Metformin Preserves β-Cell Compensation in Insulin Secretion and Mass Expansion in Prediabetic Nile Rats

Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic β-cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and β-cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on β-cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human β-cell compensation in function and mass expansion. In this study, we investigated the action of metformin on β-cells in vivo and in vitro. A 7-week metformin treatment improved glucose tolerance by reducing hepatic glucose output and enhancing insulin secretion. Although high-dose metformin inhibited β-cell glucose-stimulated insulin secretion in vitro, stimulation of β-cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, β-cells in NRs receiving metformin exhibited increased endoplasmic reticulum (ER) chaperones and alleviated apoptotic unfold protein response (UPR) without changes in the expression of cell identity genes. Additionally, metformin did not suppress β-cell mass compensation or proliferation. Taken together, despite the conflicting role indicated by in vitro studies, administration of metformin does not exert a negative effect on β-cell function or cell mass and, instead, early metformin treatment may help protect β-cells from exhaustion and decompensation.     

Real-time organic aerosol chemical speciation in the indoor environment using extractive electrospray ionization mass spectrometry

Understanding the sources and composition of organic aerosol (OA) in indoor environments requires rapid measurements, since many emissions and processes have short timescales. However, real-time molecular-level OA measurements have not been reported indoors. Here, we present quantitative measurements, at a time resolution of five seconds, of molecular ions corresponding to diverse aerosol-phase species, by applying extractive electrospray ionization mass spectrometry (EESI-MS) to indoor air analysis for the first time, as part of the highly instrumented HOMEChem field study. We demonstrate how the complex spectra of EESI-MS are screened in order to extract chemical information and investigate the possibility of interference from gas-phase semivolatile species. During experiments that simulated the Thanksgiving US holiday meal preparation, EESI-MS quantified multiple species, including fatty acids, carbohydrates, siloxanes, and phthalates. Intercomparisons with Aerosol Mass Spectrometer (AMS) and Scanning Mobility Particle Sizer suggest that EESI-MS quantified a large fraction of OA. Comparisons with FIGAERO-CIMS shows similar signal levels and good correlation, with a range of 100 for the relative sensitivities. Comparisons with SV-TAG for phthalates and with SV-TAG and AMS for total siloxanes also show strong correlation. EESI-MS observations can be used with gas-phase measurements to identify co-emitted gas- and aerosol-phase species, and this is demonstrated using complementary gas-phase PTR-MS observations.     

Investigating measurements of fine particle (PM2.5) emissions from the cooking of meals and mitigating exposure using a cooker hood

There is growing awareness that indoor exposure to particulate matter with diameter ≤ 2.5 μm (PM_2.5) is associated with an increased risk of adverse health effects. Cooking is a key indoor source of PM_2.5 and an activity conducted daily in most homes. Population scale models can predict occupant exposures to PM_2.5, but these predictions are sensitive to the emission rates used. Reported emission rates are highly variable and are typically for the cooking of single ingredients and not full meals. Accordingly, there is a need to assess PM_2.5 emissions from the cooking of complete meals. Mean PM_2.5 emission rates and source strengths were measured for four complete meals. Temporal PM_2.5 concentrations and particle size distributions were recorded using an optical particle counter (OPC), and gravimetric sampling was used to determine calibration factors. Mean emission rates and source strengths varied between 0.54—3.7 mg/min and 15—68 mg, respectively, with 95% confidence. Using a cooker hood (apparent capture efficiency > 90%) and frying in non‐stick pans were found to significantly reduce emissions. OPC calibration factors varied between 1.5 and 5.0 showing that a single value cannot be used for all meals and that gravimetric sampling is necessary when measuring PM_2.5 concentrations in kitchens.     

Mesoscale pore structure of a high-performance concrete by coupling focused ion beam/scanning electron microscopy and small angle X-ray scattering

This contribution couples (a) Small angle X-ray scattering (SAXS) experiments of a high-performance concrete (HPC) at the millimetric scale, and (b) Focused ion beam/scanning electron microscopy (FIB/SEM) of the cement paste of the HPC, with 10-20 nm voxel size. The aim is to improve the understanding of the 3D pore network of the HPC at the mesoscale (tens of nm), which is relevant for fluid transport. The mature HPC is an industrial concrete, based on pure Portland CEMI cement, and planned for use as structural elements for deep underground nuclear waste storage. Small angle X-ray scattering patterns are computed from the 3D pore images given by FIB/SEM (volumes of 61-118 μm³). They are positively correlated with SAXS measurements (volumes of 5 mm³). Aside from correlations with FIB/SEM data, experimental SAXS allows to investigate a wider range of effects on the pore structure. These are mainly the HPC drying state, the presence of aggregates (by analyzing data on cement paste alone), and the use of Poly Methyl MethAcrylate resin impregnation.     

Effectiveness of portable HEPA air cleaners on reducing indoor PM2.5 and NH3 in an agricultural cohort of children with asthma: A randomized intervention trial

We conducted a randomized trial of portable HEPA air cleaners with pre-filters designed to also reduce NH₃ in non-smoking homes of children age 6-12 with asthma in Yakima Valley (Washington, USA). Participants were recruited through the Yakima Valley Farm Workers Clinic asthma education program. All participants received education on home triggers while intervention families additionally received two HEPA cleaners (child's sleeping area, main living area). Fourteen-day integrated samples of PM_2.5 and NH₃ were measured at baseline and one-year follow-up. We fit ANCOVA models to compare follow-up concentrations in HEPA vs control homes, adjusting for baseline concentrations. Seventy-one households (36 HEPA, 35 control) completed the study. Most were single-family homes, with electric heat and stove, A/C, dogs/cats, and mean (SD) 5.3 (1.8) occupants. In the sleeping area, baseline geometric mean (GSD) PM_2.5 was 10.7 (2.3) μg/m³ (HEPA) vs 11.2 (1.9) μg/m³ (control); in the living area, it was 12.5 (2.3) μg/m³ (HEPA) vs 13.6 (1.9) μg/m³ (control). Baseline sleeping area NH₃ was 62.4 (1.6) μg/m³ (HEPA) vs 65.2 (1.8) μg/m³ (control). At follow-up, HEPA families had 60% (95% CI, 41%-72%; p < .0001) and 42% (19%-58%; p = .002) lower sleeping and living area PM_2.5, respectively, consistent with prior studies. NH₃ reductions were not observed.     

Incorporation of organic liquids into geopolymer materials - A review of processing,properties and applications

Geopolymers, composed of an amorphous three-dimensional inorganic network and synthesized by the activation of a solid alumino-silicate precursor with an alkaline activating solution, have attracted increasing attention because of their environmental benefits and favorable characteristics. This review deals with the development of organic/inorganic composite materials made by adding organic liquids into inorganic geopolymer matrices. Firstly, the incorporation processing approaches are presented and are divided into three categories: (i) Direct incorporation, (ii) Pre-emulsification (iii) Solid impregnation. Their main advantages and drawbacks are discussed in relation to the aimed properties. Secondly, this review highlights that geopolymers are low-cost candidates allowing technologically significant applications, through the incorporation of various organic liquids. Aside from the well-studied immobilization of industrial waste streams commonly known as stabilization/solidification (S/S), the development of highly porous geopolymer foams and the design of reinforced organic/inorganic composite matrices are being notably investigated. This review aims at summarizing the main published results, and fostering further investigations into innovative uses of organic liquids incorporated into geopolymers for a wide range of applications.     

Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth

Laminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that mutations may impair skeletal muscle growth. Using human muscle stem cells (MuSCs) carrying LMNA-CMD mutations, we observe impaired myogenic fusion with disorganized cadherin/β catenin adhesion complexes. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective fusion of activated MuSCs, defective protein synthesis and defective remodeling of the neuromuscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the yes-associated protein (YAP). We also observe defects in MuSC activation and YAP signaling in muscle biopsies from LMNA-CMD patients. These phenotypes are not recapitulated in closely related but less severe EDMD models. In conclusion, combining studies in vitro, in vivo, and patient samples, we find that LMNA-CMD mutations interfere with mechanosignaling pathways in skeletal muscle, implicating A-type lamins in the regulation of skeletal muscle growth.     

Numerical Evaluation of Grouting Scenarios for Reducing Water Inflows from Major Faults in Underground Excavations

Mine Water and the Environment - Water inflows through fracture networks are a major economic and safety issue in underground mines. Although pre-grouting of pilot holes during mine development...     

Rapid Synthesis and Antiproliferative Properties of Polyazamacrocycle-Based Bi- and Tetra-Gold(I) Phosphine Dithiocarbamate Complexes

A family of bi- and tetrametallic gold(I) phosphine dithiocarbamate complexes were synthesized, starting from cyclam and dimethylcyclam polyazamacrocycles, respectively, along with their monometallic gold(I) chloridophosphine precursors. Their antiproliferative properties were evaluated on two cancer cell lines (A549 and NSCLC-N6-L16). Most of the mono- and bimetallic complexes displayed strong activities and, in particular, one bimetallic derivative showed antiproliferative properties in the low micromolar range. Insights into the structure–activity relationships are given, along with determination of the thioredoxin reductase inhibition potential, two-photon imaging of the fluorescent derivatives, and evaluation of gold uptake.     

Synthesis and Application of Methyl N,O-Hydroxylamine Muramyl Peptides

The innate immune system's interaction with bacterial cells plays a pivotal role in a variety of human diseases. Carbohydrate units derived from a component of bacterial cell wall, peptidoglycan (PG), are known to stimulate an immune response. Nonetheless, access to modified late-stage peptidoglycan intermediates is limited due to their synthetic complexity. A method to rapidly functionalize PG fragments is needed to better understand the natural host–PG interactions. Here methyl N,O-hydroxylamine linkers are incorporated onto a synthetic PG derivative, muramyl dipeptide (MDP). The modification of MDP maintained the ability to stimulate a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) immune response dependent on the expression of nucleotide-binding oligomerization domain-containing protein 2 (Nod2). Intrigued by this modification's maintenance of biological activity, several applications were explored. Methyl N,O-hydroxylamine MDP was amendable to N-hydroxylsuccinimide (NHS) chemistry for bioconjugation to fluorophores as well as a self-assembled monolayer for Nod2 surface plasmon resonance analysis. Finally, linker incorporation was applicable to larger PG fragments, both enzymatically generated from Escherichia coli or chemically synthesized. This methodology provides rapid access to PG probes in one step and allows for the installation of a variety of chemical handles to advance the molecular understanding of PG and the innate immune system.