Integration of Sensor-Based and Self-Reported Metrics in a Sleep Diary: A Pilot Exploration.

OBJECTIVES: Discrepancies between sleep diaries and sensor-based sleep parameters are widely recognized. This study examined the effect of showing sensor-based sleep parameters while completing a daily diary. The provision of sensor-based data was expected to reduce variance but not change the mean of self-reported sleep parameters, which would in turn align better with sensor-based data compared to a control diary. METHOD: In a crossover study, 24 volunteers completed week-long periods of control diary (digital sleep diary without sensor-based data feedback) or integrated diary (diary with device feedback), washout, and then the other diary condition. RESULTS: The integrated diary reduced self-reported total sleep time (TST) by <10 minutes and reduced variance in TST. The integrated diary did not impact mean sleep onset latency (SOL) and, unexpectedly, the variance in SOL increased. The integrated diary improved both bias and limits of agreement for SOL and TST. CONCLUSIONS: Integration of wearable, sensor-based device data in a sleep diary has little impact on means, mixed evidence for less variance, and better agreement with sensor-based data than a traditional diary. How the diary impacts reporting and sensor-based sleep measurements should be explored.

G-quadruplex structural dynamics at MAPK12 promoter dictates transcriptional switch to determine stemness in breast cancer.

P38γ (MAPK12) is predominantly expressed in triple negative breast cancer cells (TNBC) and induces stem cell (CSC) expansion resulting in decreased survival of the patients due to metastasis. Abundance of G-rich sequences at MAPK12 promoter implied the functional probability to reverse tumorigenesis, though the formation of G-Quadruplex (G4) structures at MAPK12 promoter is elusive. Here, we identified two evolutionary consensus adjacent G4 motifs upstream of the MAPK12 promoter, forming parallel G4 structures. They exist in an equilibria between G4 and duplex, regulated by the binding turnover of Sp1 and Nucleolin that bind to these G4 motifs and regulate MAPK12 transcriptional homeostasis. To underscore the gene-regulatory functions of G4 motifs, we employed CRISPR-Cas9 system to eliminate G4s from TNBC cells and synthesized a naphthalene diimide (NDI) derivative (TGS24) which shows high-affinity binding to MAPK12-G4 and inhibits MAPK12 transcription. Deletion of G4 motifs and NDI compound interfere with the recruitment of the transcription factors, inhibiting MAPK12 expression in cancer cells. The molecular basis of NDI-induced G4 transcriptional regulation was analysed by RNA-seq analyses, which revealed that MAPK12-G4 inhibits oncogenic RAS transformation and trans-activation of NANOG. MAPK12-G4 also reduces CD44High/CD24Low population in TNBC cells and downregulates internal stem cell markers, arresting the stemness properties of cancer cells.

Switchable tetraplex elements in the heterogeneous nuclear ribonucleoprotein K promoter: micro-environment dictated structural transitions of G/C rich elements.

We have elucidated the hnRNP K promoter as a hotspot for tetraplex-based molecular switches receptive to micro-environmental stimuli. We have characterised the structural features of four tetraplex-forming loci and identified them as binding sites of transcription factors. These segments form either G-quadruplex or i-motif structures, the structural dynamicity of which has been studied in depth via several biophysical techniques. The tetraplexes display high dynamicity and are influenced by both pH and KCl concentrations in vitro. The loci complementary to these sequences form additional non-canonical secondary structures. In the cellular context, the most eminent observation of this study is the binding of hnRNP K to the i-motif forming sequences in its own promoter. We are the first to report a probable transcriptional autoregulatory function of hnRNP K in coordination with higher-order DNA structures. Herein, we also report the positive interaction of the endogenous tetraplexes with Sp1, a well-known transcriptional regulator. Treatment with tetraplex-specific small molecule ligands further uncovered G-quadruplexes' functioning as repressors and i-motifs as activators in this context. Together, our findings strongly indicate the critical regulatory role of the identified tetraplex elements in the hnRNP K promoter.Communicated by Ramaswamy H. Sarma.

Unraveling the structural aspects of the G-quadruplex in SMO promoter and elucidating its contribution in transcriptional regulation.

We located a 25 nt G-rich sequence in the promoter region of SMO oncogene. We performed an array of biophysical and biochemical assays and confirmed the formation of a parallel G quadruplex (SMO1-GQ) by the identified sequence. SMO1-GQ is highly conserved in primates. For a comprehensive characterization of the SMO quadruplex structure, we have performed spectroscopic and in silico analysis with established GQ binder small molecules TMPyP4 and BRACO-19. We observed comparatively higher stable interaction of BRACO-19 with SMO1-GQ. Structure-based, rational drug design against SMO1-GQ to target SMO oncogene requires a detailed molecular anatomy of the G-quadruplex. We structurally characterised the SMO1-GQ using DMS footprinting assay and molecular modelling, docking, and MD simulation to identify the probable atomic regions that interact with either of the small molecules. We further investigated SMO1-GQ in vivo by performing chromatin immunoprecipitation (ChIP) assay. ChIP data revealed that this gene element functions as a scaffold for a number of transcription factors: specificity protein (Sp1), nucleolin (NCL), non-metastatic cell 2 (NM23-H2), cellular nucleic acid binding protein (CNBP), and heterogeneous nuclear ribonucleoprotein K (hnRNPK) which reflects the SMO1-P1 G-quadruplex to be the master regulator of SMO1 transcriptional activity. The strong binding interaction detected between SMO1-GQ and BRACO-19 contemplates the potential of the G quadruplex as a promising anti-cancer druggable target to downregulate SMO1 oncogene driven cancers.Communicated by Ramaswamy H. Sarma.

Modeling and monitoring the effects of three partly conserved Ile residues in the dimerization domain of a Mip-like virulence factor from Escherichia coli.

FKBP22, an Escherichia coli-made peptidyl-prolyl cis-trans isomerase, has shown considerable homology with Mip-like virulence factors. While the C-terminal domain of this enzyme is used for executing catalytic function and binding inhibitor, the N-terminal domain is employed for its dimerization. To precisely determine the underlying factors of FKBP22 dimerization, its structural model, developed using a suitable template, was carefully inspected. The data show that the dimeric FKBP22, like dimeric Mip proteins, has a V-like shape. Further, it dimerizes using 40 amino acid residues including Ile 9, Ile 17, Ile 42, and Ile 65. All of the above Ile residues except Ile 9 are partly conserved in the Mip-like proteins. To confirm the roles of the partly conserved Ile residues, three FKBP22 mutants, constructed by substituting them with an Ala residue, were studied as well. The results together indicate that Ile 65 has little role in maintaining the dimeric state or enzymatic activity of FKBP22. Conversely, both Ile 17 and Ile 42 are essential for preserving the structure, enzymatic activity, and dimerization ability of FKBP22. Ile 42 in particular looks more essential to FKBP22. However, none of these two Ile residues is required for binding the cognate inhibitor. Additional computational studies also indicated the change of V-shape and the dimeric state of FKBP22 due to the Ala substitution at position 42. The ways Ile 17 and Ile 42 protect the structure, function, and dimerization of FKBP22 have been discussed at length.Communicated by Ramaswamy H. Sarma.

Anticipatory cardiac deceleration estimates cognitive performance in virtual reality beyond tonic heart period and heart period variability.

Anticipatory cardiac deceleration is the lengthening of heart period before an expected event. It appears to reflect preparation that supports rapid action. The current study sought to bolster anticipatory deceleration as a practical and unique estimator of performance efficiency. To this end, we examined relationships between deceleration and virtual reality performance under low and high time pressure. Importantly, we investigated whether deceleration separately estimates performance beyond basal heart period and basal high-frequency heart rate variability (other vagally influenced metrics related to cognition). Thirty participants completed an immersive virtual reality (VR) cognitive performance task across six longitudinal sessions. Anticipatory deceleration and basal heart period/heart period variability were quantified from electrocardiography collected during pre-task anticipatory countdowns and baseline periods, respectively. At the between-person level, we found that greater anticipatory declaration was related to superior accuracy and faster response times (RT). The relation between deceleration and accuracy was stronger under high relative to low time pressure, when good performance requires greater efficiency. Findings for heart period and heart period variability largely converge with the prior literature, but importantly, were statistically separate from deceleration effects on performance. Lastly, deceleration effects were detected using anticipatory periods that are more practical (shorter and more intermittent) than those typically employed. Taken together, findings suggest that anticipatory deceleration is a unique and practical correlate of cognitive-motor efficiency apart from heart period and heart period variability in virtual reality.

New Xanthone Derivatives as Potent G-Quadruplex Binders for Developing Anti-Cancer Therapeutics.

Xanthone is an important scaffold for various medicinally relevant compounds. However, it has received scant attention in the design of agents that are cytotoxic to cancer cells via targeting the stabilization of G-quadruplex (G4) nucleic acids. Specific G4 DNA recognition against double-stranded (ds) DNA is receiving epoch-making interest for the development of G4-mediated anticancer agents. Toward this goal, we have synthesized xanthone-based derivatives with various functionalized side-arm substituents that exhibited significant selectivity for G4 DNA as compared to dsDNA. The specific interaction has been demonstrated by performing various biophysical experiments. Based on the computational study as well as the competitive ligand binding assay, it is inferred that the potent compounds exhibit an end-stacking mode of binding with G4 DNA. Additionally, compound-induced conformational changes in the flanking nucleotides form the binding pocket for effective interaction. Selective action of the compounds on cancer cells suggests their effectiveness as potent anti-cancer agents. This study promotes the importance of structure-based screening approaches to get molecular insights for new scaffolds toward desired specific recognition of non-canonical G4 DNA structures.

The cofactors and domains of a staphylococcal capsule-producing enzyme preserve its structure, stability, shape and dimerization ability.

CapF, a staphylococcal capsule-producing enzyme, binds Zn2+ ion and NADPH using its C-terminal domain (CTD) and N-terminal domain (NTD), respectively. To elucidate the roles of cofactors and domains, we have systematically investigated the related recombinant proteins, rCapF, rCTD, recombinant NTD (rNTD) and the Zn2+-free rCapF/rCTD, Apo-rCapF/Apo-rCTD. The results show that the secondary structure, tertiary structure, shape and surface hydrophobicity of Apo-rCapF and Apo-rCTD are different from those of rCapF and rCTD. The removal of Zn2+ made rCapF thermo-sensitive, whereas both rCTD and Apo-rCTD are thermo-resistant proteins. Further, Apo-rCapF and rCapF existed as the dimers, whereas rCTD and Apo-rCTD formed a mixture of dimers and tetramers in the aqueous solution. Zn2+ maintained the structure of NTD as well. The NADPH binding activity and Cys accessibility of rNTD, rCapF and Apo-rCapF were significantly different from each other. The binding of NADPH to the above three proteins freely occurred, liberated heat at 25°C and increased their diameters. In addition, the structure, stability, shape and oligomerization ability of rNTD, rCTD and rCapF little resembled each other. Collectively, the domains and cofactors of CapF contribute to preserving its conformation, stability, shape and dimerization ability.

Serine 106 preserves the tertiary structure, function, and stability of a cyclophilin from Staphylococcus aureus.

SaCyp, a staphylococcal cyclophilin involved in both protein folding and pathogenesis, has a Ser residue at position 106 and a Trp residue at position 136. While Ser 106 of SaCyp aligned with a cyclosporin A (CsA) binding Ala residue, its Trp 136 aligned with a Trp or a Phe residue of most other cyclophilins. To demonstrate the exact roles of Ser 106 and Trp 136 in SaCyp, we have elaborately studied rCyp[S106A] and rCyp[W136A], two-point mutants of a recombinant SaCyp (rCyp) harboring an Ala substitution at positions 106 and 136, respectively. Of the mutants, rCyp[W136A] showed the rCyp-like CsA binding affinity and peptidyl-prolyl cis-trans isomerase (PPIase) activity. Conversely, the PPIase activity, CsA binding affinity, stability, tertiary structure, surface hydrophobicity, and Trp accessibility of rCyp[S106A] notably differed from those of rCyp. The computational experiments also reveal that the structure, dimension, and fluctuation of SaCyp are not identical to those of SaCyp[S106A]. Furthermore, Ser at position 106 of SaCyp, compared to Ala at the same position, formed a higher number of non-covalent bonds with CsA. Collectively, Ser 106 is an indispensable residue for SaCyp that keeps its tertiary structure, function, and stability intact.Communicated by Ramaswamy H. Sarma.

Sequence driven interaction of amino acids in de-novo designed peptides determines c-Myc G-quadruplex unfolding inducing apoptosis in cancer cells.

c-MYC proto-oncogene harbors a putative G-quadruplex structure (Pu27) at the NHEIII1 domain, which can shuffle between transcriptional inhibitor quadruplex and transcriptionally active duplex. In cancer cells this quadruplex destabilization is preferred and NHEIII1 domain assume a duplex topology thereby inducing c-MYC overexpression and tumorigenesis. Hence, the c-MYC quadruplex acts as an excellent target for anti-cancer therapy. Though researcher have tried to develop G-quadruplex targeted small molecules, work with G-quadruplex targeting peptides is very limited. Here we present a peptide that can bind to c-MYC quadruplex, destabilize the tetrad core, and permit the formation of a substantially different structure from the quartet core seen in the canonical G-quadruplexes. Such conformation potentially acted as a roadblock for transcription factors thereby reducing cMYC expression. This event sensitizes the cancer cell to activate apoptotic cascade via the c-MYC-VEGF-A-BCL2 axis. This study provides a detailed insight into the peptide-quadruplex interface that encourages better pharmacophore design to target dynamic quadruplex structure. We believe that our results will contribute to the development, characterization, and optimization of G-quadruplex binding peptides for potential clinical application.

Identifying Biomarkers for Accurate Detection of Stress.

Substance use disorder (SUD) is a dangerous epidemic that develops out of recurrent use of alcohol and/or drugs and has the capability to severely damage one's brain and behaviour. Stress is an established risk factor in SUD's development of addiction and in reinstating drug seeking. Despite this expanding epidemic and the potential for its grave consequences, there are limited options available for management and treatment, as well as pharmacotherapies and psychosocial treatments. To this end, there is a need for new and improved devices dedicated to the detection, management, and treatment of SUD. In this paper, the negative effects of SUD-related stress were discussed, and based on that, a few significant biomarkers were selected from a set of eight features collected by a chest-worn device, RespiBAN Professional, on fifteen individuals. We used three machine learning classifiers on these optimal biomarkers to detect stress. Based on the accuracies, the best biomarkers to detect stress and those considered as features for classification were determined to be electrodermal activity (EDA), body temperature, and a chest-worn accelerometer. Additionally, the differences between mental stress and physical stress, as well as different administrations of meditation during the study, were identified and analysed. Challenges, implications, and applications were also discussed. In the near future, we aim to replicate the proposed methods in individuals with SUD.

Data Fusion-Based Musculoskeletal Synergies in the Grasping Hand.

The hypothesis that the central nervous system (CNS) makes use of synergies or movement primitives in achieving simple to complex movements has inspired the investigation of different types of synergies. Kinematic and muscle synergies have been extensively studied in the literature, but only a few studies have compared and combined both types of synergies during the control and coordination of the human hand. In this paper, synergies were extracted first independently (called kinematic and muscle synergies) and then combined through data fusion (called musculoskeletal synergies) from 26 activities of daily living in 22 individuals using principal component analysis (PCA) and independent component analysis (ICA). By a weighted linear combination of musculoskeletal synergies, the recorded kinematics and the recorded muscle activities were reconstructed. The performances of musculoskeletal synergies in reconstructing the movements were compared to the synergies reported previously in the literature by us and others. The results indicate that the musculoskeletal synergies performed better than the synergies extracted without fusion. We attribute this improvement in performance to the musculoskeletal synergies that were generated on the basis of the cross-information between muscle and kinematic activities. Moreover, the synergies extracted using ICA performed better than the synergies extracted using PCA. These musculoskeletal synergies can possibly improve the capabilities of the current methodologies used to control high dimensional prosthetics and exoskeletons.

Selection of Optimal Physiological Features for Accurate Detection of Stress.

Stress is an established risk factor in the development of addiction and in reinstating drug seeking. Substance use disorder (SUD) is a dangerous epidemic that affects the brain and behavior. Despite this growing epidemic and its subsequent consequences, there are limited management and treatment options, pharmacotherapies and psychosocial treatments available. To this end, there is a need for new and improved personalized devices and treatments for the detection and management of SUD. Based on documented negative effects of stress in SUD, in this paper, our objective was to select a few significant physiological features from a set of 8 features collected by a chest-worn RespiBAN Professional in 15 individuals. We used three machine learning classifiers on these optimal physiological features to detect stress. Our results indicate that best accuracies were achieved when electrodermal activity (EDA), body temperature and chest-worn accelerometer were considered as features for the classification. Challenges, implications and applications were discussed. In the near future, the proposed methods will be replicated in individuals with SUD.

Multi-granular Analysis and Physiological Interpretations of Heart Rate Variability Metrics During VR-Shooting Difficulty Induced Stress.

Physiological sensing of virtual reality (VR)-induced stressors are increasingly utilized to improve human training and assess the impact of gaming difficulty-induced stress on a person's health and well-being. However, the prior art sparsely explores the multi-level cardiovascular dynamics for psychophysiological demands in a VR environment. This treatise discusses the experimental findings and physiological interpretations of various heart rate variability (HRV) metrics extracted from 31 participants during a Go/No-Go VR-based shooting task across multiple timeframes. The VR-shooting exercise consists of firing at the enemy targets while sparing the friendly ones for different shooting difficulty levels: low-difficulty and high-difficulty with in-between baselines. Ex-perimental results demonstrate consistent shooting difficulty-induced stress patterns at multi-granular levels in response to the heterogeneous inputs (exogenous and endogenous factors). The physiological interpretations highlight the intricate inter-play between cardio-physiological components: sympathetic and parasympathetic response across multiple timescales (sessions and blocks) and shooting difficulty levels.

Musculoskeletal Synergies in the Grasping Hand.

Investigations on how the central nervous system (CNS) effortlessly conducts complex hand movements have led to an extensive study of synergies or movement primitives. Of the different types of hand synergies, kinematic and muscle synergies have been widely studied in literature, but only a few studies have fused both. In this paper kinematic and muscle activities recorded from the activities of daily living were first fused and then dimensionally reduced through principal component analysis (PCA). By using these principal components or musculoskeletal synergies in a weighted linear combination, the recorded kinematics and muscle activities were reconstructed. The performance of these musculoskeletal synergies in reconstructing the movements was compared to the kinematic and muscle synergies reported previously in the literature by us and others. The results from these findings indicate that musculoskeletal synergies perform better than the synergies extracted without fusion. These newly demonstrated musculoskeletal synergies might improve neural control of robotics, prosthetics and exoskeletons. Clinical Relevance- In this paper, musculoskeletal synergies were extracted from the fusion of kinematic and muscle activities recorded from the activities of daily living. These newly demonstrated musculoskeletal synergies might enhance our understanding of neural control of robotics, prosthetics and exoskeletons.

A pilot study to understand the relationship between cortical arousals and leg movements during sleep.

Leg movements during sleep occur in patients with sleep pathology and healthy individuals. Some (but not all) leg movements during sleep are related to cortical arousals which occur without conscious awareness but have a significant effect of sleep fragmentation. Detecting leg movements during sleep that are associated with cortical arousals can provide unique insight into the nature and quality of sleep. In this study, a novel leg movement monitor that uses a unique capacitive displacement sensor and 6-axis inertial measurement unit, is used in conjunction with polysomnography to understand the relationship between leg movement and electroencephalogram (EEG) defined cortical arousals. In an approach that we call neuro-extremity analysis, directed connectivity metrics are used to interrogate causal linkages between EEG and leg movements measured by the leg movement sensors. The capacitive displacement measures were more closely related to EEG-defined cortical arousals than inertial measurements. Second, the neuro-extremity analysis reveals a temporally evolving connectivity pattern that is consistent with a model of cortical arousals in which brainstem dysfunction leads to near-instantaneous leg movements and a delayed, filtered signal to the cortex leading to the cortical arousal during sleep.

A deep residual inception network with channel attention modules for multi-label cardiac abnormality detection from reduced-lead ECG.

Objective.Most arrhythmias due to cardiovascular diseases alter the heart's electrical activity, resulting in morphological alterations in electrocardiogram (ECG) recordings. ECG acquisition is a low-cost, non-invasive process and is commonly used for continuous monitoring as a diagnostic tool for cardiac abnormality identification. Our objective is to diagnose twenty-nine cardiac abnormalities and sinus rhythm using varied lead ECG signals.Approach.This work proposes a deep residual inception network with channel attention mechanism (RINCA) for twenty-nine cardiac arrhythmia classification along with normal ECG from multi-label ECG signal with different lead combinations. TheRINCAarchitecture employing the inception-based convolutional neural network backbone uses residual skip connections with the channel attention mechanism. The inception model facilitates efficient computation and prevents overfitting while exploring deeper networks through dimensionality reduction and stacked 1-dimensional convolutions. The residual skip connections alleviate the vanishing gradient problem. The attention modules selectively leverage the temporally significant segments in a sequence and predominant channels for multi-lead ECG signals, contributing to the decision-making.Main results.Exhaustive experimental evaluation on the large-scale 'PhysioNet/Computing in Cardiology Challenge (2021)' dataset demonstratesRINCA's efficacy. On the hidden test data set,RINCAachieves the challenge metric score of 0.55, 0.51, 0.53, 0.51, and 0.53 (ranked 2nd, 5th, 4th, 5th and 4th) for the twelve-lead, six-lead, four-lead, three-lead, and two-lead combination cases, respectively.Significance.The proposedRINCAmodel is more robust against varied sampling frequency, recording time, and data with heterogeneous demographics than the existing art. The explainability analysis showsRINCA's potential in clinical interpretations.

Curcumin arrests G-quadruplex in the nuclear hyper-sensitive III1 element of c-MYC oncogene leading to apoptosis in metastatic breast cancer cells.

c-MYC is deregulated in triple negative breast cancer (TNBC) pointing to be a promising biomarker for breast cancer treatment. Precise level of MYC expression is important in the control of cellular growth and proliferation. Designing of c-MYC-targeted antidotes to restore its basal level of cellular expression holds an optimistic approach towards anti-cancer treatment. MYC transcription is dominantly controlled by Nuclear Hypersensitive Element III-1 (NHEIII1) upstream of the promoter region possessing G-Quadruplex silencer element (Pu-27). We have investigated the selective binding-interaction profile of a natural phytophenolic compound Curcumin with native MYC G-quadruplex by conducting an array of biophysical experiments and in silico based Molecular Docking and Molecular Dynamic (MDs) simulation studies. Curcumin possesses immense anti-cancerous properties. We have observed significantly increased stability of MYC-G Quadruplex and thermodynamic spontaneity of Curcumin-MYC GQ binding with negative ΔG value. Transcription of MYC is tightly regulated by a complex mechanism involving promoters, enhancers and multiple transcription factors. We have used Curcumin as a model drug to understand the innate mechanism of controlling deregulated MYC back to its basal expression level. We have checked MYC-expression at transcriptional and translational level and proceeded for Chromatin Immuno-Precipitation assay (ChIP) to study the occupancy level of SP1, Heterogeneous nuclear ribonucleoprotein K (hnRNPK), Nucleoside Diphosphate Kinase 2 (NM23-H2) and Nucleolin at NHEIII1 upon Curcumin treatment of MDA-MB-231 cells. We have concluded that Curcumin binding tends to drive the equilibrium towards stable G-quadruplex formation repressing MYC back to its threshold-level. On retrospection of the synergistic effect of upregulated c-MYC and BCL-2 in cancer, we have also reported a new pathway [MYC-E2F-1-BCL-2-axis] through which Curcumin trigger apoptosis in cancer cells.Communicated by Ramaswamy H. Sarma.

A conserved arginine residue in a staphylococcal anti-sigma factor is required to preserve its kinase activity, structure, and stability.

RsbW, σB, and RsbV, encoded by Staphylococcus aureus and related bacteria, act as an anti-sigma factor, an sigma factor, and an anti-anti-sigma factor, respectively. The interaction between RsbW and σB blocks the transcription initiation activity of the latter protein. RsbW also functions as a serine kinase and phosphorylates RsbV in the presence of ATP. Our modeling study indicates that the RsbW-RsbV complex is stabilized by twenty-four intermolecular non-covalent bonds. Of the bond-forming RsbW residues, Arg 23, and Glu 49 are conserved residues. To understand the roles of Arg 23 in RsbW, rRsbW[R23A], a recombinant S. aureus RsbW (rRsbW) harboring Arg to Ala change at position 23, was investigated using various probes. The results reveal that rRsbW[R23A], like rRsbW, exists as the dimers in the aqueous solution. However, rRsbW[R23A], unlike rRsbW, neither interacted with a chimeric RsbV (rRsbV) nor formed the phosphorylated rRsbV in the presence of ATP. Furthermore, the tertiary structure and hydrophobic surface area of rRsbW[R23A] matched little with those of rRsbW. Conversely, both rRsbW[R23A] and rRsbW showed interaction with a recombinant σB (rσB). rRsbW and rRsbW[R23A] were also unfolded via the formation of at least one intermediate in the presence of urea. However, the thermodynamic stability of rRsbW significantly differed from that of rRsbW[R23A]. Our molecular dynamics (MD) simulation study also reveals the substantial change of structure, dimension, and stability of RsbW due to the above mutation. The ways side chain of critical Arg 23 contributes to maintaining the tertiary structure, and stability of RsbW was elaborately discussed.Communicated by Ramaswamy H. Sarma.

Frontiers in G-Quadruplex therapeutics in cancer: Selection of small molecules, peptides and aptamers.

G-Quadruplex, a unique secondary structure in nucleic acids found throughout human genome, elicited widespread interest in the field of therapeutic research. Being present in key regulatory regions of oncogenes, RNAs and telomere, G-Quadruplex structure regulates transcription, translation, splicing, etc. Changes in its structure and stability leads to differential expression of oncogenes causing cancer. Thus, targeting G-Quadruplex structures with small molecules/other biologics has shown elevated research interest. Covering previous reports, in this review, we try to enlighten the facts on the structural diversity in G-Quadruplex ligands aiming to provide newer insights to design first-in-class drugs for the next-generation cancer treatment.