A facile strategy for the large-scale preparation of starch-based AIE luminescent nanoaggregates via host-guest interactions and their versatile applications.

Luminescent nanomaterials with outstanding optical properties have attracted growing interest due to their widespread applications. However, large-scale fabrication of luminescent nanomaterials with desired properties through a simple and economical process remains challenging. As a renewable natural resource, starch is non-toxic, easily accessible, and inexpensive, making it a popular choice for uses in various biomedical fields. In this work, we present a facile assembly strategy for the fabrication of starch-based luminescent nanoaggregates using starch as the host material and aggregation-induced emission luminogens (AIEgens) as guest molecules. By employing simple procedures under mild conditions, highly luminescent nanoparticles with small sizes, high water dispersibility, and low cytotoxicity are prepared on a large scale. The resulting nano-assemblies demonstrate significantly enhanced fluorescence intensities, reduced susceptibility to photobleaching and low cytotoxicity. These fluorescent supramolecular aggregates can be employed in various application fields, including the fabrication of fluorescent hydrogels, fingerprint detection, cell imaging and in vivo lymphatic system imaging. The methodology developed in this work has immense potential to greatly promote the production of high-quality nanoparticles on the industrial scale, offering a cost-effective solution that can meet the needs of various applications and pave the way for wider implementation of nanotechnology.

An AIE-active bacterial inhibitor and photosensitizer for selective imaging, killing, and photodynamic inactivation of bacteria over mammalian cells.

Photodynamic therapy is becoming increasingly popular for combat of bacteria. In the clinical photodynamic combat of bacteria, one critical issue is to avoid the potential damage to the host since the reactive oxygen species produced by photosensitizers are also harmful to mammalian cells. In this work, we report an aggregation-induced-emission-active bacterial inhibitor and photosensitizer, OEO-TPE-MEM (OTM), for the imaging, killing, and light-enhanced inactivation of bacteria. OTM could efficiently bind to and kill Gram-positive bacteria, while its affinity to Gram-negative bacteria is lower, and a higher OTM concentration is required for killing Gram-negative bacteria. OTM is also an efficient photosensitizer and could efficiently sensitize the production of reactive oxygen species, which enhances its killing effect on both Gram-positive and Gram-negative bacteria. More interestingly, OTM is very biocompatible with normal mammalian cells both in the dark and under light irradiation. OTM in mice models with bacteria-infected wounds could promote the healing of infected wounds without affecting their organs and blood parameters, which makes it an excellent candidate for clinical applications.

A dual organelle-targeting mechanosensitive probe.

Cells are responsive to the mechanical environment, but the methods to detect simultaneously how different organelles react in mechanobiological processes remain largely unexplored. We herein report a dual organelle-targeting fluorescent probe, (E)-1-[3-(diethoxyphosphoryl)propyl]-4-[4-(diethylamino)styryl]pyridin-1-ium bromide (ASP-PE), for mechanical mapping in live cells. ASP-PE is aggregation-induced emission active and is sensitive to the local mechanical environment. It targets the plasma membrane (PM) and intracellular mitochondria in cells by its phosphonate moiety and pyridinium. In this work, through ASP-PE staining, changes of membrane tension in the PM and mitochondria in response to varied osmotic pressure and substrate stiffness are visualized using fluorescence lifetime imaging microscopy. The mechanobiological importance of actin filaments and microtubules in the PM and mitochondria is also investigated using this probe. Computational simulations are applied to study the sensing mechanism of the probe. This study introduces a unique tool for mapping the membrane tension in the PM and mitochondria together, providing us great opportunities to study organelle's interactions in mechanobiology.

A new multivariate t distribution with variant tail weights and its application in robust regression analysis.

In this paper, we propose a new kind of multivariate t distribution by allowing different degrees of freedom for each univariate component. Compared with the classical multivariate t distribution, it is more flexible in the model specification that can be used to deal with the variant amounts of tail weights on marginals in multivariate data modeling. In particular, it could include components following the multivariate normal distribution, and it contains the product of independent t-distributions as a special case. Subsequently, it is extended to the regression model as the joint distribution of the error terms. Important distributional properties are explored and useful statistical methods are developed. The flexibility of the specified structure in better capturing the characteristic of data is exemplified by both simulation studies and real data analyses.

Non-infective left ventricular lead complications requiring re-intervention following cardiac resynchronization therapy: prevalence, causes and outcomes.

PURPOSE: Left ventricular (LV) lead complications in cardiac resynchronization therapy are challenging and poorly reported. We aimed to establish prevalence, causes and outcomes of LV lead complications requiring re-intervention. METHODS: We analysed the rate of complications in 2551 consecutive patients who received a transvenous de novo LV lead as part of a cardiac resynchronization therapy device between 2000 and 2018. LV lead complications requiring re-intervention were identified; those due to infection were excluded. Patient, procedural and device characteristics, and outcomes were examined for non-infective LV lead complications requiring re-intervention. RESULTS: During a median of 4.7 years, 142 (5.6%) patients required re-intervention for non-infective LV lead complications with a decrease from 10.7% between 2000 and 2004, 8.7% between 2005 and 2009, 3.2% between 2010 and 2014 to 3.2% after 2014. The most common complications were LV lead displacement (50%), high pacing threshold (28%) and phrenic nerve stimulation (15%). Of the complications, 79 (56%) occurred within 90 days post-implant and 63 (44%) later. At the end of the study period, 132/142 patients (93%) had a functional LV lead. Lead re-intervention was associated with higher risk of complications (20%), but no increase in mortality (P = 0.19). Quadripolar leads had longer longevity and lower risk of complications compared with unipolar and bipolar LV leads. CONCLUSIONS: A small but significant proportion of patients required LV lead re-intervention for complications following de novo implant. Lead displacement accounted for half of the re-interventions. Re-intervention was associated with a higher complication rate, but 92% of these patients had functional LV leads at the end of follow-up.

Primary care heart failure service identifies a missed cohort of heart failure patients with reduced ejection fraction.

AIMS: We explored whether a missed cohort of patients in the community with heart failure (HF) and left ventricular systolic dysfunction (LVSD) could be identified and receive treatment optimization through a primary care heart failure (PCHF) service. METHODS AND RESULTS: PCHF is a partnership between Inspira Health, National Health Service Cardiologists and Medtronic. The PCHF service uses retrospective clinical audit to identify patients requiring a prospective face-to-face consultation with a consultant cardiologist for clinical review of their HF management within primary care. The service is delivered via five phases: (i) system interrogation of general practitioner (GP) systems; (ii) clinical audit of medical records; (iii) patient invitation; (iv) consultant reviews; and (v) follow-up. A total of 78 GP practices (864 194 population) have participated. In total, 19 393 patients' records were audited. HF register was 9668 (prevalence 1.1%) with 6162 patients coded with LVSD (prevalence 0.7%). HF case finder identified 9725 additional patients to be audited of whom 2916 patients required LVSD codes adding to the patient medical record (47% increase in LVSD). Prevalence of HF with LVSD increased from 0.7% to 1.05%. A total of 662 patients were invited for consultant cardiologist review at their local GP practice. The service found that within primary care, 27% of HF patients identified for a cardiologist consultation were eligible for complex device therapy, 45% required medicines optimization, and 47% of patients audited required diagnosis codes adding to their GP record. CONCLUSION: A PCHF service can identify a missed cohort of patients with HF and LVSD, enabling the optimization of prognostic medication and an increase in device prescription.

A near-infrared AIE fluorescent probe for myelin imaging: From sciatic nerve to the optically cleared brain tissue in 3D.

Myelin, the structure that surrounds and insulates neuronal axons, is an important component of the central nervous system. The visualization of the myelinated fibers in brain tissues can largely facilitate the diagnosis of myelin-related diseases and understand how the brain functions. However, the most widely used fluorescent probes for myelin visualization, such as Vybrant DiD and FluoroMyelin, have strong background staining, low-staining contrast, and low brightness. These drawbacks may originate from their self-quenching properties and greatly limit their applications in three-dimensional (3D) imaging and myelin tracing. Chemical probes for the fluorescence imaging of myelin in 3D, especially in optically cleared tissue, are highly desirable but rarely reported. We herein developed a near-infrared aggregation-induced emission (AIE)-active probe, PM-ML, for high-performance myelin imaging. PM-ML is plasma membrane targeting with good photostability. It could specifically label myelinated fibers in teased sciatic nerves and mouse brain tissues with a high-signal-to-background ratio. PM-ML could be used for 3D visualization of myelin sheaths, myelinated fibers, and fascicles with high-penetration depth. The staining is compatible with different brain tissue-clearing methods, such as ClearT and ClearT2 The utility of PM-ML staining in demyelinating disease studies was demonstrated using the mouse model of multiple sclerosis. Together, this work provides an important tool for high-quality myelin visualization across scales, which may greatly contribute to the study of myelin-related diseases.

Evolution of Microstructure, Texture and Mechanical Properties for Multilayered Al Matrix Composites by Accumulative Roll Bonding.

Carbon nanotubes (CNTs) reinforced aluminum matrix nanocomposites were fabricated by Accumulative Roll Bonding (ARB). The surface morphologies, mechanical properties, grains texture and orientation of the Al/CNTs nanocomposites were characterized, and the mechanisms and influences of CNTs contents and ARB cycles on the mechanical performance and grain textures of Al/CNTs were investigated and revealed. The strength of the composites rose with increase of the CNTs content, and the ARB cycles showed a 26% improvement when the CNTs content varied from 0 to 1 volume percent (vol.%). The increase in the mass fraction of the carbon nanotubes made the grain distribution in the Al/CNTs nanocomposite samples more diffuse. Besides, the stable texture of the hot rolled crystal grains on the α orientation are constantly turning to {011}< 011> with the mass fraction of the reinforcing phase increased.

Fluorescence Imaging and Photodynamic Inactivation of Bacteria Based on Cationic Cyclometalated Iridium(III) Complexes with Aggregation-Induced Emission Properties.

Antibacterial photodynamic therapy (PDT) is one of the emerging methods for curbing multidrug-resistant bacterial infections. Effective fluorescent photosensitizers with dual functions of bacteria imaging and PDT applications are highly desirable. In this study, three cationic and heteroleptic cyclometalated Ir(III) complexes with the formula of [Ir(CˆN)2 (NˆN)][PF6 ] are prepared and characterized. These Ir(III) complexes named Ir(ppy)2 bP, Ir(1-pq)2 bP, and Ir(2-pq)2 bP are comprised of three CˆN ligands (i.e., 2-phenylpyridine (ppy), 1-phenylisoquinoline (1-pq), and 2-phenylquinoline (2-pq)) and one NˆN bidentate co-ligand (bP). The photophysical characterizations demonstrate that these Ir(III) complexes are red-emitting, aggregation-induced emission active luminogens. The substitution of phenylpyridine with phenylquinoline isomers in the molecules greatly enhances their UV and visible-light absorbance as well as the photoinduced reactive oxygen species (ROS) generation ability. All three Ir(III) complexes can stain both Gram-positive and Gram-negative bacteria efficiently. Interestingly, even though Ir(1-pq)2 bP and Ir(2-pq)2 bP are constitutional isomers with very similar structures and similar ROS generation ability in buffer, the former eradicates bacteria much more effectively than the other through white light-irradiated photodynamic inactivation. This work will provide valuable information on the rational design of Ir(III) complexes for fluorescence imaging and efficient photodynamic inactivation of bacteria.

The Association Between Coffee Consumption and Metabolic Syndrome in Adults: A Systematic Review and Meta-Analysis.

Previous meta-analyses that found an inverse association between coffee consumption and metabolic syndrome pooled data from cross-sectional and longitudinal studies, which could lead to potentially misleading conclusions. Hence, this work aimed to reassess this association by analyzing data from the 2 types of studies separately and including recent studies. Online databases including PubMed, Scopus, Embase, The Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, and Science Direct were searched for relevant studies published up to July 2020. Both cross-sectional and longitudinal studies were included if published after 1999, reported both effect estimates and CIs, and presented results adjusted for confounding variables. Data of the highest coffee consumption level in each study, as well as those of medium consumption levels in studies with ≥3 consumption categories, were pooled using random-effect models, with sex-stratified and sex-adjusted results being analyzed separately. Results were obtained based on data from 13 cross-sectional studies involving 280,803 participants and 2 longitudinal studies involving 17,014 participants. The overall sex-adjusted association of the highest consumption level was not significant (n = 9 studies; OR: 0.88; 95% CI: 0.70, 1.10; I2: 91.5%) and the 2 longitudinal studies both yielded no association. Subgroup analysis revealed inverse associations in both males and females, as well as in Caucasians with medium coffee consumption (n = 4 studies, OR: 0.88; 95% CI: 0.84, 0.93; I2: 0%). Although residual confounding could affect the results of this meta-analysis, our findings suggested with a low certainty that coffee consumption may not be associated with metabolic syndrome, a finding that is different from those of previous meta-analyses and could be due to variation in characteristics of study participants. More longitudinal studies are also needed to further assess the temporal association between coffee consumption and metabolic syndrome. This meta-analysis was registered at https://www.crd.york.ac.uk/prospero as CRD42018110650.

A simple yet effective AIE-based fluorescent nano-thermometer for temperature mapping in living cells using fluorescence lifetime imaging microscopy.

We designed and synthesized a novel nano-thermometer using aggregation-induced-emission (AIE) dye as the reporter and household butter as the matrix. This temperature nanosensor showed decreased fluorescence intensities (∼2%/°C) and shorter fluorescence lifetimes (∼0.11 ns/°C) upon increasing the environmental temperature in the physiological temperature range. Such fluorescence responses were reversible and independent of the environmental pH and ionic strength. The application of these nano-thermometers in temperature sensing in living cells using fluorescence lifetime imaging microscopy (FLIM) was also demonstrated. To the best of our knowledge, this is the first example of AIE-based nano-thermometer for temperature sensing in living cells. This work also provides us with a simple and low-cost method for rapid fabrication of an effective nanosensor based on AIE mechanism.

A Small-Molecule AIE Chromosome Periphery Probe for Cytogenetic Studies.

The chromosome periphery (CP) is a complex network that covers the outer surface of chromosomes. It acts as a carrier of nucleolar components, helps maintain chromosome structure, and plays an important role in mitosis. Current methods for fluorescence imaging of CP largely rely on immunostaining. We herein report a small-molecule fluorescent probe, ID-IQ, which possesses aggregation-induced emission (AIE) property, for CP imaging. By labelling the CP, ID-IQ sharply highlighted the chromosome boundaries, which enabled rapid segmentation of touching and overlapping chromosomes, direct identification of the centromere, and clear visualization of chromosome morphology. ID-IQ staining was also compatible with fluorescence in situ hybridization and could assist the precise location of the gene in designated chromosome. Altogether, this study provides a versatile cytogenetic tool for improved chromosome analysis, which greatly benefits the clinical diagnostic testing and genomic research.

Ultrafast labeling and high-fidelity imaging of mitochondria in cancer cells using an aggregation-enhanced emission fluorescent probe.

An aggregation-enhanced emission mitochondrial probe, LIQ-3, was developed for ultrafast labeling within one minute and for distinguishing cancer cells from normal cells. Furthermore, the probe revealed high-fidelity tracking of mitochondria in a three-dimensional localization with advantages that include a specific targeting capacity and a high signal-to-noise ratio.

A new multivariate zero-adjusted Poisson model with applications to biomedicine.

Recently, although advances were made on modeling multivariate count data, existing models really has several limitations: (i) The multivariate Poisson log-normal model (Aitchison and Ho, 1989) cannot be used to fit multivariate count data with excess zero-vectors; (ii) The multivariate zero-inflated Poisson (ZIP) distribution (Li et al., 1999) cannot be used to model zero-truncated/deflated count data and it is difficult to apply to high-dimensional cases; (iii) The Type I multivariate zero-adjusted Poisson (ZAP) distribution (Tian et al., 2017) could only model multivariate count data with a special correlation structure for random components that are all positive or negative. In this paper, we first introduce a new multivariate ZAP distribution, based on a multivariate Poisson distribution, which allows the correlations between components with a more flexible dependency structure, that is some of the correlation coefficients could be positive while others could be negative. We then develop its important distributional properties, and provide efficient statistical inference methods for multivariate ZAP model with or without covariates. Two real data examples in biomedicine are used to illustrate the proposed methods.

Experimental warming and antecedent fire alter leaf element composition and increase soil C:N ratio in sub-alpine open heathland.

Plant communities in alpine ecosystems worldwide are being altered by climate warming. In the alpine open heathland of the Bogong High Plains, Australia, warming and fire have affected the growth and phenology of plants, and have recently been found to alter soil nutrient availability. We examined the effects of nine years of passive warming by open-top chambers and nine years post-fire on (i) the soluble and extractable nutrients and toxic elements available for plant uptake in the soil and (ii) on the element composition of leaves of seven dominant sub-alpine open heathland plants. Warming increased soil C, soil C:N, and decreased soil δ13C, indicating an accumulation of soil organic matter and C sequestration. Warming increased soil δ15N, indicating increased N mineralization, which concurred with the increased availability of NH4+ (measured by ion-exchange membranes). Leaf element composition varied among the plant species in response to changes in soil element availabilities, suggesting the importance of species-specific knowledge. Warming decreased leaf N concentration and increased leaf C:N, generally in the plant community, and specifically in Asterolasia trymalioides, Carex breviculmis, Poa hiemata, and Rytidosperma nudiflorum. Warming increased soil P availability, but did not significantly affect leaf P in any species. Antecedent fire increased soil C:N, and decreased concentrations of Ca and Mg in Celmisia pugioniformis more than in the other species. The results suggest that warming and fire changed the nutrient composition of plants and increased soil C:N, which might lead to progressive N limitation in the alpine ecosystem.

Convexity of Ruin Probability and Optimal Dividend Strategies for a General Lévy Process.

We consider the optimal dividends problem for a company whose cash reserves follow a general Lévy process with certain positive jumps and arbitrary negative jumps. The objective is to find a policy which maximizes the expected discounted dividends until the time of ruin. Under appropriate conditions, we use some recent results in the theory of potential analysis of subordinators to obtain the convexity properties of probability of ruin. We present conditions under which the optimal dividend strategy, among all admissible ones, takes the form of a barrier strategy.

PICK1 mediates synaptic recruitment of AMPA receptors at neurexin-induced postsynaptic sites.

In the CNS, synapse formation and maturation play crucial roles in the construction and consolidation of neuronal circuits. Neurexin and neuroligin localize on the opposite sides of synaptic membrane and interact with each other to promote the assembly and specialization of synapses. However, the excitatory synapses induced by the neurexin-neuroligin complex are initially immature synapses that lack AMPA receptors. Previously, PICK1 (protein interacting with C kinase 1) was shown to cluster and regulate the synaptic localization of AMPA receptors. Here, we report that during synaptogenesis induced by neurexin in cultured neurons from rat hippocampus, PICK1 recruited AMPA receptors to immature postsynaptic sites. This synaptic recruitment of AMPA receptors depended on the interaction between GluA2 and PICK1, and on the lipid-binding ability of PICK1, but not the interaction between PICK1 and neuroligin. Last, our results demonstrated that the recruitment of GluA2 to synapses could be prevented by ICA69 (islet cell autoantigen 69 kDa), a key binding partner of PICK1. Our study showed that PICK1, being negatively regulated by ICA69, could facilitate synapse maturation.

An electronic environment and contact direction sensitive scoring function for predicting affinities of protein-ligand complexes in Contour(®).

Contour(®) is a computational structure-based drug design technology that grows drug-like molecules by assembling context sensitive fragments in well-defined binding pockets. The grown molecules are scored by a novel empirical scoring function developed using high-resolution crystal structures of diverse classes of protein-ligand complexes and associated experimental binding affinities. An atomic model bearing features of the valence bond and VSEPR theories embodying their molecular electronic environment has been developed for non-covalent intermolecular interactions. On the basis of atomic hybridization and polarization states, each atom is modeled by features representing electron lone pairs, p-orbitals, and polar and non-polar hydrogens. A simple formal charge model was used to differentiate between polar and non-polar atoms. The interaction energy and the desolvation contribution of the protein-ligand association energy is computed as a linear sum of pair-wise interactions and desolvation terms. The pair-wise interaction energy captures short-range positive electrostatic interactions via hydrogen bonds, electrostatic repulsion of like charges, and non-bond contacts. The desolvation energy is estimated by calculating the energy required to desolvate interaction surfaces of the protein and the ligand in the complex. The scoring function predicts binding energies of a diverse set of protein-ligand complexes used for training with a correlation coefficient of 0.61. It also performs equally well in predicting association energies of a diverse validation set of protein-ligand complexes with a correlation coefficient of 0.57, which is equivalent to or better than 12 other scoring functions tested against this set including X-Score, GOLD, and DrugScore.

Syncope in paced patients with sick sinus syndrome from the DANPACE trial: incidence, predictors and prognostic implication.

OBJECTIVES: Syncope is a cause of significant morbidity in sick sinus syndrome (SSS) which may not be resolved with permanent pacemaker therapy. We aimed to determine the incidence, predictors and prognostic implication of syncope in paced patients with SSS. METHODS: We studied 1415 patients (mean age 72.9 years, SD 11.1) with SSS who were randomised in the DANPACE study to either rate-responsive single chamber pacing (n=707) or rate-responsive dual chamber pacing (n=708). Main outcome measures were patient-reported syncope after pacemaker implantation and mortality. RESULTS: Mean follow-up was 5.4 years (SD 2.6). A total of 247 (17.5%) patients experienced syncope after pacemaker implantation (135 (19%) from the rate-responsive single chamber pacing group, and 112 (15.8%) from the rate-responsive dual chamber pacing group. Predictors of syncope post pacemaker implantation included: age 0-39 years (HR 2.9, 95% CI 1.4 to 6.3, p=0.01; reference range 60-79 years), age ≥80 years (HR 1.4, 95% CI 1.0 to 1.8, p=0.03), syncope prior to pacemaker implant (HR 1.8, 95% CI 1.4 to 2.3, p<0.001), previous myocardial infarction (HR 1.5, 95% CI 1.1 to 2.1, p=0.03), heart failure (HR 1.4, 95% CI 1.0 to 1.9, p=0.046), and high Charlson comorbidity index (HR 1.6, 95% CI 1.1 to 2.2, p=0.01). Patients who experienced syncope post pacemaker implant had higher mortality compared with patients who did not (adjusted HR 1.6, 95% CI 1.3 to 2.1, p<0.001). CONCLUSIONS: Syncope in paced patients with SSS is common, and is associated with higher mortality. The predictors identified in this study suggest a multifactorial aetiology of syncope.

PICK1 and ICA69 control insulin granule trafficking and their deficiencies lead to impaired glucose tolerance.

Diabetes is a metabolic disorder characterized by hyperglycemia. Insulin, which is secreted by pancreatic beta cells, is recognized as the critical regulator of blood glucose, but the molecular machinery responsible for insulin trafficking remains poorly defined. In particular, the roles of cytosolic factors that govern the formation and maturation of insulin granules are unclear. Here we report that PICK1 and ICA69, two cytosolic lipid-binding proteins, formed heteromeric BAR-domain complexes that associated with insulin granules at different stages of their maturation. PICK1-ICA69 heteromeric complexes associated with immature secretory granules near the trans-Golgi network (TGN). A brief treatment of Brefeldin A, which blocks vesicle budding from the Golgi, increased the amount of PICK1 and ICA69 at TGN. On the other hand, mature secretory granules were associated with PICK1 only, not ICA69. PICK1 deficiency in mice caused the complete loss of ICA69 and led to increased food and water intake but lower body weight. Glucose tolerance tests demonstrated that these mutant mice had high blood glucose, a consequence of insufficient insulin. Importantly, while the total insulin level was reduced in PICK1-deficient beta cells, proinsulin was increased. Lastly, ICA69 knockout mice also displayed similar phenotype as the mice deficient in PICK1. Together, our results indicate that PICK1 and ICA69 are key regulators of the formation and maturation of insulin granules.