Reactivity Profile Research Articles

Resilient Stress Reactivity Profiles Predict Mental Health Gains from Online Contemplative Training: A Randomized Clinical Trial.

Low-dose app-based contemplative interventions for mental health are increasingly popular, but heterogeneity in intervention responses indicates that a personalized approach is needed. We examined whether different longitudinal resilience-vulnerability trajectories, derived over the course of the COVID-19 pandemic, predicted differences in diverse mental health outcomes after mindfulness and socio-emotional dyadic online interventions. The CovSocial project comprised a longitudinal assessment (phase 1) and an open-label efficacy trial (phase 2). A community sample of 253 participants received 12 min daily app-based socio-emotional dyadic or mindfulness-based interventions, with weekly online coaching for 10 weeks. Before and after the intervention, participants completed validated self-report questionnaires assessing mental health. Stress reactivity profiles were derived from seven repeated assessments during the COVID-19 pandemic (January 2020 to March/April 2021) and were categorized into resilient (more plasticity) or vulnerable (less plasticity) stress recovery profiles. After both interventions, only individuals with resilient stress reactivity profiles showed significant improvements in depression symptomatology, trait anxiety, emotion regulation, and stress recovery. Those with vulnerable profiles did not show significant improvements in any outcome. Limitations of this study include the relatively small sample size and potential biases associated with participant dropout. Brief app-based mental interventions may be more beneficial for those with greater levels of stress resiliency and plasticity in response to stressors. More vulnerable individuals might require more intense and personalized intervention formats.

Silylium-Catalyzed Activation of Donor- Acceptor Strained Rings and Annulation with Indoles.

Leveraging the unique reactivity profile of donor-acceptor aminocyclopropanes and cyclobutanes allows the preparation of complex nitrogen-substituted molecules. While most reports focus on donor-acceptor strained rings with two geminal carbonyl groups as acceptors, mono carbonyl acceptor systems, despite their synthetic relevance, have been considerably less studied. Herein we describe catalytic annulation reactions ofaminocyclopropane and aminocyclobutane monoesters employing silylium catalysis to activate these less reactive donor-acceptor systems.

Photoactive Ni-Complexes in Metallaphotoredox Catalysis: A Successful Match in C–C Cross-Coupling Reactions

AbstractNickel catalysis is a well-established and powerful tool for C–C cross-coupling reactions, and its versatility has expanded significantly over past decades by its combination with visible-light photocatalysis in metallaphotoredox chemistry. Photocatalysis enables the activation of traditionally inert substrates and turnover of the Ni catalyst through a single-electron transfer processes. In recent years, dual catalysis has been further empowered by photoactive Ni intermediates, which exhibit distinct reactivity profiles from their ground states and complement existing protocols. This short review focuses on the emergent subclass of metallaphotoredox catalysis in which the synergy of a photoactive Ni catalyst and a typical photocatalyst (e.g., a polypyridyl Ir complex) provide solutions to challenging C–C bond formation.1 Introduction2 Photoactive Nickel Complexes3 HAT-Mediated C–C Cross-Coupling4 Halofunctionalization of π-Systems5 Photoelimination of an Aryl Radical6 Conclusion

Synthesis, Characterization, In Silico DFT, Molecular Docking, and Dynamics Simulation Studies of Phenylhydrazono Phenoxyquinolones for Their Hypoglycemic Efficacy.

A series of novel 24 phenylhydrazono phenoxyquinoline derivatives were synthesized with moderate to excellent yield and screened for their efficacy against the α-amylase enzyme through in silico studies. The structures were characterized using spectroscopic techniques such as 1HNMR, 13CNMR, and HREI-MS. Comprehensive computational studies including, drug-likeness and ADMET profiling, quantum chemical calculations, molecular docking, and molecular dynamics (MD) simulation studies, were performed. A density functional theory study of the synthesized compounds indicated a favorable reactivity profile. The synthesized novel analogues were docked against α-amylase (PDB 6OCN) enzymes to investigate the binding interactions. Based on the docking studies, one of the compounds was found to be the hit with the highest negative binding affinity for α-amylase. A MD simulation study indicated stable binding throughout the simulation.

Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome.

Research on microglia in Down syndrome (DS) has shown that microglial activation, increased inflammatory gene expression, and oxidative stress occur at different ages in DS brains. However, most studies resulted in simplistic definitions of microglia as quiescent or active, ignoring potential intermediate states. Indeed, recent work on microglial cells in young DS brains indicated that those evolve through different intermediate activation phenotypes before reaching a fully activated state. Here we used single nucleus RNA sequencing, to examine how trisomy affects microglial states in the Ts65Dn mouse model of DS. Despite no substantial changes in the proportion of glial populations, differential expression analysis revealed cell type-specific gene expression changes, most notably in astroglia, microglia, and oligodendroglia. Focusing on microglia, we identified differential expression of genes associated with different microglial states, including disease-associated microglia (DAMs), activated response microglia (ARMs), and human Alzheimer's disease microglia (HAMs), in trisomic microglia. Furthermore, pseudotime analysis reveals a unique reactivity profile in Ts65Dn microglia, with fewer in a homeostatic state and more in an intermediate aberrantly reactive state than in euploid microglia. This comprehensive understanding of microglial transcriptional dynamics sheds light on potential pathogenetic mechanisms but also possible avenues for therapy for neurodevelopmental disorders.

Energy potential of biomass from rice husks in bangladesh: An experimental study for thermochemical and physical characterization

Rice husks, abundant leftovers from rice production, offer immense potential as a renewable energy source through thermochemical conversion processes. However, their efficient utilization hinges on understanding their unique thermal properties and reaction kinetics. This study addresses a critical gap by meticulously analyzing four prominent Bangladeshi rice husk varieties: BR22, BRRI Dhan46, BRRI Dhan47, and BRRI Dhan49. Through rigorous experimentation, we unveil a comprehensive dataset encompassing their physical, chemical, and thermochemical characteristics. Our investigation reveals favorable alignment of moisture content with various conversion technologies, alongside suitable bulk density for efficient handling. Proximate analysis sheds light on crucial components like ash, volatile matter, and fixed carbon, vital for optimizing combustion efficiency. Furthermore, elemental analysis not only highlights the presence of ash-forming elements but also assures low nitrogen and sulfur content, suggesting potential environmental benefits compared to conventional fuels. Delving into thermochemical characteristics, we measured higher heating values ranging from 13.31 MJ/kg to 14.42 MJ/kg, confirming the viability of these rice husk varieties for energy conversion. Thermogravimetric and kinetic analyses further illuminate their unique decomposition behavior, with BRRI Dhan47 exhibiting the highest decomposition rate, emphasizing the distinct reactivity profiles of different varieties. This extensive dataset empowers researchers and industry professionals with valuable insights for informed decision-making. By understanding the unique attributes of each rice husk variety and their behavior during conversion, we can optimize operational parameters for various thermochemical methods. Ultimately, this study bridges a critical research gap and paves the way for more efficient and sustainable utilization of rice husks as a renewable energy source, contributing to a greener future.

Integrated insights into the structure, spectroscopy, and reactivity of a novel Brucinium Tetraphenylborate: A comprehensive computational and experimental study

The current study examines the crystal development and structure of a recently synthesized 2,3-dimethoxystrychnidin-10-one (brucine) tetraphenylborate, using both experimental and theoretical examinations. Brucinium tetraphenylborate crystal (1) was successfully synthesized and characterized using Single Crystal X-ray Diffraction. The crystal lattice is intricately defined by prevailing N/C-H···O hydrogen bonds and O/C-H···π interactions, establishing a cohesive molecular network. To elucidate intermolecular interactions within the crystal packing, Hirshfeld surface analysis and 2D fingerprint plots are employed. Validation of experimental findings is conducted through rigorous Density Functional Theory (DFT) calculations employing the B3LYP and CAM-B3LYP functionals, in conjunction with the 6–311+G* basis set. The reactivity profile of the title molecule is systematically explored through the analysis of frontier molecular orbitals (FMO), HOMO-LUMO energies, molecular electrostatic potential (MEP), and global chemical reactivity descriptors. Notably, computational insights reveal that the energy gap (Eg) and other chemical reactivity descriptors are intricately associated with both tetraphenylborate and brucine moieties. This emphasizes their pivotal roles in the overall activity and antioxidant capacity of the molecule. This research contributes to the understanding of the intricate molecular dynamics, shedding light on key factors influencing the compound's reactivity and potential antioxidant properties.

Single-domain antibodies reveal unique borrelicidal epitopes on the Lyme disease vaccine antigen, outer surface protein A (OspA).

Camelid-derived, single-domain antibodies (VHHs) have proven to be extremely powerful tools in defining the antigenic landscape of immunologically heterogeneous surface proteins. In this report, we generated a phage-displayed VHH library directed against the candidate Lyme disease vaccine antigen, outer surface protein A (OspA). Two alpacas were immunized with recombinant OspA serotype 1 from Borrelia burgdorferi sensu stricto strain B31, in combination with the canine vaccine RECOMBITEK Lyme containing lipidated OspA. The phage library was subjected to two rounds of affinity enrichment ("panning") against recombinant OspA, yielding 21 unique VHHs within two epitope bins, as determined through competition enzyme linked immunosorbent assays (ELISAs) with a panel of OspA-specific human monoclonal antibodies. Epitope refinement was conducted by hydrogen exchange-mass spectrometry. Six of the monovalent VHHs were expressed as human IgG1-Fc fusion proteins and shown to have functional properties associated with protective human monoclonal antibodies, including B. burgdorferi agglutination, outer membrane damage, and complement-dependent borreliacidal activity. The VHHs displayed unique reactivity profiles with the seven OspA serotypes associated with B. burgdorferi genospecies in the United States and Europe consistent with there being unique epitopes across OspA serotypes that should be considered when designing and evaluating multivalent Lyme disease vaccines.

2-Aminophenanthroline Ligands Enable Mild, Undirected, Iridium-Catalyzed Borylation of Alkyl C-H Bonds.

The catalytic, undirected borylation of alkyl C-H bonds typically occurs at high reaction temperatures or with excess substrate, or both, because of the low reactivity of alkyl C-H bonds. Here we report a new iridium system comprising 2-anilino-1,10-phenanthroline as the ligand that catalyzes the borylation of alkyl C-H bonds with little to no induction period and with high reaction rates. This superior activation and reactivity profile of 2-aminophenanthroline-ligated catalysts leads to broader reaction scope, including reactions of sensitive substrates, such as epoxides and glycosidic acetals, enhanced diastereoselectivity, and higher yields of borylated products. These catalysts also enable the borylation of alkanes, amines, and ethers at room temperature for the first time. Mechanistic studies imply that facile N-borylation occurs under the reaction conditions and that iridium complexes containing N-boryl aminophenanthrolines are competent precatalysts for the reaction.

Characterization, Anti-glycation, Anti-inflammation, and Lipase Inhibitory Properties of Rauvolfia vomitoriaLeaf Extract: In Vitro and In Silico Evaluations for Obesity Treatment.

Pancreatic lipase (PLP) is an enzyme responsible for the catalytic hydrolysis of fats and its inhibition is relevant for obesity management. Side effects linked with orthodox inhibitors have, however, paved the way for an increased search for safe natural sources. The present study investigated the anti-glycation, anti-inflammatory, and anti-lipase properties of Rauvolfia vomitoria aqueous (ARV), ethanolic (ERV), and methanolic (MRV) leaf extracts coupled with the molecular interactions of selected bioactive compounds with PLP using in vitro and in silico techniques. Phytochemical constituents were characterized using spectroscopic techniques. Drug-likeness and chemical reactivity profile of selected bioactive compounds were analyzed using SwissADME and quantum chemical calculations. FT-IR and GC-MS affirmed the presence of phenolic compounds including 3-phenyl-2-ethoxypropylphthalimide and 5-methyl-2-phenyl-1H-indole. All extracts showed moderate anti-glycation, anti-inflammatory, and lipase inhibitory capacities relative to standard controls. However, MRV exhibited the highest lipase inhibition (IC50, 0.17 ± 0.01mg/mL), using a mixed-inhibition pattern. MRV interaction with PLP resulted in decreased secondary structure components of PLP (α-sheet, β-turn). MRV compounds (MCP20, MCP28, etc.) exhibited low chemical hardness, EHOMO-ELUMO energy gap, and high chemical reactivity. Foremost MRV compounds obeyed Lipinski's rule of five for drug-likeness and interacted with PHE-78 amongst others at PLP catalytic domain with high binding affinity (≥ - 9.3kcal/mol). Pi-alkyl hydrophobic interaction and hydrogen bonding were predominantly involved. Our findings provide scientific insights into the ethnotherapeutic uses of R. vomitoria extracts for the management of obesity and related complications, plus useful information for optimizable drug-like candidates against obesity.

Global Reactivity Profiling of the Catalytic Lysine in Human Kinome for Covalent Inhibitor Development.

Advances in targeted covalent inhibitors (TCIs) have been made by using lysine-reactive chemistries. Few aminophiles possessing balanced reactivity/stability for the development of cell-active TCIs are however available. We report herein lysine-reactive activity-based probes (ABPs; 2-14) based on the chemistry of aryl fluorosulfates (ArOSO2 F) capable of global reactivity profiling of the catalytic lysine in human kinome from mammalian cells. We concurrently developed reversible covalent ABPs (15/16) by installing salicylaldehydes (SA) onto a promiscuous kinase-binding scaffold. The stability and amine reactivity of these probes exhibited a broad range of tunability. X-ray crystallography and mass spectrometry (MS) confirmed the successful covalent engagement between ArOSO2 F on 9 and the catalytic lysine of SRC kinase. Chemoproteomic studies enabled the profiling of >300 endogenous kinases, thus providing a global landscape of ligandable catalytic lysines of the kinome. By further introducing these aminophiles into VX-680 (a noncovalent inhibitor of AURKA kinase), we generated novel lysine-reactive TCIs that exhibited excellent in vitro potency and reasonable cellular activities with prolonged residence time. Our work serves as a general guide for the development of lysine-reactive ArOSO2 F-based TCIs.

Global Reactivity Profiling of the Catalytic Lysine in Human Kinome for Covalent Inhibitor Development

AbstractAdvances in targeted covalent inhibitors (TCIs) have been made by using lysine‐reactive chemistries. Few aminophiles possessing balanced reactivity/stability for the development of cell‐active TCIs are however available. We report herein lysine‐reactive activity‐based probes (ABPs; 2–14) based on the chemistry of aryl fluorosulfates (ArOSO2F) capable of global reactivity profiling of the catalytic lysine in human kinome from mammalian cells. We concurrently developed reversible covalent ABPs (15/16) by installing salicylaldehydes (SA) onto a promiscuous kinase‐binding scaffold. The stability and amine reactivity of these probes exhibited a broad range of tunability. X‐ray crystallography and mass spectrometry (MS) confirmed the successful covalent engagement between ArOSO2F on 9 and the catalytic lysine of SRC kinase. Chemoproteomic studies enabled the profiling of >300 endogenous kinases, thus providing a global landscape of ligandable catalytic lysines of the kinome. By further introducing these aminophiles into VX‐680 (a noncovalent inhibitor of AURKA kinase), we generated novel lysine‐reactive TCIs that exhibited excellent in vitro potency and reasonable cellular activities with prolonged residence time. Our work serves as a general guide for the development of lysine‐reactive ArOSO2F‐based TCIs.

Reactivity of Enyne-Allenes Generated via an Alder-Ene Reaction.

Tandem transformations of 1,3-diynyl propiolate derivatives are described. The Alder-ene reaction generates an enyne-allene, which undergoes a formal 1,7-H shift or a Diels-Alder reaction, depending on the substituent on the alkyne. A terminal or aryl-substituted alkyne promotes a 1,7-H shift to generate a new enyne-allene, which undergoes a Myers-Saito cycloaromatization followed by a 1,5-H transfer-mediated cyclization to form highly functionalized benzo-fused 6-membered cycles. The reactivity of the preformed enyne-allene shows comparable reactivity profiles.

Different reactive profiles of calmodulin in the CSF samples of Chinese patients of four types of genetic prion diseases.

Calmodulin (CaM) levels exhibit significant elevation in the brain tissue of rodent and cell line models infected with prion, as well as in the cerebrospinal fluid (CSF) samples from patients diagnosed with sporadic Creutzfeldt-Jakob disease (sCJD). However, the status of CSF CaM in patients with genetic prion diseases (gPrDs) remains unclear. This study aims to assess the characteristics of CSF CaM in Chinese patients presenting four subtypes of gPrDs. A total of 103 CSF samples from patients diagnosed with T188K-gCJD, E200K-gCJD, D178N-FFI, P102L-GSS were included in this study, along with 40 CSF samples from patients with non-prion diseases (non-PrDs). The presence of CSF CaM and 14-3-3 proteins was assessed using Western blots analysis, while levels of CSF 14-3-3 and total tau were measured using enzyme-linked immunosorbent assays (ELISAs). Statistical methods including multivariate logistic regression were employed to evaluate the association between CSF CaM positivity and relevant clinical, laboratory, and genetic factors. The positive rates of CSF CaM were significantly higher in cases of T188K-gCJD (77.1%), E200K-gCJD (86.0%), and P102-GSS (90.9%) compared to non-PrD cases (22.5%). In contrast, CSF CaM positivity was slightly elevated in D178N-FFI (34.3%). CSF CaM positivity was remarkably high in patients who tested positive for CSF 14-3-3 by Western blot and exhibited high levels of total tau (≥1400 pg/ml) as measures by ELISA. Multivariate logistic regression analysis confirmed a significant association between CSF CaM positivity and specific mutations in PRNP, as well as with CSF 14-3-3 positivity. Furthermore, the diagnostic performance of CaM surpassed that of 14-3-3 and tau when analyzing CSF samples from T188K-gCJD and E200K-gCJD patients. Western blot analysis reveals significant variations in the positivity of CSF CaM among the four genotypes of gPrD cases, demonstrating a positive correlation with 14-3-3 positivity and elevated tau levels in CSF.

A Study of Serum C - Reactive Protein, Uric Acid and Lipid Profile in Patients with Psoriasis Visiting Dermatology Department, PBM Hospital, Bikaner

A Study of Serum C - Reactive Protein, Uric Acid and Lipid Profile in Patients with Psoriasis Visiting Dermatology Department, PBM Hospital, Bikaner

Location-agnostic site-specific protein bioconjugation via Baylis Hillman adducts

Proteins labelled site-specifically with small molecules are valuable assets for chemical biology and drug development. The unique reactivity profile of the 1,2-aminothiol moiety of N-terminal cysteines (N-Cys) of proteins renders it highly attractive for regioselective protein labelling. Herein, we report an ultrafast Z-selective reaction between isatin-derived Baylis Hillman adducts and 1,2-aminothiols to form a bis-heterocyclic scaffold, and employ it for stable protein bioconjugation under both in vitro and live-cell conditions. We refer to our protein bioconjugation technology as Baylis Hillman orchestrated protein aminothiol labelling (BHoPAL). Furthermore, we report a lipoic acid ligase-based technology for introducing the 1,2-aminothiol moiety at any desired site within proteins, rendering BHoPAL location-agnostic (not limited to N-Cys). By using this approach in tandem with BHoPAL, we generate dually labelled protein bioconjugates appended with different labels at two distinct specific sites on a single protein molecule. Taken together, the protein bioconjugation toolkit that we disclose herein will contribute towards the generation of both mono and multi-labelled protein-small molecule bioconjugates for applications as diverse as biophysical assays, cellular imaging, and the production of therapeutic protein–drug conjugates. In addition to protein bioconjugation, the bis-heterocyclic scaffold we report herein will find applications in synthetic and medicinal chemistry.

Examining Reactivity and Recovery Patterns of Pain-Evoked Cortisol and Alpha-Amylase Trajectories: Relations Between Psychological Markers of Risk and Resilience

Chronic low back pain (cLBP) is one of the leading causes of disability globally and represents an enormous burden to aging adults. While numerous factors contribute to cLBP, dysregulation in the hypothalamic-pituitary-adrenal axis and autonomic nervous system functioning have been implicated in its pathogenesis. It is well documented that negative psychological states can modulate biological stress responsivity in chronic pain; however, little is known regarding the influence of positive psychological factors in this relationship. The aim of this study was to examine the association between psychological risk and resilience factors with patterns of physiological stress reactivity and recovery in 60 older adults with cLBP. Participants completed measures of hope, optimism, pain catastrophizing, and perceived stress, and underwent psychophysical pain testing assessing responses to painful pressure, heat, and cold stimuli. Salivary samples were obtained prior to pain induction and at 7 time points spanning 90 minutes after pain testing terminated. To examine reactivity and recovery profiles in hypothalamic-pituitary-adrenal axis and autonomic nervous system function, samples were assayed for cortisol and alpha-amylase, respectively. Results revealed higher levels of hope and optimism were associated with increased cortisol reactivity (p’s < .003) and more rapid recovery (p’s = .001). Further, pain catastrophizing and perceived stress were associated with cortisol reactivity, with lower levels of these factors predicting larger increases in cortisol from baseline to peak levels (p’s < .04). No significant differences in reactivity or recovery patterns emerged for alpha-amylase. Overall, findings highlight the role of psychological risk and resilience factors in modulating physiological stress reactivity. PerspectiveThis article investigated whether psychosocial risk and resilience factors were associated with stress reactivity and recovery in response to laboratory-based pain testing in older adults with chronic low back pain. Results indicate that high resilience factors may be protective by modulating adrenocortical reactivity and recovery profiles.

In Silico Exploration of Phytoconstituents and Identification of Hits Against α-Amylase for Antidiabetic Potential

In the pursuit of effective diabetes management, inhibiting α-amylase activity stands as a critical strategy. This inhibition regulates post-meal blood sugar levels by retarding carbohydrate digestion, mitigating abrupt glucose spikes, and enhancing glycemic control, thus safeguarding against diabetic complications. In this study, molecular docking and DFT investigations were conducted on phytochemical compounds sourced from various plants, unveiling Conanine, Friedelin, Sennoside A, and Sennoside B as promising candidates. These compounds demonstrated robust binding affinities exceeding -9 kcal/mol when targeted against α-amylase, with Conanine leading the charge at -9.5 kcal/mol. Sennoside A and Sennoside B exhibited their effectiveness by forming multiple hydrogen bonds with the enzyme, underlining their strong binding interactions. Furthermore, DFT calculations affirmed the favorable chemical reactivity profiles of these ligands, characterized by significant HOMO-LUMO energy gaps. This research offers valuable insights into potential therapeutic agents for diabetes management, promising better glycemic control and a brighter future for individuals with diabetes.

Unveiling the Full Dynamical and Reactivity Profiles of Acetylcholinesterase: A Comprehensive All-Atom Investigation

Unveiling the Full Dynamical and Reactivity Profiles of Acetylcholinesterase: A Comprehensive All-Atom Investigation

UBE2A and UBE2B are recruited by an atypical E3 ligase module in UBR4.

UBR4 is a 574 kDa E3 ligase (E3) of the N-degron pathway with roles in neurodevelopment, age-associated muscular atrophy and cancer. The catalytic module that carries out ubiquitin (Ub) transfer remains unknown. Here we identify and characterize a distinct E3 module within human UBR4 consisting of a 'hemiRING' zinc finger, a helical-rich UBR zinc-finger interacting (UZI) subdomain, and an N-terminal region that can serve as an affinity factor for the E2 conjugating enzyme (E2). The structure of an E2-E3 complex provides atomic-level insight into the specificity determinants of the hemiRING toward the cognate E2s UBE2A/UBE2B. Via an allosteric mechanism, the UZI subdomain modestly activates the Ub-loaded E2 (E2∼Ub). We propose attenuated activation is complemented by the intrinsically high lysine reactivity of UBE2A, and their cooperation imparts a reactivity profile important for substrate specificity and optimal degradation kinetics. These findings reveal the mechanistic underpinnings of a neuronal N-degron E3, its specific recruitment of UBE2A, and highlight the underappreciated architectural diversity of cross-brace domains with Ub E3 activity.