Association of Interleukin 23 Receptor Polymorphisms with Predisposition to Rheumatoid Arthritis: An Updated Meta and Trial Sequential Analysis.

The etiology of Rheumatoid Arthritis (RA) development remained unclear, and several factors, such as environmental, genetic, and immune system dysfunction, have been attributed to the susceptibility. Interleukin 23 (IL23) induces expansion of the Th17 cells through the IL-23 receptor (IL-23R) and believes in playing a major role in RA pathogenesis. Various genetic mutants in the IL23R gene (rs10489629, rs1343151, rs2201841, rs7517847, rs1004819, rs10889677, rs11209026, rs7530511) have been associated with the susceptibility RA, but results are contradictories. We performed a meta-analysis to establish the association of IL23R polymorphisms with susceptibility RA. For the meta-analysis, a detailed search of databases like Google Scholar, PubMed, Scopus, Web of Science, and Science Direct was conducted, and data were extracted from the included reports. The meta-analysis was performed by the Comprehensive Meta-Analysis v3 software. A significant association of IL-23R rs11209026 (AA vs. GG: Odds ratio = 2.250, p-value = 0.01; AA vs. GG+GA: Odds ratio = 2.271, p-value = 0.01), rs1343151 (A vs. G: Odds ratio = 1.091, p-value = 0.001; AA vs. GG: Odds ratio = 1.209, p-value = 0.001; GA vs. GG: Odds ratio = 1.116, p-value = 0.004; AA+GA vs. GG: Odds ratio = 1.135, p-value = 0.000; AA vs. GG+GA: Odds ratio = 1.144, p-value = 0.012) and rs10889677 (CA vs. CC: Odds ratio = 1.375, p-value = 0.041) polymorphisms were observed with increased susceptibility for the development of RA. In contrast, IL-23R rs10489629 (G vs. A: odds ratio = 0.901, p-value = 0.047, GG vs. AA: Odds ratio = 0.763, p-value = 0.022, GG vs. AA+AG: Odds ratio = 0.852, p-value = 0.00) and IL23R rs2201841 (CC vs. TT+TC: Odds ratio = 0.826, p-value = 0.026) variants were linked with protection against the development of RA. In addition, the trial sequential analysis revealed the inclusion of a sufficient number of studies in the present meta-analysis, and no further additional studies are required. IL-23R variants are associated with genetic susceptibility or resistance against the development of RA.

Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment.

The mTOR signaling pathway plays a pivotal and intricate role in the pathogenesis of glioblastoma, driving tumorigenesis and proliferation. Mutations or deletions in the PTEN gene constitutively activate the mTOR pathway by expressing growth factors EGF and PDGF, which activate their respective receptor pathways (e.g., EGFR and PDGFR). The convergence of signaling pathways, such as the PI3K-AKT pathway, intensifies the effect of mTOR activity. The inhibition of mTOR has the potential to disrupt diverse oncogenic processes and improve patient outcomes. However, the complexity of the mTOR signaling, off-target effects, cytotoxicity, suboptimal pharmacokinetics, and drug resistance of the mTOR inhibitors pose ongoing challenges in effectively targeting glioblastoma. Identifying innovative treatment strategies to address these challenges is vital for advancing the field of glioblastoma therapeutics. This review discusses the potential targets of mTOR signaling and the strategies of target-specific mTOR inhibitor development, optimized drug delivery system, and the implementation of personalized treatment approaches to mitigate the complications of mTOR inhibitors. The exploration of precise mTOR-targeted therapies ultimately offers elevated therapeutic outcomes and the development of more effective strategies to combat the deadliest form of adult brain cancer and transform the landscape of glioblastoma therapy.

Pulsatile signaling of bistable switches reveal the distinct nature of pulse processing by mutual activation and mutual inhibition loop.

Cells often encounter various external and internal signals in a non-sustained pulsatile manner with varying amplitude, duration and residual value. However, the effect of signal pulse on the regulatory networks is poorly understood. In order gain a quantitative understating of pulse processing by bistable switches, we investigated pulse induced population inversion kinetics in bistable switches generated either by mutual activation or by mutual inhibition motifs. We show that a transient intense pulse or a prolonged weak pulse both can induce population inversion, however by distinct mechanisms. An intense pulse facilitates the population inversion by reducing the inversion time, while a weak prolonged pulse allows more late responders to flip their steady state causing increased average transition time. Although the inversion is controlled by the pulse amplitude and duration, however the fate of the inverted state is dictated by the residual signal that determines the mean residence at the flipped state. Therefore, population inversion and its maintenance require a proper tuning of all three signal parameters. Bistable system of mutual activation motif is more prone to make a transient response to the pulse however it is less susceptible to flip its steady state. While the bistability of mutual inhibition motif does not make a transient response yet it is more prone to switch its steady state. By comparing the pulse parameters and statistical properties of associated times scales, we conclude that a bistable switch originating from mutual activation loop is less susceptible to spurious signals as compared to the mutual inhibition loop.

Interleukin 17A rs2275913 polymorphism is associated with susceptibility to systemic lupus erythematosus: A meta and trial sequential analysis.

BACKGROUND: The role of cytokines in the development of systemic lupus erythematosus (SLE) has received much attention. Interleukin-17 A upregulates several inflammation-related genes and is thought to have a crucial role in SLE development. The susceptibility to SLE development has been linked to functional genetic variations of the IL-17A gene; nevertheless, the findings have been conflicting. We conducted a meta-analysis that included previously published reports to establish a definitive conclusion on the role of the IL-17A rs2275913 polymorphism in SLE propensity. MATERIALS AND METHODS: The PubMed, Google Scholar, and Scopus databases were used to find eligible published articles. All analyses were conducted using Comprehensive Meta-analysis V3.1. Funnel plots and Egger's regression analysis were used to assess publication bias. Q statistics and I2 test explored the heterogeneity among the included studies. Combined odds ratio, 95% confidence interval were calculated for each comparison model. RESULTS: Based on the inclusion and exclusion criteria, a total of four reports, comprising of 608 SLE patients and 815 healthy controls, were considered for the present meta-analysis. The homozygous comparison (AA vs. GG: combined odds ratio= 2.046, p = 0.005) and recessive genetic model (AA vs. GG+GA: combined odds ratio=1.901, p = 0.010) analysis revealed a significant association of rs2275913 with susceptibility to the development of SLE. However, other genetic comparisons (A vs. G, GA vs. GG, AA+GA vs. GG) failed to demonstrate such association. Furthermore, trial sequential analysis revealed a sufficient number of studies, including enough cases and controls that have already been considered to conclude the role of IL17-A rs2275913 polymorphism in SLE. CONCLUSIONS: IL-17A rs2275913 polymorphism is associated with susceptibility to SLE development.

Gold(I)-Catalyzed [4 + 2] Annulation between Arylynes and C,N-Diaryl Nitrones for Chemoselective Synthesis of Quinoline Scaffolds via Gold Acetylide Intermediates.

Gold-catalyzed synthesis of quinoline derivatives via [4 + 2] annulation between terminal arylynes and nitrones is described. Our mechanistic analysis supports the participation of alkynylgold intermediates, instead of a typical gold-carbene species in recently reported gold catalysis. These nucleophilic alkynylgold species react with nitrones via Povarov-type reactions. Cheap, readily available materials and a broad substrate scope manifest the advantage of this method.

Aza-Oxa-Triazole Based Macrocycles with Tunable Properties: Design, Synthesis, and Bioactivity.

A modular platform for the synthesis of tunable aza-oxa-based macrocycles was established. Modulations in the backbone and the side-chain functional groups have been rendered to achieve the tunable property. These aza-oxa-based macrocycles can also differ in the number of heteroatoms in the backbone and the ring size of the macrocycles. For the proof of concept, a library of macrocycles was synthesized with various hanging functional groups, different combinations of heteroatoms, and ring sizes in the range of 17-27 atoms and was characterized by NMR and mass spectrometry. In light of the importance of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and the significance of triazole groups for various applications, we employed the click-reaction-based macrocyclization. The competence of the synthesized macrocycles in various biomedical applications was proven by studying the interactions with the serum albumin proteins; bovine serum albumin and human serum albumin. It was observed that some candidates, based on their hanging functional groups and specific backbone atoms, could interact well with the protein, thus improving the bioactive properties. On the whole, this work is a proof-of-concept to explore the backbone- and side-chain-tunable macrocycle for different properties and applications.

A Stochastic Model of the Yeast Cell Cycle Reveals Roles for Feedback Regulation in Limiting Cellular Variability.

The cell division cycle of eukaryotes is governed by a complex network of cyclin-dependent protein kinases (CDKs) and auxiliary proteins that govern CDK activities. The control system must function reliably in the context of molecular noise that is inevitable in tiny yeast cells, because mistakes in sequencing cell cycle events are detrimental or fatal to the cell or its progeny. To assess the effects of noise on cell cycle progression requires not only extensive, quantitative, experimental measurements of cellular heterogeneity but also comprehensive, accurate, mathematical models of stochastic fluctuations in the CDK control system. In this paper we provide a stochastic model of the budding yeast cell cycle that accurately accounts for the variable phenotypes of wild-type cells and more than 20 mutant yeast strains simulated in different growth conditions. We specifically tested the role of feedback regulations mediated by G1- and SG2M-phase cyclins to minimize the noise in cell cycle progression. Details of the model are informed and tested by quantitative measurements (by fluorescence in situ hybridization) of the joint distributions of mRNA populations in yeast cells. We use the model to predict the phenotypes of ~30 mutant yeast strains that have not yet been characterized experimentally.

Sequence-Defined Tertiary Amine-Based Oligomer Employing a Scalable, Support-Free, and Protection/Deprotection-Free Iterative Strategy.

Sequence-defined oligomers (SDOs) with their unique monomeric sequence and customizable nature are attracting the attention of researchers globally. The structural and functional diversity attainable in SDOs makes this platform promising, albeit with challenges in the synthesis. Herein, we report the design and synthesis of a novel class of SDO by incorporating tertiary amines into the backbone from commercially available inexpensive materials. Tertiary amines were selected due to their various material and biomedical applications. Even though the synthesis and purification of amine compounds are challenging, their various significant applications, such as pharmaceuticals, catalysts, surfactants, corrosion inhibitors, dye intermediates, polymer additives, rubber accelerators, gas treating agents, agriculture, and analytical chemistry, make them fascinating. The synthetic strategy that is designed here is extremely efficient and economical for the scalable synthesis of the SDO and is support-free, protection-deprotection chemistry-free, and catalyst/template-free. Most importantly, no extra design and synthesis of the monomer is required here. The key reactions employed for the SDO synthesis are (i) transformation of the hydroxy group to a halide and (ii) substitution of the halide by the secondary amine units. Including the purifying processes, the multigram synthesis of 4-mer was completed in 12-14 h. The synthetic strategy was established by synthesizing two different sequences of SDOs. The SDOs are characterized by 1H NMR and LC-MS. The tandem MS (MS/MS) experiment was conducted in order to validate the sequences over the SDO chain. Furthermore, the SDO platform was advanced in two ways: (i) by increasing the chain length via attaching a linker, which provides a rapid method for increasing the tertiary amine over the SDO chain, and (ii) postsynthetic modification of SDO with other functional groups, including guanidine for biological importance and a well-known fluorophore dansyl group for material significance.

Dansyl-tagged xanthate ester as a capping agent to synthesize fluorescent silver nanoparticles with binding affinity toward serum albumin.

Developing multifunctional nanomaterials with distinct photochemical properties, such as high quantum yield, improved photostability, and good biocompatibility is critical for a wide range of biomedical applications. Motivated by this, we designed and synthesized a dansyl-tagged xanthate-based capping agent (DX) for the synthesis of fluorescent silver nanoparticles (AgNPs). The capping agent DX was characterized by 1 H and 13 C-NMR, LC-MS, and FT-IR. The synthesized DX-capped fluorescent AgNPs were thoroughly characterized by UV-visible spectroscopy, fluorescence spectroscopy, field emission scanning electron microscope (FE-SEM), transmission electron microscope (TEM), dynamic light scattering (DLS), and zeta potential. The fluorescent AgNPs showed distinct surface plasmon resonance absorption at λmax = 414 nm, fluorescence at λmax = 498 nm, quantum yield = 0.24, zeta potential = +18.6 mV, average size = 18.2 nm. Furthermore, the biological activity of the fluorescent AgNPs was validated by its interaction with the most abundant protein in the blood, that is, BSA (Bovine serum albumin) and HSA (Human serum albumin) with binding constant of 2.34 × 104 M-1 and 2.14 × 104 M-1 respectively. Interestingly, fluorescence resonance energy transfer (FRET) was observed between the fluorescent AgNPs and BSA/HSA with a FRET efficiency of 77.23% and 56.36%, respectively, indicating strong interaction between fluorescent AgNPs and BSA/HSA.

Investigating Lycotoxin-An1a (An1a), a defense antiviral peptide from Alopecosa nagpag venom as prospective anti-dengue agent against DENV-2 NS2B-NS3 protease.

Dengue fever is a global health concern with no effective therapy. Screening synthetic chemicals, animal-originated compounds, and phytocompounds against Dengue virus (DENV) targets has failed to find dengue antivirals. The current study examines animal drugs as antagonists against NS2B-NS3Pro, one of DENV's most promising therapeutic targets for dengue fever. Antiviral-Lycotoxin-An1a (An1a), a defence antiviral peptide isolated from the venom of Alopecosa nagpag, a toxic spider. Based on prior in vitro research, it was discovered that the venom peptide suppresses the action of DENV-2 NS2B-NS3Pro. An1a peptide with NS2B-NS3Pro wild type (WT) and two mutants (H51N and S135A) was tested for anti-dengue characteristics using in silico analysis. The WT NS2B-NS3Pro has a catalytic triad of His51, Asp75, and Ser135 in the active site, but the mutants have N51 instead of His51 and Ala135 instead of Ser135. The dynamic sites of the three proteases (WT, H51N, S135A) and the peptide toxin (An1a) were taken into account to achieve molecular docking of An1a with WT NS2B-NS3Pro in conjunction with H51N and S135A. Cluspro-2 performs rigid-flexible docking to predict peptide binding affinity, effectiveness, and inhibitory consistency. Since the ligand had a higher binding affinity, docking score, and molecular interaction network, MD simulations and MM-GBSA free energy calculations were used to investigate the stability of the three protein-peptide complexes. The computer-aided screening and manufacture of spider venom-based anti-dengue medicines yielded intriguing results in the preliminary studies. This study is significant in defining the ideal therapeutic candidate against dengue infections.

Evaluation of the inhibitory potency of anti-dengue phytocompounds against DENV-2 NS2B-NS3 protease: virtual screening, ADMET profiling and molecular dynamics simulation investigations.

Dengue fever has been a worldwide concern, with 50-100 million new infections each year mainly due to five different serotypes of the Dengue virus (DENV). Designing a perfect anti-dengue agent that can inhibit all the serotypes by distinguishing antigenic differences is quite difficult. Previous anti-dengue researches have included chemical compounds screening against DENV enzymes. The ongoing analysis is meant for investigation of the plant-based compounds as antagonistic to DENV-2 focusing on the specific NS2B-NS3Pro target, a trypsin like serine protease that cuts the DENV polyprotein into separate proteins crucial for viral reproduction. Initially, a virtual library of more than 130 phytocompounds was prepared from previously published reports of plants with anti-dengue properties, which were then virtually screened and shortlisted against the WT, H51N and S135A mutant of DENV-2 NS2B-NS3Pro. The three top-most compounds were viewed as Gallocatechin (GAL), Flavokawain-C (FLV), and Isorhamnetin (ISO) showing docking scores of -5.8, -5.7, -5.7 kcal/mol for WT, -7.5, -6.8, -7.6 kcal/mol for the H51N, and -6.9, -6.5, -6.1 kcal/mol for the S135A mutant protease, respectively. 100 ns long MD simulations and MM-GBSA based free energy calculations were performed on the NS2B-NS3Pro complexes to witness the relative binding affinity of the compounds and favourable molecular interactions network. A comprehensive analysis of the study reveals some promising outcomes with ISO as the topmost compound with favourable pharmacokinetic properties for the WT and mutants (H51N and S135A) as well, suggesting as a novel anti-NS2B-NS3Pro agent with better adapting characters in both the mutants.Communicated by Ramaswamy H. Sarma.

Investigation of airborne spread of COVID-19 using a hybrid agent-based model: a case study of the UK.

Agent-based models have been proven to be quite useful in understanding and predicting the SARS-CoV-2 virus-originated COVID-19 infection. Person-to-person contact was considered as the main mechanism of viral transmission in these models. However, recent understanding has confirmed that airborne transmission is the main route to infection spread of COVID-19. We have developed a computationally efficient agent-based hybrid model to study the aerial propagation of the virus and subsequent spread of infection. We considered virus, a continuous variable, spreads diffusively in air and members of populations as discrete agents possessing one of the eight different states at a particular time. The transition from one state to another is probabilistic and age linked. Recognizing that population movement is a key aspect of infection spread, the model allows unbiased movement of agents. We benchmarked the model to recapture the temporal stochastic infection count data of the UK. The model investigates various key factors such as movement, infection susceptibility, new variants, recovery rate and duration, incubation period and vaccination on the infection propagation over time. Furthermore, the model was applied to capture the infection spread in Italy and France.

Origin, heterogeneity, and interconversion of noncanonical bistable switches from the positive feedback loops under dual signaling.

Designing new functional motifs with unique properties is an important objective in the realm of synthetic biology. We uncover emergent properties of positive feedback loops (PFLs) under dual input signaling using pseudo potential energy-based high-throughput bifurcation analysis. We show that under dual signaling a single PFL generates a variety of noncanonical bistable switches, with one or more bistable regions, due to fusion of multiple canonical bistable switches. Regulatory signs of the dual signaling must be coherent for mutual inhibition loop and incoherent for mutual activation loop of the PFL. Occurrence probabilities show that some of the noncanonical switches, such as isola and mushroom, are highly recurrent under random parameterization. Phase diagrams of the noncanonical switches reveal that feedback strengths of the PFL control the transition from one switch to another. Our calculations decipher the design principles of noncanonical bistable switches that originate from synthetically feasible simple PFL motifs under dual signaling.

Protocol for potential energy-based bifurcation analysis, parameter searching, and phase diagram analysis of noncanonical bistable switches.

We have explored the design principles of noncanonical bistable switches using high-throughput bifurcation analysis of positive feedback loops under dual signaling. Here, we present a protocol to carry out bifurcation analysis using pseudo-potential energy of the dynamical system. We also describe steps to perform automated parameter searching for canonical and noncanonical switches and multi-parameter phase diagram analysis of these switches. For complete details on the use and execution of this protocol, please refer to Das et al.1.

Small Molecule Targeting Immune Cells: A Novel Approach for Cancer Treatment.

Conventional and cancer immunotherapies encompass diverse strategies to address various cancer types and stages. However, combining these approaches often encounters limitations such as non-specific targeting, resistance development, and high toxicity, leading to suboptimal outcomes in many cancers. The tumor microenvironment (TME) is orchestrated by intricate interactions between immune and non-immune cells dictating tumor progression. An innovative avenue in cancer therapy involves leveraging small molecules to influence a spectrum of resistant cell populations within the TME. Recent discoveries have unveiled a phenotypically diverse cohort of innate-like T (ILT) cells and tumor hybrid cells (HCs) exhibiting novel characteristics, including augmented proliferation, migration, resistance to exhaustion, evasion of immunosurveillance, reduced apoptosis, drug resistance, and heightened metastasis frequency. Leveraging small-molecule immunomodulators to target these immune players presents an exciting frontier in developing novel tumor immunotherapies. Moreover, combining small molecule modulators with immunotherapy can synergistically enhance the inhibitory impact on tumor progression by empowering the immune system to meticulously fine-tune responses within the TME, bolstering its capacity to recognize and eliminate cancer cells. This review outlines strategies involving small molecules that modify immune cells within the TME, potentially revolutionizing therapeutic interventions and enhancing the anti-tumor response.

Nitrosoarenes Implement Cascade Cyclization of 1-Allenyl-2-alkynylbenzenes through Diradical Mechanism.

This work reports cascade cyclization between 1-allenyl-2-alkynylbenzenes and nitrosoarenes. When these two components reacted alone under N2, N,O-functionalized indane-fused isoxazolidines 3 were obtained selectively. DFT calculations verify that this reaction sequence involves unprecedented nitrone/alkyne cycloadditions, followed by diradical rearrangement.

Roughness in the periodic potential induces absolute negative mobility in a driven Brownian ratchet.

Absolute negative mobility, where particles move opposite to the direction as governed by the external load, is an anomalous transport property of a Brownian ratchet and has technological implications in mass separation and bioanalytical applications. We numerically investigated here the effect of roughness in symmetric periodic potential on the negative mobility of a driven inertial Brownian ratchet in the presence of an external load. We show that the microscopic spatial heterogeneity of the potential can generate negative mobility which would not otherwise be possible under smooth potential in the concerned parameter space. We determined the optimal condition in terms of parameter space for such anomalous behavior. Our calculations indicate that the shift of balance towards the negative velocity phase in the temporal oscillations of velocity and weakly chaotic dynamics are responsible factors for roughness-induced negative mobility. These calculations highlight a constructive role of roughness in the anomalous transport properties of Brownian ratchet.

A model of yeast cell-cycle regulation based on multisite phosphorylation.

In order for the cell's genome to be passed intact from one generation to the next, the events of the cell cycle (DNA replication, mitosis, cell division) must be executed in the correct order, despite the considerable molecular noise inherent in any protein-based regulatory system residing in the small confines of a eukaryotic cell. To assess the effects of molecular fluctuations on cell-cycle progression in budding yeast cells, we have constructed a new model of the regulation of Cln- and Clb-dependent kinases, based on multisite phosphorylation of their target proteins and on positive and negative feedback loops involving the kinases themselves. To account for the significant role of noise in the transcription and translation steps of gene expression, the model includes mRNAs as well as proteins. The model equations are simulated deterministically and stochastically to reveal the bistable switching behavior on which proper cell-cycle progression depends and to show that this behavior is robust to the level of molecular noise expected in yeast-sized cells (approximately 50 fL volume). The model gives a quantitatively accurate account of the variability observed in the G1-S transition in budding yeast, which is governed by an underlying sizer+timer control system.

Potential Landscapes, Bifurcations, and Robustness of Tristable Networks.

Bistable switches that produce all-or-none responses have been found to regulate a number of natural cellular decision making processes, and subsequently synthetic switches were designed to exploit their potential. However, an increasing number of studies, particularly in the context of cellular differentiation, highlight the existence of a mixed state that can be explained by tristable switches. The criterion for designing robust tristable switches still remains to be understood from the perspective of network topology. To address such a question, we calculated the robustness of several 2- and 3-component network motifs, connected via only two positive feedback loops, in generating tristable signal response curves. By calculating the effective potential landscape and following its modifications with the bifurcation parameter, we constructed one-parameter bifurcation diagrams of these models in a high-throughput manner for a large combinations of parameters. We report here that introduction of a self-activatory positive feedback loop, directly or indirectly, into a mutual inhibition loop leads to generating the most robust tristable response. The high-throughput approach of our method further allowed us to determine the robustness of four types of tristable responses that originate from the relative locations of four bifurcation points. Using the method, we also analyzed the role of additional mutual inhibition loops in stabilizing the mixed state.