Acute perturbation strategies in interrogating RNA polymerase II elongation factor function in gene expression.

The regulation of gene expression catalyzed by RNA polymerase II (Pol II) requires a host of accessory factors to ensure cell growth, differentiation, and survival under environmental stress. Here, using the auxin-inducible degradation (AID) system to study transcriptional activities of the bromodomain and extraterminal domain (BET) and super elongation complex (SEC) families, we found that the CDK9-containing BRD4 complex is required for the release of Pol II from promoter-proximal pausing for most genes, while the CDK9-containing SEC is required for activated transcription in the heat shock response. By using both the proteolysis targeting chimera (PROTAC) dBET6 and the AID system, we found that dBET6 treatment results in two major effects: increased pausing due to BRD4 loss, and reduced enhancer activity attributable to BRD2 loss. In the heat shock response, while auxin-mediated depletion of the AFF4 subunit of the SEC has a more severe defect than AFF1 depletion, simultaneous depletion of AFF1 and AFF4 leads to a stronger attenuation of the heat shock response, similar to treatment with the SEC inhibitor KL-1, suggesting a possible redundancy among SEC family members. This study highlights the usefulness of orthogonal acute depletion/inhibition strategies to identify distinct and redundant biological functions among Pol II elongation factor paralogs.

A synthetic lethality screen reveals ING5 as a genetic dependency of catalytically dead Set1A/COMPASS in mouse embryonic stem cells.

Embryonic stem cells (ESCs) are defined by their ability to self-renew and the potential to differentiate into all tissues of the developing organism. We previously demonstrated that deleting the catalytic SET domain of the Set1A/complex of proteins associated with SET1 histone methyltransferase (Set1A/COMPASS) in mouse ESCs does not impair their viability or ability to self-renew; however, it leads to defects in differentiation. The precise mechanisms by which Set1A executes these functions remain to be elucidated. In this study, we demonstrate that mice lacking the SET domain of Set1A are embryonic lethal at a stage that is unique from null alleles. To gain insight into Set1A function in regulating pluripotency, we conducted a CRISPR/Cas9-mediated dropout screen and identified the MOZ/MORF (monocytic leukaemia zinc finger protein/monocytic leukaemia zinc finger protein-related factor) and HBO1 (HAT bound to ORC1) acetyltransferase complex member ING5 as a synthetic perturbation to Set1A. The loss of Ing5 in Set1AΔSET mouse ESCs decreases the fitness of these cells, and the simultaneous loss of ING5 and in Set1AΔSET leads to up-regulation of differentiation-associated genes. Taken together, our results point toward Set1A/COMPASS and ING5 as potential coregulators of the self-renewal and differentiation status of ESCs.

All-Atom Molecular Dynamics Simulations of Uncharged Linear Polymer Bottlebrushes: Effect of the Brush Sizes and the Number of Side-Chain Monomers.

Bottlebrush polymers (BBPs), characterized by grafted polymer side chains on linear backbone polymer chain, have emerged as a unique and versatile class of macromolecules with extensive applications in the fields of material science, electronics, battery materials, self-healing technology, etc. In this paper, we employ all-atom molecular dynamics (MD) simulations to present a comprehensive study of poly(methyl methacrylate)-g-poly(2-ethyl-2-oxazoline) (PMMA-g-PEtOx) BBP and its structural and hydration properties for varying number of backbone monomers (NBB) and side chain monomers (NSC), as well as properties of water molecules supported by the BBP. We find that the radius of gyration follows a scaling of Rg ∼NSC0.36 for smaller grafts and Rg ∼ NSC0.52-0.58 for longer grafts. We also find that the overall shape of the bottlebrush goes from a rod to sphere-like shape with the increase in NSC. Both the hydration per side chain monomer and hydrogen bonds (HBs) per oxygen and nitrogen of the side chain monomer reduce with an increase in NSC, caused by a corresponding enhancement in localization of the side chain monomers in the interior of the BBP. Furthermore, steric influences ensure the number of water-oxygen HBs is much more than the number of water-nitrogen HBs (with oxygen and nitrogen atoms belonging to the monomer side chains). Also, the BBP-supported water molecules demonstrate two distinctly ordered domains with one more structured and one less structured. The more structured domain disappears with an increase in NSC that causes more side chain monomers to localize in the interior of the BBPs. Finally, we observe that despite the highly negative partial charges of the oxygen and nitrogen atoms (of the side chain monomers), the dipole orientation distributions of water molecules around these atoms exhibit the presence of a neutral environment rather than an anionic environment. Overall, we anticipate that our study will generate significant interest in probing the various BBP systems in greater atomistic detail.

Antidiabetic features of AdipoAI, a novel AdipoR agonist.

Adiponectin is an antidiabetic endogenous adipokine that plays a protective role against the unfavorable metabolic sequelae of obesity. Recent evidence suggests a sinister link between hypoadiponectinemia and development of insulin resistance/type 2 diabetes (T2D). Adiponectin's insulin-sensitizing property is mediated through the specific adiponectin receptors R1 and R2, which activate the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR) α pathways. AdipoAI is a novel synthetic analogue of endogenous adiponectin with possibly similar pharmacological effects. Thus, there is a need of orally active small molecules that activate Adipoq subunits, and their downstream signaling, which could ameliorate obesity related type 2 diabetes. In the study we aim to investigate the effects of AdipoAI on obesity and T2D. Through in-vitro and in-vivo analyses, we investigated the antidiabetic potentials of AdipoAI and compared it with AdipoRON, another orally active adiponectin receptors agonist. Our results showed that in-vitro treatment of AdipoAI (0-5 µM) increased adiponectin receptor subunits AdipoR1/R2 with increase in AMPK and APPL1 protein expression in C2C12 myotubes. Similarly, in-vivo, oral administration of AdipoAI (25 mg/kg) observed similar effects as that of AdipoRON (50 mg/kg) with improved control of blood glucose and insulin sensitivity in diet-induced obesity (DIO) mice models. Further, AdipoAI significantly reduced epididymal fat content with decrease in inflammatory markers and increase in PPAR-α and AMPK levels and exhibited hepatoprotective effects in liver. Further, AdipoAI and AdipoRON also observed similar results in adipose tissue. Thus, our results suggest that low doses of orally active small molecule agonist of adiponectin AdipoAI can be a promising therapeutic target for obesity and T2D.

Predictive accuracy of histopathological profile and immunohistochemical markers for the aging of abrasion: an autopsy-based study.

Wound age estimation is a crucial medicolegal task for forensic pathologists. The main objective of the current study was to evaluate the ability of the histopathological profile and immunohistochemical markers (CD14 and IL-8) to predict the age of abrasion and, furthermore, identify the relationship between the histopathological profile and immunohistochemical markers in abrasion aging. The study involved postmortem cases (n = 246) of abrasion injuries in which the injury infliction time was known. The test skin samples were taken from the abrasion site, and an adjacent area of uninjured skin was sampled for control. Hematoxylin and eosin stain was applied to tissue sections for the histopathological analysis. The semi-quantitative evaluation was made for expressing immunohistochemical markers CD14 and IL-8 on the infiltrating inflammatory cells. The study showed that the age of abrasion was significantly higher (p < 0.05) among the cases with positive staining than those with negative staining for both CD14 and IL-8. Additionally, the study found a significant association between the age of the abrasion and the IHC staining for IL-8. However, no significant association was seen between the age of abrasion and the CD-14 IHC staining. The odds ratio (95% confidence interval) for more than 72 h of the age of abrasion was compared to 0 to 72 h of the age of abrasion. The odds ratios were 39.00 (4.177-364.13) for the predominant mononuclear cell infiltration and 84.50 (9.287-768.814) for cases with the appearance of fibroblast, granulation tissue, and collagen deposition when compared to an unremarkable change on histopathological examination. Positive staining of immunohistochemical markers CD14 and IL-8 for the age of abrasion of more than 72 h showed a sensitivity of 40% and 80.95%, respectively, and specificity of 71.6% and 52.5%, respectively. The quantification of the histopathological changes of predominant mononuclear cell infiltration and the appearance of fibroblast, granulation tissue formation, and collagen deposition showed a significant correlation for the age of abrasion of more than 72 h. The immunohistochemical analysis revealed IL-8 as a more accurate marker than CD14 in identifying abrasions older than 72 h.

Reusable Sugar-Based Gelator for Marine Oil-Spill Recovery and Waste Water Treatment.

In this work, the gelation ability of a series of novel pyridine-based glucose tailored gelators (DPHAEN, DPHABN, and DPHAHN) with a flexible alkyl chain has been examined in binary solvent mixtures using a number of techniques, for example, UV spectroscopy, FT-IR spectroscopy, NMR spectroscopy, rheology measurement, SEM, XRD, and computational study. Proposed herein is an environment-friendly method to realize toxic dye separation and oil/water separation. It has been found that gels in a selective binary solvent mixture are efficient reusable absorbers of toxic dye molecules. A new gravitational force-driven, simple one-step, toxic dye removal and oil-water separation method is presented for sustainable filtration of waste water and simultaneous collection of oil. The gel column also showed high stability and reusability over repeated use and can be easily scaled for efficient clean-up of a large number of toxic dyes and oil spills present in water. Studies also exposed that the gel column can simultaneously separate dye molecules and mineral oils from water. This simple, green, and efficient method overcomes a nontrivial hurdle for environmentally safe separation of toxic dyes as well as oil/water mixtures and offers insights into the design of advanced materials for practical oil/water separation.

Three-Dimensional Deposits from Drying Particle-Laden Drops.

Formation of inhomogeneous (in the form of a "coffee ring") or homogeneous deposits accompanies the drying of a particle-laden drop. Invariably, this deposition occurs in a two-dimensional (2D) space (x, y plane) (and might have a finite thickness in z), where the evaporating drop is positioned. Here, we show an interesting extension of this problem: we demonstrate the occurrence of evaporation-mediated particle deposits that span three dimensions (x, y, and z). The extent of the span in this 3rd dimension (z) is comparable to the span in x and y and hence is much larger than the finite thickness (in z) of the 2D deposits. Particle-laden drops are introduced in an uncured and heavier (than the drop) polydimethysiloxane (PDMS) film, enabling the drop to come to the uncured PDMS surface and breach it and get partly exposed to the surrounding air enforcing the onset of evaporation. The subsequent curing of the drop-laden PDMS film ensures that the drop is occupying a three-dimensional (3D) cavity; as a consequence, the evaporation-driven flow field, depending on the particle sizes, leads to a deposition pattern that spans three dimensions. We consider particles of three different sizes: coffee particles (20-50 µm), silver nanoparticles (∼20 nm), and carbon nanotubes (CNTs) (1-2 µm). The coffee particles form a ring-like deposit in the x, y plane, while the much smaller silver nanoparticles (NPs) and CNTs form a 3D deposit that spans in x, y, and z directions. We anticipate that the present finding of the evaporation-triggered three-dimensional (3D) particle deposits will enable unprecedented self-assembly-driven fabrication of various materials, structures, and functional devices as well as patterning and coating in 3D spaces.

Direct visualization of nanoparticle morphology in thermally sintered nanoparticle ink traces and the relationship among nanoparticle morphology, incomplete polymer removal, and trace conductivity.

A key challenge encountered by printed electronics is that the conductivity of sintered metal nanoparticle (NP) traces is always several times smaller than the bulk metal conductivity. Identifying the relative roles of the voids and the residual polymers on NP surfaces in sintered NP traces, in determining such reduced conductivity, is essential. In this paper, we employ a combination of electron microscopy imaging and detailed simulations to quantify the relative roles of such voids and residual polymers in the conductivity of sintered traces of a commercial (Novacentrix) silver nanoparticle-based ink. High resolution transmission electron microscopy imaging revealed details of the morphology of the inks before and after being sintered at 150 °C. Prior to sintering, NPs were randomly close packed into aggregates with nanometer thick polymer layers in the interstices. The 2D porosity in the aggregates prior to sintering was near 20%. After heating at 150 °C, NPs sintered together into dense aggregates (nanoaggregates or NAgs) with sizes ranging from 100 to 500 nm and the 2D porosity decreased to near 10%. Within the NAgs, the NPs were mostly connected via sintered metal bridges, while the outer surfaces of the NAgs were coated with a nanometer thick layer of polymer. Motivated by these experimental results, we developed a computational model for calculating the effective conductivity of the ink deposit represented by a prototypical NAg consisting of NPs connected by metallic bonds and having a polymer layer on its outer surface placed in a surrounding medium. The calculations reveal that a NAg that is 35%-40% covered by a nanometer thick polymeric layer has a similar conductivity compared to prior experimental measurements. The findings also demonstrate that the conductivity is less influenced by the polymer layer thickness or the absolute value of the NAg dimensions. Most importantly, we are able to infer that the reduced value of the conductivity of the sintered traces is less dependent on the void fraction and is primarily attributed to the incomplete removal of the polymeric material even after sintering.

Resveratrol and 3,3'-Diindolylmethane Differentially Regulate Aryl Hydrocarbon Receptor and Estrogen Receptor Alpha Activity through Multiple Transcriptomic Targets in MCF-7 Human Breast Cancer Cells.

Inhibitory crosstalk between estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AHR) regulates 17ß-estradiol (E2)-dependent breast cancer cell signaling. ERα and AHR are transcription factors activated by E2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. Dietary ligands resveratrol (RES) and 3,3'diindolylmethane (DIM) also activate ERα while only DIM activates AHR and RES represses it. DIM and RES are reported to have anti-cancer and anti-inflammatory properties. Studies with genome-wide targets and AHR- and ERα-regulated genes after DIM and RES are unknown. We used chromatin immunoprecipitation with high-throughput sequencing and transcriptomics to study ERα as well as AHR coregulation in MCF-7 human breast cancer cells treated with DIM, RES, E2, or TCDD alone or E2+TCDD for 1 and 6 h, respectively. ERα bound sites after being DIM enriched for the AHR motif but not after E2 or RES while AHR bound sites after being DIM and E2+TCDD enriched for the ERE motif but not after TCDD. More than 90% of the differentially expressed genes closest to an AHR binding site after DIM or E2+TCDD also had an ERα site, and 60% of the coregulated genes between DIM and E2+TCDD were common. Collectively, our data show that RES and DIM differentially regulate multiple transcriptomic targets via ERα and ERα/AHR coactivity, respectively, which need to be considered to properly interpret their cellular and biological responses. These novel data also suggest that, when both receptors are activated, ERα dominates with preferential recruitment of AHR to ERα target genes.

Numerical Study of the Coalescence and Mixing of Drops of Different Polymeric Materials.

In this study, we employ direct numerical simulation (DNS) to investigate the solutal hydrodynamics dictating the three-dimensional coalescence of microscopic, identical-sized sessile drops of different but miscible shear-thinning polymeric liquids (namely, PVAc or polyvinyl acetate and PMMA or polymethylmethacrylate), with the drops being in partially wetted configuration. Despite the ubiquitousness of the interaction of different dissimilar droplets in a variety of engineering problems ranging from additive manufacturing to understanding the behavior of photonic crystals, coalescence of drops composed of different polymeric and non-Newtonian materials has not been significantly explored. Interaction of such dissimilar droplets often involves simultaneous drop spreading, coalescence, and mixing. The mixing dynamics of the dissimilar drops are governed by interphase diffusion, the residual kinetic energy of the drops stemming from the fact that coalescence starts before the spreading of the drops have been completed, and the solutal Marangoni convection. We provide the three-dimensional velocity fields and velocity vectors inside the completely miscible, dissimilar coalescing droplets. Our simulations explicate the relative influence of these different effects in determining the flow field at different locations and at different time instances and the consequent mixing behavior inside the interacting drops. We also show the non-monotonic (in terms of the direction of migration) propagation of the mixing front of the miscible coalescing drops over time. We also establish that the overall mixing (on either side of the mixing front) speeds up as the Marangoni effects dictate the mixing. We anticipate that our study will provide an important foundation for studying miscible multi-material liquid systems, which will be crucial for applications such as inkjet or aerosol jet printing, lab-on-a-chip, polymer processing, etc.

Machine learning enabled quantification of the hydrogen bonds inside the polyelectrolyte brush layer probed using all-atom molecular dynamics simulations.

The configuration of densely grafted charged polyelectrolyte (PE) brushes is strongly dictated by the properties and behavior of the counterions that screen the PE brush charges and the solvent molecules (typically water) that solvate the brush molecules and these screening counterions. Only recently, efforts have been made to study the PE brushes atomistically, thereby shedding light on the properties of brush-supported ions and water molecules. However, even for such efforts, there are limitations associated with using a generic definition to estimate certain properties of water and ions inside the brush layer. For example, water-water hydrogen bonds (HBs) will behave differently for locations outside and inside the brush layer, given the fact that the densely closely grafted PE brush molecules create a soft nanoconfinement where the water connectivity becomes highly disrupted: therefore, using the same definition to quantify the HBs inside and outside the brush layer will be unwise. In this paper, we address this limitation by employing an unsupervised machine learning (ML) approach to predict the water-water hydrogen bonding inside a cationic PE brush layer modeled using all-atom molecular dynamics (MD) simulations. The ML method, which relies on a clustering approach and uses the equilibrium coordinates of the water molecules (obtained from the all-atom MD simulations) as the input, is capable of identifying the structural modification of water-water HBs (revealed through appropriate clustering of the data) inside the PE brush layer induced soft nanoconfinement. Such capabilities would not have been possible by using a generic definition of the HBs. Our calculations lead to four key findings: (1) the clusters formed inside and outside the brush layer are structurally similar; (2) the margin of the cluster is shorter inside the PE brush layer confirming the possible disruption of the HBs inside the PE brush layer; (3) the average "hydrogen-acceptor-oxygen-donor-oxygen" angle that defines the HB is reduced for the HBs formed inside the brush layer; (4) the use of the generic definition (definition usable for characterizing the HBs in brush-free bulk) leads to an overprediction of the number of HBs formed inside the PE brush layer.

Coarse-grained modelling of DNA plectoneme pinning in the presence of base-pair mismatches.

Damaged or mismatched DNA bases result in the formation of physical defects in double-stranded DNA. In vivo, defects in DNA must be rapidly and efficiently repaired to maintain cellular function and integrity. Defects can also alter the mechanical response of DNA to bending and twisting constraints, both of which are important in defining the mechanics of DNA supercoiling. Here, we use coarse-grained molecular dynamics (MD) simulation and supporting statistical-mechanical theory to study the effect of mismatched base pairs on DNA supercoiling. Our simulations show that plectoneme pinning at the mismatch site is deterministic under conditions of relatively high force (>2 pN) and high salt concentration (>0.5 M NaCl). Under physiologically relevant conditions of lower force (0.3 pN) and lower salt concentration (0.2 M NaCl), we find that plectoneme pinning becomes probabilistic and the pinning probability increases with the mismatch size. These findings are in line with experimental observations. The simulation framework, validated with experimental results and supported by the theoretical predictions, provides a way to study the effect of defects on DNA supercoiling and the dynamics of supercoiling in molecular detail.

Viscoelastic substrate decouples cellular traction force from other related phenotypes.

Survival and maintenance of normal physiological functions depends on continuous interaction of cells with its microenvironment. Cells sense the mechanical properties of underlying substrate by applying force and modulate their behaviour in response to the resistance offered by the substrate. Most of the studies addressing cell-substrate mechanical interactions have been carried out using elastic substrates. Since tissues within our body are viscoelastic in nature, here we explore the effect of substrate's viscoelasticity on various properties of mesenchymal stem cells. Here, we used two sets of polyacrylamide substrates having similar storage modulus (G' = 1.1-1.6 kPa) but different loss modulus (G" = 45 Pa and 300 Pa). We report that human mesenchymal stem cells spread more but apply less force on the viscoelastic substrate (substrate with higher loss modulus). We further investigated the effect of substrate viscoelasticity on the expression of other contractility-associated proteins such as focal adhesion (FA) proteins (Vinculin, Paxillin, Talin), cytoskeletal proteins (actin, mysion, intermediate filaments, and microtubules) and mechano-sensor protein Yes-Associated Protein (YAP). Our results show that substrate viscoelasticity decouples cellular traction from other known traction related phenotypes.

The ßγ subunit of heterotrimeric G proteins interacts with actin filaments during neuronal differentiation.

The ßγ subunit of heterotrimeric G proteins, a key molecule in the G protein-coupled receptors (GPCRs) signaling pathway, has been shown to be an important factor in the modulation of the microtubule cytoskeleton. Gßγ has been shown to bind to tubulin, stimulate microtubule assembly, and promote neurite outgrowth of PC12 cells. In this study, we demonstrate that in addition to microtubules, Gßγ also interacts with actin filaments, and this interaction increases during NGF-induced neuronal differentiation of PC12 cells. We further demonstrate that the Gßγ-actin interaction occurs independently of microtubules as nocodazole, a well-known microtubule depolymerizing agent did not inhibit Gßγ-actin complex formation in PC12 cells. A confocal microscopic analysis of NGF-treated PC12 cells revealed that Gßγ co-localizes with both actin and microtubule cytoskeleton along neurites, with specific co-localization of Gßγ with actin at the distal end of these neuronal processes. Furthermore, we show that Gßγ interacts with the actin cytoskeleton in primary hippocampal and cerebellar rat neurons. Our results indicate that Gßγ serves as an important modulator of the neuronal cytoskeleton by interacting with both microtubules and actin filaments, and is likely to participate in various aspects of neuronal differentiation including axon and growth cone formation.

Wood Ionic Cable.

The combination of good stability, biocompatibility, and high mechanical strength is attractive for bio-related material applications, but it remains challenging to simultaneously achieve these properties in a single, ionically conductive material. Here a "wood" ionic cable, made of aligned wood nanofibrils, demonstrating a combination of biocompatibility, high mechanical strength, high ionic conductivity, and excellent stability is reported. The wood ionic cable possesses excellent flexibility and exhibits high tensile strength up to 260 MPa (in the dry state) and ≈80 MPa (in the wet state). The nanochannels within the highly aligned cellulose nanofibrils and the presence of negative charges on the surfaces of these nanochannels, originating from the cellulose hydroxyl groups, provide new opportunities for ion regulation at low salt concentrations. Ion regulation in turn enables the wood ionic cable to have unique nanofluidic ionic behaviors. The Na+ ion conductivity of the wood ionic cable can reach up to ≈1.5 × 10-4 S cm-1 at low Na+ ion concentration (1.0 × 10-5 mol L-1 ), which is an order of magnitude higher than that of bulk NaCl solution at the same concentration. The scalable, biocompatible wood ionic cable enables novel ionic device designs for potential ion-regulation applications.

Coalescence of Microscopic Polymeric Drops: Effect of Drop Impact Velocities.

In this paper, we employ the direct numerical simulation (DNS) method for probing three-dimensional, axisymmetric coalescence of microscale, power-law-obeying, and shear-thinning polymeric liquid drops of identical sizes impacting a solid, solvophilic substrate with a finite velocity. Unlike the cases of drop coalescence of Newtonian liquid drops, coalescence of non-Newtonian polymeric drops has received very little attention. Our study bridges this gap by providing (1) the time-dependent, three-dimensional (3D) velocity field and 3D velocity vectors inside two coalescing polymeric drops in the presence of a solid substrate and (2) the effect of the drop impact velocity (on the solid substrate), quantified by the Weber number (We), on the coalescence dynamics. Our simulations reveal that the drop coalescence is qualitatively similar for different We values, although the velocity magnitudes involved, the time required to attain different stages of coalescence, and the time needed to attain equilibrium vary drastically for finitely large We values. Finally, we provide detailed simulation-based, as well as physics-based, scaling laws describing the growth of the height and the width of the bridge (formed due to coalescence) dictating the 3D coalescence event. Our analyses reveal distinct scaling laws for the growth of bridge height and width for early and late stages of coalescence as a function of We. We also provide simulation-based coalescence results for the case of two unequal sized drops impacting on a substrate (nonaxisymmetric coalescence) as well as results for axisymmetric coalescence for drops of different rheology. We anticipate that our findings will be critical in better understanding events such as inkjet or aerosol jet polymer printing, dynamics of polymer blends, and many more.

Demographic and clinical profile of youth onset diabetes patients in India-Results from the baseline data of a clinic based registry of people with diabetes in India with young age at onset-[YDR-02].

BACKGROUND: We here report the demographic and clinical profile of the patients enrolled in the Indian Council of Medical Research funded Registry of people with diabetes in India with young age at onset (YDR) from 1 January 2000 to 31 July 2011. METHODS: The YDR registry recruits all diabetes cases (newly diagnosed or treated) reporting on or after 1 January 2000 with age of diagnosis ≤25 years, and residing within the assigned geographical area of the reporting centres. A baseline proforma was used to obtain information on demographic and clinical details at registration. RESULTS: The registry has enrolled 5546 patients (49.5% male; 50.5% female) with youth onset diabetes from 205 reporting centres linked to 8 regional collaborating centres (RCC) across India. T1DM (63.9%; n = 3545) and T2DM (25.3%; n = 1401) were the commonest variants of youth onset diabetes, though their relative proportion varied across RCCs. The mean (SD) age at diagnosis for T1DM was 12.9 (6.5) years, while that for T2DM was 21.7 (3.7) years. Nearly half the T1DM patients were registered within 6 months of the onset of disease. Most cases of T2DM (47.3%) were registered after 3 years from their date of diagnosis. 56.1% of patients had at least one episode of hospitalization at registration. CONCLUSION: The observations from YDR registry indicate the need to establish a surveillance system in India to monitor diabetes in youth, not only to understand its complex etiology and natural history but also due to its detrimental socio economic impact.

Atomistic explorations of mechanisms dictating the shear thinning behavior and 3D printability of graphene flake infused epoxy inks.

Nanofiller-based epoxy inks have found extensive use in fabricating 3D printed nanocomposites for applications in aerospace, automobile, and marine systems. In this paper, we employ an all-atom molecular dynamic (MD) simulation to atomistically explore the mechanisms dictating the shear-thinning behavior of the graphene flake-infused (GFI) epoxy inks. We compare our findings with those for pure epoxy inks: non-equilibrium MD (NEMD) simulations reveal that both the GFI epoxy ink and pure epoxy ink demonstrate shear thinning behavior, i.e., their viscosities decrease with an increase in the shear rate. However, interestingly, the viscosity of the GFI epoxy ink is larger than that of pure epoxy for smaller shear rates, while for higher shear rates, the viscosities of these two materials are similar. This indicates a much more favorable viscosity profile for the GFI epoxy inks in the context of 3D printing. From the context of exploring the nanoscale mechanism, we identify the tendency of the bisphenol F molecules (the key constituent of the epoxy inks) and the graphene flakes (for the case of GFI epoxy inks) to align along the shear planes (in the presence of a shear flow) allowing the dissipation of viscous force among them ensuring shear-thinning behavior for both pure epoxy and GFI epoxy inks. In this context, we also identify that the bisphenol F chains prefer to localize along a given shear plane to reduce the effect of tension forces: such an alignment ensures that the radius of gyration for the bisphenol F molecules (for both pure epoxy and GFI epoxy inks) is larger for the case of finite shear and has a non-monotonic variation with the shear rate. Finally, the equilibrium MD (EMD) simulations establish that the presence of the graphene flakes significantly slows down the rotational dynamics of the bisphenol F molecules that are adsorbed to these graphene flakes and, as a result, causes the zero-shear viscosity of the GFI epoxy to be three orders of magnitude larger than that of the pure epoxy. This difference provides a qualitative justification of the viscosity of the GFI epoxy being larger than that of pure epoxy at smaller shear rate values.

Traumatic herniation of intestine through ruptured skin at the ankle.

Vehicular runover of pedestrians is a commonly reported occurrence in literature. The usual presentations at autopsy are avulsion of the intra-abdominal viscera, solid organ crushing, hemorrhage, fracture of pelvic bone and vertebra, and herniation of the abdominal contents. There are reports of many cases where the abdominal and thoracic viscera have herniated out of their respective compartment following rupture of the diaphragm. Herniation of the intestine through natural orifices or other anatomical openings of the body has also been reported. This herniation occurs following a reduction in the anteroposterior diameter and acute increase in intra-abdominal pressure, displacing the abdominal contents out of their normal position through some natural anatomical openings inside the body following the path of least resistance. We report an interesting case of vehicular runover where the intestinal coils have come out of the body at the ankle. The authors describe the plausible mechanism and the route through which the intestine could have traversed.

Cellulose ionic conductors with high differential thermal voltage for low-grade heat harvesting.

Converting low-grade heat into useful electricity requires a technology that is efficient and cost effective. Here, we demonstrate a cellulosic membrane that relies on sub-nanoscale confinement of ions in oxidized and aligned cellulose molecular chains to enhance selective diffusion under a thermal gradient. After infiltrating electrolyte into the cellulosic membrane and applying an axial temperature gradient, the ionic conductor exhibits a thermal gradient ratio (analogous to the Seebeck coefficient in thermoelectrics) of 24 mV K-1-more than twice the highest value reported until now. We attribute the enhanced thermally generated voltage to effective sodium ion insertion into the charged molecular chains of the cellulosic membrane, which consists of type II cellulose, while this process does not occur in natural wood or type I cellulose. With this material, we demonstrate a flexible and biocompatible heat-to-electricity conversion device via nanoscale engineering based on sustainable materials that can enable large-scale manufacture.