aminothiazole were prepared and tested, with the aim to disclose novel antitubercular chemotypes. These studies, combined, were instrumental in designing improved compounds such as 42g and 42l, escaping metabolic degradation by human liver microsomes and, at the same time, maintaining good antitubercular activity against both drug-susceptible and drug-resistant strains.

Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action.

The free fatty acid receptors FFAR1 and FFAR4 are considered promising therapeutic targets for management of metabolic and inflammatory diseases. However, there is a need for entirely novel chemical scaffolds, since many of the highly similar lipophilic chemotypes in development have been abandoned by the pharmaceutical industry, due to toxic effects on hepatocytes and β-cells. Our group has recently reported the discovery of a 1,3,5-triazine-2-amine-based compound that acts as an allosteric agonist on FFAR1. Here, we present the synthesis and investigation of the structure-activity relationship of an extensive set of analogues of which many display dual-acting agonist properties for both FFAR1 and FFAR4. In several rounds of optimization, we discovered multiple analogues with single-digit nanomolar potency on FFAR1. Pending additional optimization for metabolic stability, the compounds in this study present novel ways of providing beneficial glycemic control while avoiding the notorious toxicity challenges associated with previously identified chemotypes.

Dominance phenomena: mutation, scattering and cluster algebras

An exchange matrix B B dominates an exchange matrix B ′ B’ if the signs of corresponding entries weakly agree, with the entry of B B always having weakly greater absolute value. When B B dominates B ′ B’ , interesting things happen in many cases (but not always): the identity map between the associated mutation-linear structures is often mutation-linear; the mutation fan for B B often refines the mutation fan for B ′ B’ ; the scattering (diagram) fan for B B often refines the scattering fan for B ′ B’ ; and there is often an injective homomorphism from the principal-coefficients cluster algebra for B ′ B’ to the principal-coefficients cluster algebra for B B , preserving g \mathbf {g} -vectors and sending the set of cluster variables for B ′ B’ (or an analogous larger set) into the set of cluster variables for B B (or an analogous larger set). The scope of the description “often” is not the same in all four contexts and is not settled in any of them. In this paper, we prove theorems that provide examples of these dominance phenomena.

Screening of a Halogen-Enriched Fragment Library Leads to Unconventional Binding Modes.

We conceived the Halogen-Enriched Fragment Library (HEFLib) to investigate the potential of halogen bonds in the early stages of drug discovery. As the number of competitive interactions increases with ligand size, we reasoned that a binding mode relying on halogen bonding is more likely for fragments than highly decorated molecules. Thus, fragments could feature unexplored binding modes. We screened the HEFLib against the human kinase DYRK1a and verified micromolar binding fragments via isothermal titration calorimetry (ITC). The crystal structure of one fragment revealed a noncanonical binding mode, despite the fragment's classical hinge binding motif. In addition, the fragment occupies a secondary binding site. Both binding modes feature a halogen bond, which we evaluated by ab initio calculations. Structure-affinity relationship (SAR) from a set of analogues improves the affinity, provides a promising fragment-growth vector, and highlights the benefits and applicability of halogen bonds in early lead development.

LEAVES IN IRON OXIDE: REMARKABLE PRESERVATION OF A NEOGENE FLORA FROM NEW CALEDONIA

Abstract A Neogene hematite-goethite concretionary ‘ironstone' horizon in laterized fluvial sediments in the Massif du Sud of New Caledonia yields abundant fossil dicotyledonous angiosperm leaves. The leaves are preserved in iron oxide, mainly goethite, which replicates the morphology and anatomy of the leaf tissues and comprises 73% of the matrix. Organic remains are minimal and associated with aluminosilicate clay. Leaf tissues are preserved three-dimensionally in multiple ways including casts/molds, permineralization/petrifaction, and replacement. Although the mesophyll is less well preserved, reflecting its greater susceptibility to decay, cellular details of vascular and epidermal tissues are commonly evident. Analyses of leaves from an analogous modern setting reveal the early encrustation and impregnation of tissues by amorphous iron-oxides and clays in association with a microbial biofilm. We propose a taphonomic model in which the fossil leaves, like their modern counterparts, were permeated by iron oxides due to the high availability of iron derived from weathering of ultramafic basement. In contrast to the iron-rich aluminosilicate coatings that form in relatively iron-poor settings, the unusually high concentration of dissolved iron oxides permitted rapid anatomical preservation.

Mitigating Power and Memory Constraints on a Venusian Seismometer

Abstract The nearest term pathway to the deployment of a seismometer on Venus is an instrument that can operate under ambient surface conditions on battery power. We conduct a series of studies on combined hardware and software approaches to maximize the quality of data returned under the likely restrictions of minimal on-board data storage and only being able to transmit in real time during a small fraction of a multimonth deployment. We assess likely Venus seismicity by examining different terrestrial analog settings; we find that likely Venus analog settings all fall within about an order of magnitude of mean Earth in terms of seismicity level. We use the seismic record from a station in central Alaska as a Venus surrogate for algorithm development. We tested various transmission triggers and developed a simple low-memory algorithm that mimics the common terrestrial long-term average/short-term average trigger. If the seismometer can operate in coordination with an orbiter that can remotely turn off data transmission, then the frequency content of a few seconds of data can be used to distinguish small, nearby earthquakes from large, distal ones, and total data transmission can be tuned to favor the latter. If an orbiter can also turn on transmission for other nearby seismometers, it would further enhance the ability to distinguish small- and large-magnitude earthquakes autonomously and increase the chances of capturing the initial onset of significant events.

Conceptual Grounding for Bayesian Inference for Latent Variables in Factor Analysis

ABSTRACT Obtaining values for latent variables in factor analysis models, also referred to as factor scores, has long been of interest to researchers. However, many treatments of factor analysis do not focus on inference about the latent variables, and even fewer do so from a Bayesian perspective. Researchers may therefore be ill-acquainted with Bayesian thinking on this issue, despite the fact that certain existing procedures may be seen as Bayesian to some extent. The focus of this paper is to provide a conceptual grounding for Bayesian inference for latent variables, articulating not only what Bayesian inference has to say about values for latent variables, but why Bayesian inference is suited for this problem. As to why, it is argued that the notion of exchangeability motivates the form of factor analysis, as well as Bayesian inference for latent variables. The argument is supported by documenting the widespread use of Bayesian inference in analogous settings, including latent variables in other measurement models, multilevel models, and missing data. As to what, this work describes a Bayesian analysis when other parameters are known, as well as partially and fully Bayesian analyses when other parameters are unknown. This facilitates a discussion of various choices researchers have when adopting Bayesian approaches to inference about latent variables.

Discovery and In Vivo Efficacy of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 4-(2-Aminoethyl)-N-(3,5-dimethylphenyl)piperidine-1-carboxamide Hydrochloride (AP163) for the Treatment of Psychotic Disorders.

Starting from a screening hit, a set of analogs was synthesized based on a 4-(2-aminoethyl)piperidine core not associated previously with trace amine-associated receptor 1 (TAAR1) modulation in the literature. Several structure–activity relationship generalizations have been drawn from the observed data, some of which were corroborated by molecular modeling against the crystal structure of TAAR1. The four most active compounds (EC50 for TAAR1 agonistic activity ranging from 0.033 to 0.112 μM) were nominated for evaluation in vivo. The dopamine transporter knockout (DAT-KO) rat model of dopamine-dependent hyperlocomotion was used to evaluate compounds’ efficacy in vivo. Out of four compounds, only one compound (AP163) displayed a statistically significant and dose-dependent reduction in hyperlocomotion in DAT-KO rats. As such, compound AP163 represents a viable lead for further preclinical characterization as a potential novel treatment option for disorders associated with increased dopaminergic function, such as schizophrenia.

Modeling the non-Arrhenius ignition behavior of 2‐butanol: A detailed theoretical and experimental study

2-butanol is a promising alternative to fossil fuels for which production pathways are already established and which was proven to be suitable for usage within modern internal combustion engines. It is a potential octane booster for gasoline fuels, can be used in diesel engines to reduce soot production, and is applicable as a stand-alone fuel. In the present study, the previously not discussed non-Arrhenius ignition behavior of 2-butanol was revealed by recalculating and adjusting the thermodynamic properties of the fuel and its most important radicals. All relevant fuel consumption reaction rate coefficients were replaced by a consistent set of analogies without any further modifications of the rate parameters. The existing spectrum of validation targets for 2-butanol was extended by new high-pressure Rapid Compression Machine (RCM) experiments for end-of-compression pressures of peoc = 20, 30, 40, and 50 bar with high resolution of temperature to highlight the non-Arrhenius ignition behavior and to study the model performance in more detail. The kinetic model proposed in the present study can reproduce the observed non-Arrhenius behavior within the RCM regime. Kinetic analysis demonstrated that simulated Ignition Delay Times (IDTs) are very sensitive to the equilibria of the R. + O2 reactions for all 2-hydroxybutyl radicals. With the newly determined thermodynamic properties, the equilibria of the R. + O2 reactions are moved towards lower temperatures, enabling low-temperature chain branching. The shift of the equilibrium from the RO.2 side to R. + O2 within the temperature regime covered by the RCM experiments could be identified as the main reason for the observed non-Arrhenius behavior.

Blood Glucose Alterations and Continuous Glucose Monitoring in Centrifuge-Simulated Spaceflight.

INTRODUCTION: Sympathetic stimulation is known to be associated with transient alterations of blood glucose (BG) concentration; spaceflight acceleration may be similarly associated with alterations of BG, potentially posing a risk to diabetic individuals engaging in future spaceflight activities. Despite prior studies demonstrating diabetic subjects' tolerance to centrifuge-simulated spaceflight, data are lacking regarding blood glucose response to hypergravity. It remains unclear whether hypergravity or associated physiological response may pose a risk to diabetics. Continuous glucose monitors (CGM) offer a means of noninvasive glucose monitoring and may be useful in spaceflight and analog environments. Here, we describe the results of continuous glucose monitoring during centrifuge-simulated spaceflight.METHODS: Subjects participated in 1-5 centrifuge-simulated spaceflight profiles (maximum +4.0 Gz, +6.0 Gx, 6.1 G resultant). Data collection included heart rate, blood pressure, electrocardiogram, continuous glucose via CGM, intermittent fingerstick BG, and postrun questionnaires regarding symptoms related to hypergravity exposure.RESULTS: CGM data were collected from 26 subjects, including 4 diabetics. While diabetic subjects had significantly higher BG compared to nondiabetics, this was not associated with any difference in symptoms or tolerance. Transient hypergravity-associated CGM glucose alterations did not affect tolerance of the centrifuge experience. CGM data were found to be reliable with occasional exceptions, including four instances of false critical low glucose alarms.DISCUSSION: While further study is necessary to better characterize CGM fidelity during hypergravity and other spaceflight-related stressors, CGM may be a feasible option for spaceflight and analog settings. As in prior studies, individuals with well-controlled diabetes appear able to tolerate the accelerations anticipated for commercial spaceflight.Ong KM, Rossitto JJ, Ray K, Dufurrena QA, Blue RS. Blood glucose alterations and continuous glucose monitoring in centrifuge-simulated spaceflight. Aerosp Med Hum Perform. 2022; 93(9):688-695.

Enhancement of optical properties of new purine nucleobases containing electron-donating and -withdrawing peripheral groups.

Nowadays, a great deal of attention has been focused on synthesizing highly fluorescent unnatural base analogs. This has been motivated by the need to overcome the lack of fluorescence of nucleic acids' natural bases. Fluorescent unnatural base analogs, such as purines, may be used in several applications, such as DNA or RNA optical spectroscopy studies. Moreover, for purines base analogs, the optical properties, for example, emission, can be tunable through molecular engineering, improving their applications as fluorescent probes. Looking in this direction, the synthesis and optical spectroscopic studies of a new set of purines base analogs are of foremost relevance. Here, an increase in the fluorescence quantum yield was observed in molecules with NH-π-CN arrangement. The two-photon absorption (2PA) cross-sections also increased for the lower energy 2PA state. The enhancement of both properties results in a two-photon brightness of 5 and 10 times higher than in compounds lacking the NH-π-CN arrangement. For the higher energy 2PA state, an excited state absorption contribution to the 2PA cross-section values was observed, that was verified through ultrafast transient absorption measurements. The higher 2PA brightness makes the purines base analogs promising candidates as fluorescent probes in RNA and DNA spectroscopic studies.

Effects Of Specific Exercise Training During 120 Days Isolation On Physiological Kinetics And Inhibitory Control

PURPOSE: Long-term isolation is known for the detrimental effects of inactivity and decreased external stimuli on physical and cognitive systems, which is relevant for space travel in microgravity but also for pandemic-related isolation periods. Exercise countermeasures are investigated in terrestrial analog settings concerning feasibility, time efficiency, and overall beneficial effects on cardiorespiratory and cognitive fitness (i.e., positive exercise-cognition interaction). In terrestrial settings, interval (INT) and continuous (CON) treadmill exercise showed positive effects on heart rate (HR) and oxygen uptake (V̇O2) capacities and kinetics, but research for space application is still pending. We expected (I) negative effects of isolation on cognitive performance and (II) physical fitness improvements, especially from INT. METHODS: Six participants (34 ± 6 years, 3 females) spent 120 days in isolation on a simulated journey to the moon (SIRIUS-19). 8 weeks of CON, followed by 8 weeks of INT aerobic exercise on a treadmill were conducted in a crossover design. Cardiorespiratory capacities, kinetics (HR, V̇O2), and cognitive performance (Flanker task measuring inhibitory control) were assessed with an exercise protocol, including pseudo-random binary sequences (PRBS), constant work-rate phases (Rest, 3, 6, 9 km h-1, recovery), and incremental exercise for Pre, Post, and five times during isolation (ANOVA: time x phase). RESULTS: Peak values for HR (P = 0.025), V̇O2 (P = 0.012), and respiratory exchange ratio (P = 0.001) had significant time effects with lower values during isolation. Kinetics of HR and V̇O2 improved during the mission with slightly better effects for INT (both p < 0.05). Inhibitory control was not altered by 120 days of isolation. CONCLUSIONS: This study proved the successful implementation of cognitive testing within our endurance exercise test. Positive effects for INT and CON aerobic exercise were confirmed for HR, but not for V̇O2 kinetics during isolation periods. We assume the lack of general physical activity is merely compensated for by the applied exercise countermeasure, at least in 1G contexts. Currently, additional exercise modalities (i.e., strength training, passive treadmill exercise) are investigated during a consecutive 240-day mission (SIRIUS-21).

28. International perspectives on the current practice of acute spinal cord injury management: results of a global survey

28. International perspectives on the current practice of acute spinal cord injury management: results of a global survey

Substituent Orchestration in Dimethylquinoxaline Derivatives: A Tool for Fishing Out Appropriate CDK5 Inhibitors as Potential Therapeutics for Alzheimer's.

A set of new heterocyclic analogs (Compounds I-IX), comprising of 6,7 dimethyl Quinoxalines were found to be active against the receptor GSK3β (Compounds IV-V) (Chem. Biodiversity 2021, 18, e2100364). In an effort to modulate effective CDK5 inhibitors herein our hypothesis underpinned to fish out an appropriate derivative from the same quinoxaline series, as these two targets GSK3β and CDK5 shared structural resemblance with each other. Aligned to the goal we have synthesized Compounds I-IX, characterized them using a combination of spectroscopic techniques and evaluated their activities against CDK5. Our analysis reflected that the adjacently located alkoxy/hydroxy functionality derivatives namely Compounds III and VI, to be the most potent (micromolar) amongst others in the series, backed by Density Functional Theory (DFT) calculations and molecular modelling studies. Also, the efficacy of the Compounds I-IX, were monitored in few other members of the CMGC family namely DYRK1A, CLK1and CK1δ that have been known to be directly involved in hyperphosphorylation of Tau. But unfortunately in none of the targets, our quinoxaline series were active. In a nut shell further optimisation of these intelligent nucleus, would not only lead to the discovery of novel pharmacophores, but also marked selectivity against a pool of kinases, thereby implementing a distinct roadmap towards the design of potential therapeutics against Alzheimer's.

Biomimetic Total Synthesis and Investigation of the Non-Enzymatic Chemistry of Oxazinin A.

We report the first total synthesis of an antimycobacterial natural product oxazinin A that takes advantage of a multi‐component cascade reaction of anthranilic acid and a precursor polyketide containing an aldehyde. The route utilized for the synthesis of the pseudodimeric oxazinin A validates a previously proposed biosynthetic mechanism, invoking a non‐enzymatic pathway to the complex molecule. We found a 76 : 10 : 9 : 5 ratio of oxazinin diastereomers from the synthetic cascade, which is an identical match to that found in the fermentation media from the fungus Eurotiomycetes 110162. Further investigation of the non‐enzymatic formation of oxazinin A using 1H‐15N HMBC NMR spectroscopy allowed for a plausible determination of the stepwise mechanism. The developed route is highly amenable for the synthesis of diverse sets of analogs around the oxazinin scaffold to study structure–activity relationships (SAR).

Biomimetic Total Synthesis and Investigation of the Non‐Enzymatic Chemistry of Oxazinin A

AbstractWe report the first total synthesis of an antimycobacterial natural product oxazinin A that takes advantage of a multi‐component cascade reaction of anthranilic acid and a precursor polyketide containing an aldehyde. The route utilized for the synthesis of the pseudodimeric oxazinin A validates a previously proposed biosynthetic mechanism, invoking a non‐enzymatic pathway to the complex molecule. We found a 76 : 10 : 9 : 5 ratio of oxazinin diastereomers from the synthetic cascade, which is an identical match to that found in the fermentation media from the fungus Eurotiomycetes 110162. Further investigation of the non‐enzymatic formation of oxazinin A using 1H‐15N HMBC NMR spectroscopy allowed for a plausible determination of the stepwise mechanism. The developed route is highly amenable for the synthesis of diverse sets of analogs around the oxazinin scaffold to study structure–activity relationships (SAR).