Oligomer-assisted self-assembly of bisurea in organic solvent media.

We report on molecular dynamics simulation evidence revealing that an oligomer additive can be used to greatly facilitate the self-assembly of a bisurea in organic solvent media, through the initial regular packing and the subsequent stiffening of the self-assembly filament. The underlying physics is attributed to the substantially reduced diffusivities of the solute and, in particular, solvent molecules, featuring a generally weakened (thermal) Brownian force under ambient conditions. Without such oligomer-induced molecular cooling-in contrast to the usual external cooling, the original solvent medium is noted to foster instead more stabilized and disordered aggregates and, in particular, it would require a temperature reduction that is practically inaccessible in order to sustain similar stiffness of the self-assembly filament. These features, in accord with recent experimental observations, highlight the open opportunity of promoting the self-assembly of small functional molecules in general solvent media without requiring substantial changes of the system temperature, as is crucial for many practical applications including the biological/biomedical ones.

TheiaEuk: a species-agnostic bioinformatics workflow for fungal genomic characterization.

Introduction: The clinical incidence of antimicrobial-resistant fungal infections has dramatically increased in recent years. Certain fungal pathogens colonize various body cavities, leading to life-threatening bloodstream infections. However, the identification and characterization of fungal isolates in laboratories remain a significant diagnostic challenge in medicine and public health. Whole-genome sequencing provides an unbiased and uniform identification pipeline for fungal pathogens but most bioinformatic analysis pipelines focus on prokaryotic species. To this end, TheiaEuk_Illumina_PE_PHB (TheiaEuk) was designed to focus on genomic analysis specialized to fungal pathogens. Methods: TheiaEuk was designed using containerized components and written in the workflow description language (WDL) to facilitate deployment on the cloud-based open bioinformatics platform Terra. This species-agnostic workflow enables the analysis of fungal genomes without requiring coding, thereby reducing the entry barrier for laboratory scientists. To demonstrate the usefulness of this pipeline, an ongoing outbreak of C. auris in southern Nevada was investigated. We performed whole-genome sequence analysis of 752 new C. auris isolates from this outbreak. Furthermore, TheiaEuk was utilized to observe the accumulation of mutations in the FKS1 gene over the course of the outbreak, highlighting the utility of TheiaEuk as a monitor of emerging public health threats when combined with whole-genome sequencing surveillance of fungal pathogens. Results: A primary result of this work is a curated fungal database containing 5,667 unique genomes representing 245 species. TheiaEuk also incorporates taxon-specific submodules for specific species, including clade-typing for Candida auris (C. auris). In addition, for several fungal species, it performs dynamic reference genome selection and variant calling, reporting mutations found in genes currently associated with antifungal resistance (FKS1, ERG11, FUR1). Using genome assemblies from the ATCC Mycology collection, the taxonomic identification module used by TheiaEuk correctly assigned genomes to the species level in 126/135 (93.3%) instances and to the genus level in 131/135 (97%) of instances, and provided zero false calls. Application of TheiaEuk to actual specimens obtained in the course of work at a local public health laboratory resulted in 13/15 (86.7%) correct calls at the species level, with 2/15 called at the genus level. It made zero incorrect calls. TheiaEuk accurately assessed clade type of Candida auris in 297/302 (98.3%) of instances. Discussion: TheiaEuk demonstrated effectiveness in identifying fungal species from whole genome sequence. It further showed accuracy in both clade-typing of C. auris and in the identification of mutations known to associate with drug resistance in that organism.

The use of whole-genome sequencing and development of bioinformatics to monitor overlapping outbreaks of Candida auris in southern Nevada.

A Candida auris outbreak has been ongoing in Southern Nevada since August 2021. In this manuscript we describe the sequencing of over 200 C. auris isolates from patients at several facilities. Genetically distinct subgroups of C. auris were detected from Clade I (3 distinct lineages) and III (1 lineage). Open-source bioinformatic tools were developed and implemented to aid in the epidemiological investigation. The work herein compares three methods for C. auris whole genome analysis: Nullarbor, MycoSNP and a new pipeline TheiaEuk. We also describe a novel analysis method focused on elucidating phylogenetic linkages between isolates within an ongoing outbreak. Moreover, this study places the ongoing outbreaks in a global context utilizing existing sequences provided worldwide. Lastly, we describe how the generated results were communicated to the epidemiologists and infection control to generate public health interventions.

Effects of Calcium and pH on Rheological Thermal Resistance of Composite Xanthan Gum and High-Methoxyl Apple Pectin Matrices Featuring Dysphagia-Friendly Consistency.

High-methoxyl apple pectin (AP) derived from apple was employed as the main ingredient facilitating rheological modification features in developing dysphagia-friendly fluidized alimentary matrices. Xanthan gum (XG) was also included as a composite counterpart to modify the viscoelastic properties of the thickened system under different thermal processes. The results indicate that AP is extremely sensitive to thermal processing, and the viscosity is greatly depleted under a neutral pH level. Moreover, the inclusion of calcium ions echoed the modification effect on the rheological properties of AP, and both the elastic property and viscosity value were promoted after thermal processing. The modification effect of viscoelastic properties (G' and G″) was observed whne XG was incorporated into the composite formula. Increasing the XG ratio from 7:3 to 6:4 (AP:XG) triggers the rheological transformation from a liquid-like form to a solid-like state, and the viscosity value shows that the AP-XG composite system exhibits better thermal stability after thermal processing. The ambient modifiers of pH (pH < 4) and calcium chloride concentration (7.5%) with an optimal AP-XG ratio of 7:3 led to weak-gel-like behavior (G″ < G'), helping to maintain the texture properties of dysphagia-friendly features similar to those prior to the thermal processing.

Multiscale structures and rheology of bisurea-loaded resins for anti-sagging applications.

Four representative bisurea molecules (HDI-BA, MDI-BA, TDI-BA, and IPDI-BA) were synthesized and dispersed simultaneously by reacting benzylamine (BA) with various types of diisocyanates in a polyester/ortho-xylene resin medium to produce bisurea-loaded resins (BLRs) for anti-sagging application with paints and coating materials. These bisurea molecules are symmetric and differ only in the central spacer unit, thereby presenting an ideal and simplest model system to delve into the structure-performance relationship. The multiscale structural features arising from self-assembly in each of the BLRs were scrutinized using the combination of multi-angular dynamic light scattering (DLS), small-angle light/X-ray scattering (SALS/SAXS), rheology, and scanning electron/optical microscopy (SEM/OM) characterization. All four BLRs were revealed to foster micron-sized, mostly sphere-like agglomerates, with distinct hierarchical structures that correlate well with their thixotropic and anti-sagging performances. Three BLRs (HDI-BA, MDI-BA, and TDI-BA) produce similar rod-like packing units (10 × 1 × 1 nm3), with only one exception (IPDI-BA) that produces a spherical packing unit (2 nm in diameter). However, the bulk feature of the agglomeration state, which dictates the thixotropic and anti-sagging properties, cannot be readily foreseen from the chemical structure or elementary packing unit of a bisurea. The present findings, while confirming the importance of optimum molecular design that controls the early-stage self-assembly behavior of a bisurea in resin media, highlight the necessity of resolving detailed (multiscale) structural features in order to establish the full structure-performance relationship imperatively needed for like material systems and applications.

Multiscale structural and rheological features of colloidal low-methoxyl pectin solutions and calcium-induced sol-gel transition.

The multiscale structural and rheological features of a series of dilute and semidilute low-methoxyl (LM) pectin solutions and a representative pectin/calcium sol-gel sample were systematically explored using a comprehensive combination of dynamic (DLS) and static light/X-ray scattering (SALS/SLS/SAXS), rheology, and microscopy (OM/SEM) characterizations. The study focused on the rarely explored colloidal aspect of LM pectin solutions and sol-gel transition, in contrast to the polymeric features extensively explored in previous studies. A highly uniform colloid-like, micron-sized agglomerate species was revealed in dilute solutions, with a progressively increased degree of flocculation in the semidilute regime (≥1.5 wt%). The agglomerate species in these solutions was resolved to be formed by random associations of individual pectin chains (L = 30 nm, r = 0.4 nm). Adding a critical amount of Ca2+ (10 wt%) to a semidilute solution (2 wt%) has an instant and pronounced effect of enhancing the agglomerate flocculation and resulting in a locally jammed state. Meanwhile, the agglomerate interior underwent microstructural transformation, leading to hierarchical structures defined by intermediate (spherical) aggregate species (Rg,aggregate ≈ 150 nm) and its packing cylindrical bundle (d ≈ 4 nm) composed of five pectin chains. Novel rheological features observed during the LM pectin/Ca2+ sol-gel transition include the following: the dynamic modulus data exhibited excellent TTS (gelling time/relaxation time superposition) as previously observed for weakly attractive colloidal gels. Three yield points were noticed for the final gel sample, suggested to mark the bond breaking of the cluster network, cage breaking of the resulting jammed flocculates, and, eventually, breakup of a flocculate into smaller agglomerates with increasing stress amplitude.

The Low Utilization Rate of Donor Lungs in China: A Single-Center Experience.

BACKGROUND Despite the increasing number of organ donations, the utilization rate of donor lungs in China is much lower than that in many other countries. MATERIAL AND METHODS The donor lungs were evaluated before departure (stage 1), after on-site management (stage 2), and after harvesting (stage 3). Variables of donor lungs from medical institutions with lung transplant qualification (group A) and those without qualification (group B) were compared. The outcome measurements for lung recipients were early survival and primary graft dysfunction. RESULTS Among the 277 donor lungs, 140 (51%) were suitable for transplantation and 101 were sent to our institution for 62 single-lung transplantations and 50 double-lung transplantations. The acceptability rates at stage 1, stage 2, and stage 3 were 78%, 56%, and 51%, respectively. In addition, 69 (50.4%) donor lungs were abandoned for poor quality related to management, 24 (17.5%) for no adequate recipients, 15 (10.9%) for family refusal, 14 (10.2%) for organ procurement organization-related reasons, and 15 (10.9%) for other reasons. Donors in group A were ventilated longer and had longer ischemic time than those in group B. However, bronchoscopy, imaging, and oxygenation in group A achieved better results than in group B. No between-group difference in 30-day mortality or rate of grade 3 primary graft dysfunction was observed. CONCLUSIONS Problems at supply and demand ends contribute to the low utilization rate of donor lungs in China. The poor management of donor lungs and the short waiting list for lung transplantation are major reasons.

Effects of solvation shell relaxation on chain association mechanisms in poly(3-hexylthiophene) solutions.

Using poly(3-hexylthiophene) (P3HT) as a model conjugated polymer and atomistic molecular dynamics simulations with carefully verified force fields, we performed in-depth investigations of solvation shell properties of P3HT chains (15 repeating units per chain) in two representative groups of non-polar (or aprotic) organic solvents (better solvents: ortho-dichlorobenzene, bromobenzene, and chlorobenzene; poorer solvents: chloroform, para-xylene, and toluene). We demonstrated that solvation shell relaxation properties in P3HT solutions dictate the formation of regular π-π associations and, hence, crystallinity through the initial chain association and subsequent chain sliding. In contrast, the mean features of polymer-solvent interactions, including solvation free energy and radial distribution function, present little or no difference for all solvent media investigated. Better-solvent media were revealed to bear relatively large values of the first solvation shell relaxation time (τ1 ≫ 100 ps) as well as larger ratios of relaxation times for the first two solvation shells (τ1/τ2 > 2), and vice versa for poorer-solvent media (τ1 ≪ 100 ps and τ1/τ2 < 2). The linear hexyl side-chain unit was noted to substantially enlarge both quantities while notably reducing the solvation free energy as well. As discussed herein, these findings shed new light on the mechanistic features by which solvent quality impacts the degree of π-π association crucial for modern applications with crystalline conjugated polymers.

Rheological and Textural Properties of Apple Pectin-Based Composite Formula with Xanthan Gum Modification for Preparation of Thickened Matrices with Dysphagia-Friendly Potential.

Modifying the consistency of a given edible fluid matrix by incorporating food thickeners is a common nursing remedy for individuals with dysphagia when adequate water consumption is a concern. As apple pectin (AP) offers nutraceutical benefits, properly formulated apple pectin (AP)-based thickeners featuring xanthan gum (XG) can be superior candidates for preparation of dysphagia-friendly matrices (DFMs). Our recruited DFMs exhibit fluid-like behavior (loss modulus > storage modulus, G" > G') at lower AP concentrations (2 and 5%, w/w); they turn into weak/critical gels (G' ≈ G") as the concentration becomes higher (9%). In contrast, XG-DFMs display gel-like attributes with G' > G", even at rather low concentrations (<1%) and become more resistant to sugar, Na+, and Ca2+ modifications. The composite matrix of AP1.8XG0.2 (constraint at 2%) exhibits a confined viscosity of 278 ± 11.7 mPa∙s, which is considered a DFM, in comparison to only AP- or XG-thickened ones. The hardness measurements of XG0.6 and AP1.2XG0.8 are 288.33 ± 7.506 and 302.00 ± 9.849 N/m2, respectively, which potentially represent a promising formulation base for future applications with DFMs; these textural values are not significantly different from a commercially available product (p > 0.05) for dysphagia nursing administrations.

Rheological and rheo-birefringence features of semidilute ethyl cellulose dispersions under steady shear flow.

We have conducted comprehensive rheological and rheo-birefringence characterizations of a series of semidilute ethyl cellulose (EC)/α-terpineol dispersions under steady shear flow. The EC dispersions investigated have commonly been utilized as a binder agent in fabricating metal/metal-oxide pastes for a number of industrial applications, and were recently demonstrated to foster nearly monodisperse spherical aggregates under dilute conditions. Herein, semidilute EC dispersions are shown to exhibit rheological features practically no different from those known for standard entangled polymer solutions. The corresponding rheo-birefringence responses, however, reveal microstructural features that are reminiscent of general colloidal systems. The steady-state feature reveals a universal stress-birefringence relationship at various EC concentrations, along with a common critical stress (∼200 Pa) at which the EC network breaks into smaller clusters. The transient feature displays prominent and long-persisting periodic oscillations that have previously been observed only for nearly monodisperse rod-like colloids or liquid crystals. The overall findings shed new light on the role of EC serving as a commonplace polymer binder in industry and, from a scientific perspective, raise interesting questions related to the characteristic rheological and microstructural features of general polymer dispersions in overlapped regimes.

Correlation of the hierarchical structure with rheological behavior of polypseudorotaxane gel composed of pluronic and ß-cyclodextrin.

We have identified the hierarchical (primary, secondary, tertiary and quaternary) structures of a polypseudorotaxane (PPR) gel composed of the Pluronic F108 and ß-cyclodextrin system to be ß-cyclodextrin crystalline, lamellar sheets, lamellar stacks and "grains", respectively. The correlation between the rheological properties and the proposed structures under shear flows was rationalized. Alignment of lamellar stacks and reorganization of grain boundaries under shear flows were investigated by rheo-SANS, small angle X-ray scattering and small-angle light scattering. The relaxation of highly aligned lamellar stacks is slow (>2 h) after flow cessation compared to that of the regrouped grains (a few minutes). The main contribution to thixotropic behavior is likely from the faster relaxation of the reorganized grains containing highly oriented lamellar stacks. The comprehensive understanding of structure-function relationship of the PPR gel will facilitate the rational design for its applications.

Hexagonal Superalignment of Nano-Objects with Tunable Separation in a Dilute and Spacer-Free Solution.

Manipulating building-block nanomaterials to form an ordered superstructure in a dilute and spacer-free solution phase challenges the existing 5-nm node lithography and nanorobotics. The cooperative nature of nanocrystals, polymers, and cells can lead to superarrays or colloidal crystals. For known highly ordered systems, the characteristic length of materials, defined as the shortest dimension of objects, is generally larger than their separations. A spacer (small-molecule surfactant or polymer) is typically required to diminish short range van der Waals attraction, which results in a glassy or liquid state. Herein we propose a new concept of achieving highly ordered nano-objects in a dilute and spacer-free system via the synergistic effects of excellent solvation and appropriate constraints on rotational motion. As a proof of concept, this study demonstrates that aluminosilicate nanotubes (AlSiNTs) suspended in water under dilute conditions (e.g., 1.0 wt%) can spontaneously form hexagonal arrays with an intertubular distance as large as tens of nanometers. The separation distance of the ordered superstructure is also tunable via controlling the concentration and length of nanotubes. These superaligned structures are probed using small-angle x-ray scattering and cryo-TEM characterizations, with underlying mechanisms investigated at an atomic level using molecular dynamics simulations. The concept and discovery of this work can open up opportunities to a variety of applications including visible-UV photonics and nanolithography, and may be generalizable to other nano-object systems that fulfill similar requirements.

PBTTT-C16 sol-gel transition by rod associations and networking.

A low-molecular-weight poly(2,5-bis(3-hexadecylthiophen-2-yl)thieno[3,2-b]thiophene) (designated as Lw-pBTTT-C16) in a fair solvent (chlorobenzene, CB) displays peculiar structural, mechanical, and electronic features during sol-gel transition. Using comprehensive (multiscale) dynamic/static analysis schemes, the Lw-pBTTT-C16/CB solution (10 mg mL-1) is shown to capitalize on rod associations and networking to form a gel, in stark contrast with its high-molecular-weight companion previously reported to form gels through hierarchical colloidal bridging. The present study reveals, however, that the molecular weight of pBTTT-C16 has a subtle impact on the gelation behaviors through the rarely recognized, contrasting supramolecular conformations (rod-like vs. wormlike) of the aggregate clusters fostered in the pristine solution. The ac conductivity nearly doubles as a result of improved (mesoscale) packing of cylindrical aggregates near the gel state as well as enhanced backbone rigidity of the constituting chains. Other distinguishing features include: (1) there is no real crossover of the dynamic moduli (G' and G'') upon increasing the temperature from gel (T = 15 °C) to solution (T = 80 °C) states. (2) The gel is about a hundredfold softer in dynamic modulus, yet more resilient with a fivefold increase in the yield strain. Both viscoelastic features are expected to greatly benefit the gel processability. (3) The coexistent microgels and cylinder (aggregate) bundles form a peculiar gel network that has not been reported previously with polymer or colloidal gels. The overall findings provide new mechanistic insight into the phenomenological effects of molecular weight for the pBTTT-Cn series in solution, sol, gel, and thin film.

Solvent Effects on Morphology and Electrical Properties of Poly(3-hexylthiophene) Electrospun Nanofibers.

Herein, poly(3-hexylthiophene-2,5-diyl) (P3HT) nanofiber-based organic field-effect transistors were successfully prepared by coaxial electrospinning technique with P3HT as the core polymer and poly(methyl methacrylate) (PMMA) as the shell polymer, followed by extraction of PMMA. Three different solvents for the core polymer, including chloroform, chlorobenzene and 1,2,4-trichlorobenzene, were employed to manipulate the morphologies and electrical properties of P3HT electrospun nanofibers. Through the analyses from dynamic light scattering of P3HT solutions, polarized photoluminescence and X-ray diffraction pattern of P3HT electrospun nanofibers, it is revealed that the P3HT electrospun nanofiber prepared from the chloroform system displays a low crystallinity but highly oriented crystalline grains due to the dominant population of isolated-chain species in solution that greatly facilitates P3HT chain stretching during electrospinning. The resulting high charge-carrier mobility of 3.57 × 10-1 cm2·V-1·s-1 and decent mechanical deformation up to a strain of 80% make the P3HT electrospun nanofiber a promising means for fabricating stretchable optoelectronic devices.

Solution properties of imidazolium-based amphiphilic polyelectrolyte in pure- and mixed-solvent media.

The solution properties of a synthesized imidazolium-based amphiphilic polyelectrolyte dissolved in pure- and mixed-solvent media composed of two aprotic polar solvents (N,N-dimethylacetamide (DMAc) and N-methyl-2-pyrrolidone (NMP)) having a similar dielectric constant are explored in the semidilute regime (1-4 wt%). Rheological characterizations reveal that the use of mixed-solvent media (e.g., DMAc/NMP with 1 : 1 in volume fraction, designated as 1 : 1 DMAc/NMP) leads to a substantial reduction in the solution viscosity while altering the fluid attribute from gel-like (G' > G'') to critical-gel-like (G' ∼ G'' ∼ ωn, with n ≅ 0.5). To gain insight into these peculiar rheological features, dynamic light scattering analysis of the representative 1 : 1 DMAc/NMP medium indicates that the fraction and mean hydrodynamic radius of the micrometer-sized cluster alter substantially, too. Multiscale static light/X-ray scattering characterizations further reveal that only the NMP and 1 : 1 DMAc/NMP media (and not the DMAc) are capable of producing hierarchical structures of the cluster interior that are beneficial to mesoscale ion conduction, as supported by ac conductivity measurements. Overall, the present findings suggest that an appropriate selection of mixed-solvent media may offer an exceptional opportunity to promote the rheological, structural, and ion-conduction properties of a polyelectrolyte solution beyond the reach of the corresponding pure-solvent media.

Percolation behaviors of model carbon black pastes.

The percolation behaviors of a series of high-structured carbon black (CB) pastes (CB weight fractions 10-25 wt%, ethyl cellulose as the binder, α-terpineol as the solvent) were systematically investigated using analyses of rheology and impedance spectra together with characterization via small-angle X-ray scattering (SAXS) and scanning electron microscopy (SEM). When the CB concentration was near the static percolation threshold (∼20 wt%), the permittivity, ac conductance, and elastic modulus of the paste displayed notable increases, whereas the SAXS profile revealed the prevalence of isolated CB aggregates (mean radius of gyration ∼40 nm). Upon further aging at 25 and 40 °C (up to 6 h), two CB pastes near the static percolation threshold (i.e., 20 and 25 wt%) exhibited prominent temporally evolving responses, including more than tenfold increases in their ac conductance and elastic modulus, as well as a pronounced upturn in the low-q SAXS profile (q < 0.03 nm-1) and the formation of a (partially) interconnected cluster network in SEM observations of the morphologies of screen-printed films. In this case, we provide the first evidence of "(aging) Time-(relaxation) Time-Temperature-Concentration Superposition (TTTCS)" for the dynamic modulus data over a frequency range of seven orders of magnitude. This suggests that prolonged aging time imparted to CB aggregate interaction and restructuring (or gelation) may work in tandem with the known effects of the system temperature and concentration to further extend the accessible range of dynamic modulus data, in a similar way to recent reports on the effect of the curing (crosslinking) time on a carbon nanotube suspension and caramel. In combination with existing (three) master curves for two different colloidal materials, we show that there is a reasonable superposition of all the dynamic modulus data over a frequency range of 12 orders of magnitude.

Scalable Wet Deposition of Zeolite AEI with a High Degree of Preferred Crystal Orientation.

Producing zeolite films with controlled preferred orientation on an industrial scale is a long-standing challenge. Herein we report on a scalable approach to the direct wet deposition of zeolite thin films and membranes while maintaining a high degree of control over the preferred crystal orientation. As a proof of concept, thin films comprising aluminophosphate zeolite AEI were cast on silicon wafer or porous alumina substrates. Electrical properties and separation performance of the zeolite thin films/membranes were engineered through controlling degree of preferred crystal orientation.

Endoplasmic Reticulum Protein TXNDC5 Augments Myocardial Fibrosis by Facilitating Extracellular Matrix Protein Folding and Redox-Sensitive Cardiac Fibroblast Activation.

RATIONALE: Cardiac fibrosis plays a critical role in the pathogenesis of heart failure. Excessive accumulation of extracellular matrix (ECM) resulting from cardiac fibrosis impairs cardiac contractile function and increases arrhythmogenicity. Current treatment options for cardiac fibrosis, however, are limited, and there is a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of better therapeutics. Exploiting coexpression gene network analysis on RNA sequencing data from failing human heart, we identified TXNDC5 (thioredoxin domain containing 5), a cardiac fibroblast (CF)-enriched endoplasmic reticulum protein, as a potential novel mediator of cardiac fibrosis, and we completed experiments to test this hypothesis directly. OBJECTIVE: The objective of this study was to determine the functional role of TXNDC5 in the pathogenesis of cardiac fibrosis. METHODS AND RESULTS: RNA sequencing and Western blot analyses revealed that TXNDC5 mRNA and protein were highly upregulated in failing human left ventricles and in hypertrophied/failing mouse left ventricle. In addition, cardiac TXNDC5 mRNA expression levels were positively correlated with those of transcripts encoding transforming growth factor ß1 and ECM proteins in vivo. TXNDC5 mRNA and protein were increased in human CF (hCF) under transforming growth factor ß1 stimulation in vitro. Knockdown of TXNDC5 attenuated transforming growth factor ß1-induced hCF activation and ECM protein upregulation independent of SMAD3 (SMAD family member 3), whereas increasing expression of TXNDC5 triggered hCF activation and proliferation and increased ECM protein production. Further experiments showed that TXNDC5, a protein disulfide isomerase, facilitated ECM protein folding and that depletion of TXNDC5 led to ECM protein misfolding and degradation in CF. In addition, TXNDC5 promotes hCF activation and proliferation by enhancing c-Jun N-terminal kinase activity via increased reactive oxygen species, derived from NAD(P)H oxidase 4. Transforming growth factor ß1-induced TXNDC5 upregulation in hCF was dependent on endoplasmic reticulum stress and activating transcription factor 6-mediated transcriptional control. Targeted disruption of Txndc5 in mice (Txndc5-/-) revealed protective effects against isoproterenol-induced cardiac hypertrophy, reduced fibrosis (by ≈70%), and markedly improved left ventricle function; post-isoproterenol left ventricular ejection fraction was 59.1±1.5 versus 40.1±2.5 (P<0.001) in Txndc5-/- versus wild-type mice, respectively. CONCLUSIONS: The endoplasmic reticulum protein TXNDC5 promotes cardiac fibrosis by facilitating ECM protein folding and CF activation via redox-sensitive c-Jun N-terminal kinase signaling. Loss of TXNDC5 protects against ß agonist-induced cardiac fibrosis and contractile dysfunction. Targeting TXNDC5, therefore, could be a powerful new therapeutic approach to mitigate excessive cardiac fibrosis, thereby improving cardiac function and outcomes in patients with heart failure.

PBTTT-C16 sol-gel transition by hierarchical colloidal bridging.

A versatile conjugated polymer, poly(2,5-bis(3-hexadecyllthiophen-2-yl)thieno[3,2-b]thiophene) (pBTTT-C16, with Mw = 61 309 g mol-1), in a relatively good solvent (chlorobenzene, CB) medium is shown to produce gels through hierarchical colloidal bridging. Multiscale static/dynamic light and X-ray scattering analysis schemes along with complementary microscopy imaging techniques clearly reveal that upon cooling from the solution state at 80 °C to various gelation temperatures (5, 10, and 15 °C), rod-like colloidal pBTTT-C16 aggregates morph into spherical ones, triggering hierarchical colloid formation and bridging that eventually turn the solution into a gel after about one-day aging. A certain fraction of primal packing units-spherical gelators (∼1 nm in mean radius)-constitute the spherical building particles (∼10 nm) noted above, which in turn constitute loose-packing aggregate clusters (∼300 nm) in the sol state. As gelation proceeds, the aggregate cluster interiors tighten substantially, and micrometer-sized clusters (∼3 µm) formed by them begin to take shape and further interconnect to form the gel network (mean porosity size ∼240 nm and spatial inhomogeneity length ∼20 µm). Rheological measurements and kinetic analysis reveal that the gelation temperature can also have a notable impact on gel microstructure, gelation rate, and mechanical strength, resulting in, for instance, a prominently nonergodic and porous structure for the soft gel incubated at a higher temperature T = 15 °C. The ac conductivity exhibits a notable upturn near pBTTT-C16/CB gelation, well above those achieved by the counterpart pBTTT-C14 solutions, which, in interesting contrast, cannot be brought to the gel phase under similar experimental conditions.