Network analysis of transcriptomic data uncovers molecular signatures and the interplay of mRNAs, lncRNAs, and miRNAs in human embryonic stem cells.

Growing evidence has shown that besides the protein coding genes, the non-coding elements of the genome are indispensable for maintaining the property of self-renewal in human embryonic stem cells and in cell fate determination. However, the regulatory mechanisms and the landscape of interactions between the coding and non-coding elements is poorly understood. In this work, we used weighted gene co-expression network analysis (WGCNA) on transcriptomic data retrieved from RNA-seq and small RNA-seq experiments and reconstructed the core human pluripotency network (called PluriMLMiNet) consisting of 375 mRNA, 57 lncRNA and 207 miRNAs. Furthermore, we derived networks specific to the naïve and primed states of human pluripotency (called NaiveMLMiNet and PrimedMLMiNet respectively) that revealed a set of molecular markers (RPS6KA1, ZYG11A, ZNF695, ZNF273, and NLRP2 for naive state, and RAB34, TMEM178B, PTPRZ1, USP44, KIF1A and LRRN1 for primed state) which can be used to distinguish the pluripotent state from the non-pluripotent state and also to identify the intra-pluripotency states (i.e., naïve and primed state). The lncRNA DANT1 was found to be a crucial as it formed a bridge between the naive and primed state-specific networks. Analysis of the genes neighbouring DANT1 suggested its possible role as a competing endogenous RNA (ceRNA) for the induction and maintenance of human pluripotency. This was computationally validated by predicting the missing DANT1-miRNA interactions to complete the ceRNA circuit. Here we first report that DANT1 might harbour binding sites for miRNAs hsa-miR-30c-2-3p, hsa-miR-210-3p and hsa-let-7b-5p which may influence pluripotency.

Emergent Inhomogeneity and Nonlocality in a Graphene Field-Effect Transistor on a Near-Parallel Moiré Superlattice of Transition Metal Dichalcogenides.

At near-parallel orientation, twisted bilayers of transition metal dichalcogenides exhibit interlayer charge transfer-driven out-of-plane ferroelectricity. Here, we report detailed electrical transport in a dual-gated graphene field-effect transistor placed on a 2.1° twisted bilayer WSe2. We observe hysteretic transfer characteristics and an emergent charge inhomogeneity with multiple local Dirac points evolving with an increasing electric displacement field (D). Concomitantly, we also observe a strong nonlocal voltage signal at D ∼ 0 V/nm that decreases rapidly with increasing D. A linear scaling of the nonlocal signal with longitudinal resistance suggests edge mode transport, which we attribute to the breaking of valley symmetry of graphene due to the spatially fluctuating electric field from the underlying polarized moiré domains. A quantitative analysis suggests the emergence of finite-size domains in graphene that modulate the charge and the valley currents simultaneously. This work underlines the impact of interfacial ferroelectricity that can trigger a new generation of devices.

Emergent phases in graphene flat bands.

Electronic correlations in two-dimensional materials play a crucial role in stabilising emergent phases of matter. The realisation of correlation-driven phenomena in graphene has remained a longstanding goal, primarily due to the absence of strong electron-electron interactions within its low-energy bands. In this context, magic-angle twisted bilayer graphene has recently emerged as a novel platform featuring correlated phases favoured by the low-energy flat bands of the underlying moiré superlattice. Notably, the observation of correlated insulators and superconductivity, and the interplay between these phases have garnered significant attention. A wealth of correlated phases with unprecedented tunability was discovered subsequently, including orbital ferromagnetism, Chern insulators, strange metallicity, density waves, and nematicity. However, a comprehensive understanding of these closely competing phases remains elusive. The ability to controllably twist and stack multiple graphene layers has enabled the creation of a whole new family of moiré superlattices with myriad properties. Here, we review the progress and development achieved so far, encompassing the rich phase diagrams offered by these graphene-based moiré systems. Additionally, we discuss multiple phases recently observed in non-moiré multilayer graphene systems. Finally, we outline future opportunities and challenges for the exploration of hidden phases in this new generation of moiré materials.

Network approaches for modeling the effect of drugs and diseases.

The network approach is quickly becoming a fundamental building block of computational methods aiming at elucidating the mechanism of action (MoA) and therapeutic effect of drugs. By modeling the effect of drugs and diseases on different biological networks, it is possible to better explain the interplay between disease perturbations and drug targets as well as how drug compounds induce favorable biological responses and/or adverse effects. Omics technologies have been extensively used to generate the data needed to study the mechanisms of action of drugs and diseases. These data are often exploited to define condition-specific networks and to study whether drugs can reverse disease perturbations. In this review, we describe network data mining algorithms that are commonly used to study drug's MoA and to improve our understanding of the basis of chronic diseases. These methods can support fundamental stages of the drug development process, including the identification of putative drug targets, the in silico screening of drug compounds and drug combinations for the treatment of diseases. We also discuss recent studies using biological and omics-driven networks to search for possible repurposed FDA-approved drug treatments for SARS-CoV-2 infections (COVID-19).

Topochemical Modulations from 1D Iron Fluoride Precursor to 3D Frameworks.

Topochemical reactions are powerful pathways to modify inorganic extended structures, but the present approaches are limited by the degrees of freedom to tune the structural connectivity and dimensionality. In this work, we unveil a new topochemical bottom-up approach to tailor three-dimensional (3D) iron fluoride frameworks from the same one-dimensional (1D) FeF3.3H2O (IF) precursor upon reacting with iodide-based reagents (AI; A+ = Na+, K+, and NH4+). To elucidate their formation mechanism, a series of topochemical reactions are performed by varying the concentration of precursors, reaction temperatures, and durations, and their corresponding products are analyzed through X-ray diffraction, nuclear magnetic resonance, and Mössbauer spectroscopy techniques. Although the lower molar ratio of AI:IF (≈0.25:1.0) produces the same hexagonal tungsten bronze (HTB)-type AxFeF3, the topochemical reactions with higher AI:IF ratios yield weberite-Na1.95Fe2F7, tetragonal tungsten bronze (TTB)-K0.58FeF3, and pyrochlore-NH4Fe2F6 phases. Our density functional theory calculations attribute the formation of iron fluoride phases to their thermodynamic stability. Moreover, kinetics also play an important role in enabling weberite and HTB fluorides with high purity, while the pyrochlore-NH4Fe2F6 retains a minor HTB-(NH4)xFeF3 impurity. Overall, this work shows a new possibility of modulating the low-dimensional precursor to attain 3D frameworks with different structural arrangements via topochemical approaches.

Role of aminophylline in prevention of acute kidney injury in term neonates with severe perinatal asphyxia: a randomized open-label controlled trial.

Acute kidney injury (AKI) is one of the frequently observed complications in neonates with severe perinatal asphyxia. The efficacy of aminophylline in preventing or alleviating renal dysfunction in these neonates remains controversial. The current study aimed to explore whether treatment with aminophylline as adjunctive therapy is superior to standard care alone in preventing AKI in severely asphyxiated term neonates and to delineate the changes in other renal parameters. In this open-label randomized clinical trial, term neonates with severe asphyxia (n = 41) received a 5 mg/kg intravenous dose of aminophylline within the first hour after birth, in addition to standard care for birth asphyxia. The control group (n = 40) received standard care alone. Their daily urine output, weight, serum creatinine, renal functional status, and complications during the first 5 days of life were monitored and compared. The statistical package for social sciences version 25 was used for analysis. Approximately 24.39% of neonates in the aminophylline group developed AKI, compared to 35.0% in the control group (P = .088). Although urine output was generally higher in aminophylline-treated newborns than in the control group, this increase was not statistically significant (P > .05), with the most notable differences observed on the second and third postnatal days. Also, the changes in plasma creatinine levels between the two groups during this time were not statistically significant. Administering a single dose of aminophylline (5 mg/kg) within the first hour of life to severely asphyxiated term neonates might temporarily enhance urine output, but does not reduce the overall incidence of AKI.

The efficacy of aminophylline in preventing or alleviating renal dysfunction in severely asphyxiated term neonates remains inconclusive. In this open-label randomized clinical trial, severely asphyxiated term neonates in the intervention group were administered 5 mg/kg of intravenous aminophylline within the first hour of life, in addition to standard care for birth asphyxia. The control group received only the standard care. Although the difference was not statistically significant, newborns treated with aminophylline generally had higher urine output than those in the control group. There was no significant difference in the incidence of acute kidney injury or changes in plasma creatinine levels between the two groups. Complications and mortality rates were similar (P > .05) in both cohorts; however, neonates treated with aminophylline exhibited a slightly higher incidence of central nervous system side effects, including more frequent seizures, cerebral edema, and intracranial hemorrhages. Based on our study findings, we suggest that aminophylline therapy in this context should be limited to research settings and not used prophylactically.

Cholesterol-Induced Nanoscale Variations in the Thickness of Phospholipid Membranes.

Graphene-induced energy transfer (GIET) is a recently developed fluorescence-spectroscopic technique that achieves subnanometric optical localization of fluorophores along the optical axis of a microscope. GIET is based on the near-field energy transfer from an optically excited fluorescent molecule to a single sheet of graphene. It has been successfully used for estimating interleaflet distances of single lipid bilayers and for investigating the membrane organization of living mitochondria. In this study, we use GIET to measure the cholesterol-induced subtle changes of membrane thickness at the nanoscale. We quantify membrane thickness variations in supported lipid bilayers (SLBs) as a function of lipid composition and increasing cholesterol content. Our findings demonstrate that GIET is an extremely sensitive tool for investigating nanometric structural changes in biomembranes.

Effects of constant darkness on behaviour and physiology of male and female mice.

A healthy state of life suggests not only a disease-free condition but also normal psychological functioning and behaviour. To maintain a healthy life, the duration of light exposure is a crucial factor. Perturbation of the standard light-dark cycle (LD: 12 h light-12 h dark in mice) may result in brain, behavioural and physiological abnormalities. The current study determined the effects of 3 and 5 weeks of constant darkness (DD: 00 h light-24 h dark) on the behaviour, hormones, prefrontal cortex (PFC) and metabolome of male and female C57BL/6 J mice. We also studied 3 weeks of restoration in LD following 5 weeks of DD exposure. The results revealed that 3 weeks of DD affected male mice more than females, and 5 weeks of DD had a comparable impact on behaviour, hormones and the PFC of male and female mice. After restoration in LD, the DD-induced changes reverted to time-matched LD conditions in male and female mice. Furthermore, metabolome analysis corroborated male and female mice's behavioural and molecular kinetics. The present study laid the foundation for understanding how DD affects behaviour and the PFC as a function of (a) time and (b) sex and described the roles of stress and sex hormones, cytokines, neurotrophins and metabolic pathways.

EDTox: an R Shiny application to predict the endocrine disruption potential of compounds.

PURPOSE: Endocrine disruptors are a rising concern due to the wide array of health issues that it can cause. Although there are tools for mode of action (MoA)-based prediction of endocrine disruption (e.g. QSAR Toolbox and iSafeRat), none of them is based on toxicogenomics data. Here, we present EDTox, an R Shiny application enabling users to explore and use a computational method that we have recently published to identify and prioritize endocrine disrupting (ED) chemicals based on toxicogenomic data. The EDTox pipeline utilizes previously trained toxicogenomic-driven classifiers to make predictions on new untested compounds by using their molecular initiating events. Furthermore, the proposed R Shiny app allows users to extend the prediction systems by training and adding new classifiers based on new available toxicogenomic data. This functionality helps users to explore the ED potential of chemicals in new, untested exposure scenarios. AVAILABILITY AND IMPLEMENTATION: This tool is available as web application (www.edtox.fi) and stand-alone software on GitHub and Zenodo (https://doi.org/10.5281/zenodo.5817093). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Quantum Hall Interferometry in Triangular Domains of Marginally Twisted Bilayer Graphene.

Quantum Hall (QH) interferometry provides an archetypal platform for the experimental realization of braiding statistics of fractional QH states. However, the complexity of observing fractional statistics requires phase coherence over the length of the interferometer, as well as suppression of Coulomb charging energy. Here, we demonstrate a new type of QH interferometer based on marginally twisted bilayer graphene (mtBLG), with a twist angle θ ≈ 0.16°. With the device operating in the QH regime, we observe distinct signatures of electronic Fabry-Pérot and Aharonov-Bohm oscillations of the magneto-thermopower in the density-magnetic field phase space, at Landau level filling factors ν = 4, 8. We find that QH interference effects are intrinsic to the triangular AB/BA domains in mtBLG that show diminished Coulomb charging effects. Our results demonstrate phase-coherent interference of QH edge modes without any additional gate-defined complex architecture, which may be beneficial in experimental realizations of non-Abelian braiding statistics.

Pediatric Colonic Anastomosis: Can Method of Anastomosis and Wound Closure be of Help?

Background: Enhanced recovery after surgery (ERAS) protocols after colorectal surgery focused on reduced bowel preparation, standardized feeding schedule, earlier return of bowel function, and earlier resumption of normal activities. ERAS in pediatric surgical practice is not well established. The present study aims to present the results of two colonic anastomosis techniques of interrupted single-layered closure: Halsted (Horizontal Mattress) and Matheson (serosubmucosal or appositional extramucosal) along with two different methods of colostomy wound closure and their influence on the adoption of ERAS protocol of early feeding and early discharge. Materials and Methods: This single institute-based randomized control study was conducted in a tertiary care facility in Kolkata for 2.4 years. Patients were chosen randomly for serosubmucosal (Group I) and full-thickness (Group II) anastomosis. Results: Among total of 91 patients (Group I-43 and Group II-48), Return of bowel sounds and passage of bowel averaged 1.51 ± 0.51 and 1.91 ± 0.55 days in Group I and 1.91 ± 0.57 and 3.9 ± 0.66 days in Group II, respectively. Postoperative hospital stay averaged 5.88 ± 1.12 days in Group I and 8.9 ± 1.17 days in Group II. Overall 15 (16.48%) patients had complications among which SSI (Suprficial surgical site infection) and minor leaks (Group I-3 and 1 and Group II-5 and 3, respectively) which were treated conservatively (Clavien-Dindo Grade-I) and three major leaks under Group II requiring surgical intervention (Clavien-Dindo Grade-III). Conclusion: This study concludes that the technique of colostomy closure in the form serosubmucosal closure helps in the implementation of ERAS protocol by producing early bowel movement, early initiation of food, and less postoperative complications.

High-Efficiency Infrared Sensing with Optically Excited Graphene-Transition Metal Dichalcogenide Heterostructures.

Binary van der Waals heterostructures of graphene (Gr) and transition metal dichalcogenide (TMDC) have evolved as a promising candidate for photodetection with very high responsivity due to the separation of photo-excited electron-hole pairs across the interface. The spectral range of optoelectronic response in such hybrids has so far been limited by the optical bandgap of the light absorbing TMDC layer. Here, the bidirectionality of interlayer charge transfer is utilized for detecting sub-band gap photons in Gr-TMDC heterostructures. A Gr/MoSe2 heterostructure sequentially driven by visible and near infra-red (NIR) photons is employed, to demonstrate that NIR induced back transfer of charge allows fast and repeatable detection of the low energy photons (less than the optical band gap of the TMDC layer). This mechanism provides photoresponsivity as high as ≈3000 A W-1 close to the communication wavelength. The experiment provides a new strategy for achieving highly efficient photodetection over a broad range of energies beyond the spectral bandgap with the 2D semiconductor family.

Mapping Activity-Dependent Quasi-stationary States of Mitochondrial Membranes with Graphene-Induced Energy Transfer Imaging.

Graphene-induced energy transfer (GIET) was recently introduced for sub-nanometric axial localization of fluorescent molecules. GIET relies on near-field energy transfer from an optically excited fluorophore to a single sheet of graphene. Recently, we demonstrated its potential by determining the distance between two leaflets of supported lipid bilayers. Here, we use GIET imaging for mapping quasi-stationary states of the inner and outer mitochondrial membranes before and during adenosine triphosphate (ATP) synthesis. We trigger the ATP synthesis state in vitro by activating mitochondria with precursor molecules. Our results demonstrate that the inner membrane approaches the outer membrane, while the outer membrane does not show any measurable change in average axial position upon activation. The inter-membrane space is reduced by ∼2 nm. This direct experimental observation of the subtle dynamics of mitochondrial membranes and the change in intermembrane distance upon activation is relevant for our understanding of mitochondrial function.

Evidence of Lifshitz Transition in the Thermoelectric Power of Ultrahigh-Mobility Bilayer Graphene.

Resolving low-energy features in the density of states (DOS) holds the key to understanding a wide variety of rich novel phenomena in graphene-based 2D heterostructures. The Lifshitz transition in bilayer graphene (BLG) arising from trigonal warping has been established theoretically and experimentally. Nevertheless, the experimental realization of its effects on transport properties has been challenging because of its relatively low energy scale (∼1 meV). In this work, we demonstrate that the thermoelectric power (TEP) can be used as an effective probe to investigate fine changes in the DOS of BLG. We observed additional entropy features in the vicinity of the charge neutrality point (CNP) in gapped BLG. This apparent violation of the Mott formula can be explained quantitatively by considering the effects of trigonal warping, thereby serving as possible evidence of a Lifshitz transition.

Congenital Sacrococcygeal Neuroblastoma: A Report of Two Cases with Summary of Prior Published Cases.

BackgroundNeuroblastoma can arise from extra-adrenal sites in the paraspinal sympathetic chain, including the presacral region, where they must be differentiated from an immature or malignant neural lesion arising from a teratoma.Case ReportWe describe two congenital presacral neuroblastomas. The main clinical differential diagnoses were sacrococcygeal teratoma and meningomyelocele. Pathologically, they lacked teratomatous tissues, lacked germ cell serum markers, were localized without metastases, and were MYCN non-amplified. Both patients have done well without chemotherapy at 18 and 15 months of follow-up.ConclusionCongenital presacral neuroblastoma should be differentiated from teratomatous lesions, and in general have a good prognosis.

Clinico-demographic Profile and Predictors of Intensive Care Need in Children with Respiratory Syncytial Virus-associated Acute Lower Respiratory Illness during Its Recent Outbreak alongside Ongoing COVID-19 Pandemic: An Eastern Indian Perspective.

Introduction: The objective was to delineate the clinico-epidemiological characteristics of hospitalized children with respiratory syncytial virus (RSV)-associated acute lower respiratory tract infection (RSV-ALRI) during its recent outbreak and to find out the independent predictors of pediatric intensive care unit (PICU) admission. Materials and methods: Children aged between 1 month and 12 years who tested positive for RSV were included. Multivariate analysis was performed to identify the independent predictors and predictive scores were developed from the ß-coefficients. Receiver operating characteristic curve (ROC) was generated and the area under the curve (AUC) was calculated to assess the overall precision. The performance of sum scores in predicting PICU need, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive and negative likelihood ratios (LR+ and LR-) were calculated for each cutoff value. Results: The proportion of RSV positivity was 72.58%. A total of 127 children were included with a median [interquartile range (IQR)] age of 6 (2-12) months, of whom 61.42% were males and 33.07% had underlying comorbidity. Tachypnea, cough, rhinorrhea, and fever were predominant clinical presentations while hypoxia and extrapulmonary manifestations were present in 30.71% and 14.96% of children, respectively. About 30% required PICU admission, and 24.41% developed complications. Premature birth, age below 1 year, presence of underlying CHD, and hypoxia were independent predictors. The AUC [95% confidence interval (CI)] was 0.869 (0.843-0.935). Sum score below 4 had 97.3% sensitivity and 97.1% NPV whereas sum score above 6 had 98.9% specificity, 89.7% PPV, 81.3% NPV, 46.2 LR+, and 0.83 LR- to predict PICU needs. Conclusion: Awareness of these independent predictors and application of the novel scoring system will be beneficial for busy clinicians in planning the level of care needed, thereby optimizing PICU resource utilization. How to cite this article: Ghosh A, Annigeri S, Hemram SK, Dey PK, Mazumder S. Clinico-demographic Profile and Predictors of Intensive Care Need in Children with Respiratory Syncytial Virus-associated Acute Lower Respiratory Illness during Its Recent Outbreak alongside Ongoing COVID-19 Pandemic: An Eastern Indian Perspective. Indian J Crit Care Med 2022;26(11):1210-1217.

14-3-3 proteins protect AMPK-phosphorylated ten-eleven translocation-2 (TET2) from PP2A-mediated dephosphorylation.

Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes and has been implicated in cancer and aging because of its role as a global epigenetic modifier. TET2 has a large N-terminal domain and a catalytic C-terminal region. Previous reports have demonstrated that the TET2 catalytic domain remains active independently of the N-terminal domain. As such, the function of the N terminus of this large protein remains poorly characterized. Here, using yeast two-hybrid screening, co-immunoprecipitation, and several biochemical assays, we found that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3 proteins bound TET2 when it was phosphorylated at Ser-99. In particular, we observed that AMP-activated protein kinase-mediated phosphorylation at Ser-99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine levels. The interaction of 14-3-3 proteins with TET2 protected the Ser-99 phosphorylation, and disruption of this interaction both reduced TET2 phosphorylation and decreased TET2 stability. Furthermore, we noted that protein phosphatase 2A can interact with TET2 and dephosphorylate Ser-99. Collectively, these results provide detailed insights into the role of the TET2 N-terminal domain in TET2 regulation. Moreover, they reveal the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels or activity.

Spontaneous Time-Reversal Symmetry Breaking at Individual Grain Boundaries in Graphene.

Graphene grain boundaries (GBs) have attracted interest for their ability to host nearly dispersionless electronic bands and magnetic instabilities. Here, we employ quantum transport and universal conductance fluctuation measurements to experimentally demonstrate a spontaneous breaking of time-reversal symmetry across individual GBs of chemical vapor deposited graphene. While quantum transport across the GBs indicate spin-scattering-induced dephasing and hence formation of local magnetic moments, below T≲4 K we observe complete lifting of time-reversal symmetry at high carrier densities (n≳5×10^{12} cm^{-2}) and low temperature (T≲2 K). An unprecedented thirtyfold reduction in the universal conductance fluctuation magnitude with increasing doping density further supports the possibility of an emergent frozen magnetic state at the GBs. Our experimental results suggest that realistic GBs of graphene can be a promising resource for new electronic phases and spin-based applications.

Defects-assisted piezoelectric response in liquid exfoliated MoS2nanosheets.

MoS2is an intrinsic piezoelectric material which offers applications such as energy harvesting, sensors, actuators, flexible electronics, energy storage and more. Surprisingly, there are not any suitable, yet economical methods that can produce quality nanosheets of MoS2in large quantities, hence limiting the possibility of commercialisation of its applications. Here, we demonstrate controlled synthesis of highly crystalline MoS2nanosheets via liquid phase exfoliation of bulk MoS2, following which we report piezoelectric response from the exfoliated nanosheets. The method of piezo force microscopy was employed to explore the piezo response in mono, bi, tri and multilayers of MoS2nanosheets. The effective piezoelectric coefficient of MoS2varies from 9.6 to 25.14 pm V-1. We attribute piezoelectric response in MoS2nanosheets to the defects formed in it during the synthesis procedure. The presence of defects is confirmed by x-ray photoelectron spectroscopy.

A simple fabrication strategy for orientationally accurate twisted heterostructures.

Van der Waals (vdW) heterostructure is a type of metamaterial where multiple layers of 2D materials are vertically aligned at controlled misorientation. The relative rotation in between the adjacent layers, or the twist angle between them plays a crucial role in changing the electronic band structure of the superlattice. The assembly of multi-layers of precisely twisted two dimensional layered materials requires knowledge of the atomic structure at the edge of the flake. It may be artificially created by the 'tear and stack' process. Otherwise, the crystallographic orientation needs to be determined through invasive processes such as transmission electron microscopy or scanning tunneling microscopy, and via second-harmonic generation (SHG). Here, we demonstrate a simple and elegant transfer protocol using only an optical microscope as a edge identifier tool through which, controlled transfer of twisted homobilayer and heterobilayer transition metal dichalcogenides is performed with close to 100% yield. The fabricated twisted vdW heterostructures have been characterized by SHG, Raman spectroscopy and photoluminiscence spectroscopy, confirming the desired twist angle within ∼0.5° accuracy. The presented method is reliable, quick and prevents the use of invasive tools which is desirable for reproducible device functionalities.