Fabrication and properties of pressure-sintered reaction-bonded Si3N4 ceramics with addition of Eu2O3–MgO–Y2O3

Dense pressure-sintered reaction-bonded Si₃N₄ (PSRBSN) ceramics were obtained by a hot-press sintering method. Precursor Si powders were prepared with Eu₂O₃–MgO–Y₂O₃ sintering additive. The addition of Eu₂O₃–MgO–Y₂O₃ was shown to promote full nitridation of the Si powder. The nitrided Si₃N₄ particles had an equiaxial morphology, without whisker formation, after the Si powders doped with Eu₂O₃–MgO–Y₂O₃ were nitrided at 1400 °C for 2 h. After hot pressing, the relative density, Vickers hardness, flexural strength, and fracture toughness of the PSRBSN ceramics, with 5 wt% Eu₂O₃ doping, were 98.3 ± 0.2%, 17.8 ± 0.8 GPa, 697.0 ± 67.0 MPa, and 7.3 ± 0.3 MPa m^1/2, respectively. The thermal conductivity was 73.6 ± 0.2 W m^?1 K^?1, significantly higher than the counterpart without Eu₂O₃ doping, or with ZrO₂ doping by conventional methods.     

BMS Derivatives C7-Linked to β-Cyclodextrin and Hyperbranched Polyglycerol Retain Activity against R5-HIV-1NLAD8 Isolates and Can Be Deemed Potential Microbicides

Amides from indole-3-glyoxylic acid and 4-benzoyl-2-methylpiperazine, which are related to entry inhibitors developed by Bristol-Myers Squibb (BMS), have been synthesized with aliphatic chains located at the C7 position of the indole ring. These spacers contain an azido group suitable for the well-known Cu(I)-catalyzed (3+2)-cycloaddition or an activated triple bond for the nucleophilic addition of thiols under physiological conditions. Reaction with polyols (β-cyclodextrin and hyperbranched polyglycerol) decorated with complementary click partners has afforded polyol-BMS-like conjugates that are not cytotoxic (TZM.bl cells) and retain the activity against R5-HIV-1_NLAD8 isolates. Thus, potential vaginal microbicides based on entry inhibitors, which can be called of 4^th generation, are reported here for the first time.     

Structure-conductivity relationship of PrBaMnMoO6-δ through in-situ measurements: A neutron diffraction study

The structural and electrochemical properties of the double perovskite-type oxide, PrBaMnMoO_6-δ, was investigated using neutron diffraction with in-situ conductivity measurement under a dry Argon atmosphere from 25 °C to 700 °C. A Rietveld refinement of the neutron diffraction data confirmed monoclinic symmetry in the P2₁/n space group. Rietveld refinement also confirms the unit cell parameters of a = 5.6567 (1) Å, b = 5.6065 (2) Å, c = 7.9344 (1) Å and β = 84.43° with reliable atomic positions and refinement factors (R-factors). Neutron diffraction data refinement shows two minor phases (<5%), an orthorhombic AB₂O₅ type phase of PrMn₂O₅ in the Pbam (No. 32) space group with unit cell parameters, a = 7.9672 (1) Å, b = 8.9043 (2) Å and c = 5.8540 (1) Å and a scheelite phase of BaMoO₄ in the tetragonal I4₁/a (88) space group with the unit cell parameters, a = b = 5.9522 (1) Å, and c = 12.3211 (2) Å. Morphological images revealed a porous and intertwined microstructure. In-situ conductivity measurement shows that the total conductivity of this material was 130.84 Scm^?1 at 700 °C.     

The Antibacterial Drug Candidate SBC3 is a Potent Inhibitor of Bacterial Thioredoxin Reductase

Antibiotic resistance is a growing problem for public health and associated with increasing economic costs and mortality rates. Silver and silver-related compounds have been used for centuries due to their antimicrobial properties. In this work, we show that 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene silver(I) acetate/NHC*-Ag-OAc (SBC3) is a reversible, high affinity inhibitor of E. coli thioredoxin reductase (TrxR; K_i=10.8±1.2 nM). Minimal inhibition concentration (MIC) tests with different E. coli and P. aeruginosa strains demonstrated that SBC3 can efficiently inhibit bacterial cell growth, especially in combination with established antibiotics like gentamicin. Our results show that SBC3 is a promising antibiotic drug candidate targeting bacterial TrxR.     

Fat Distribution and Lipid Profile of Young Adults with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Enzyme Deficiency

We aimed to compare detailed fat distribution and lipid profile between young adults with congenital adrenal hyperplasia due to 21-hydroxylase enzyme deficiency and a control group. We also verified independent associations of treatment duration and daily hydrocortisone dose equivalent (HDE) with lipid profile within patients. This case–control study included 23 patients (7 male and 16 female) matched by an age range of young adults (18–31 years) with 20 control subjects (8 male and 12 female). Dual energy X-ray absorptiometry was used to measure the fat distribution. Male patients demonstrated elevated indices of fat mass for total (7.7 ± 2.1 vs. 4.5 ± 1.3 kg/m², p = 0.003), trunk (4.0 ± 1.2 vs. 2.2 ± 0.8 kg/m², p = 0.005), android (0.63 ± 0.24 vs. 0.32 ± 0.15 kg/m², p = 0.008), gynoid (1.34 ± 0.43 vs. 0.74 ± 0.24 kg/m², p = 0.005), arm (0.65 ± 0.16 vs. 0.39 ± 0.10 kg/m², p = 0.009), and leg regions (2.7 ± 0.8 vs. 1.6 ± 0.4 kg/m², p = 0.005) than the control group, but not in females. However, female patients demonstrated elevated ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (1.90 ± 0.46 vs. 1.39 ± 0.47, p = 0.009) than the control group, but not in males. Total fat mass was inversely correlated with total testosterone (r = −0.64, p = 0.014) and positively correlated with leptin in males (r = 0.75, p = 0.002). An elevated daily HDE (β = 0.43, p = 0.038 and β = 0.47, p = 0.033) and trunk to total fat mass ratio (β = 0.46, p = 0.025, and β = 0.45, p = 0.037) were independently correlated with impaired lipid profile markers. Although there is no altered lipid profile, male patients demonstrated an increased fat distribution. However, female patients presented with an impaired lipid profile marker but demonstrated close values of normal fat distribution. Interestingly, the dose of glucocorticoid therapy can have some role in the lipid mechanisms.     

Targeted Delivery of Anesthetic Agents to Bone Tissues using Conductive Microneedles Enhanced Iontophoresis for Painless Dental Anesthesia

Pain management during dental procedures is a cornerstone for successful daily practice. In current practice, the traditional needle and syringe injection is used to administer local anesthesia. However, the appearance of long needles and the pain associated with it often leads to dental anxiety deterring timely interventions. Microneedles (MNs) have emerged as a minimally invasive alternative to hypodermic needles and shown to be effective in transdermal drug delivery applications. In this article, the potential use of MNs for local anesthesia delivery in dentistry is explored. The development of a novel conductive MN array that can be used in combination with iontophoresis technique to achieve drug penetration through the oral mucosa and the underlying bone tissue is presented. The conductive MN array plays a dual-role, creating micro-conduits and lowering the resistance of the oral mucosa. The reduced tissue resistance further enhances the application of a low-voltage current that is able to direct and accelerate the drug molecules to target the sensory nerves supplying teeth. The successful delivery of lidocaine using this new strategy in a clinically relevant rabbit incisor model is shown to be as effective as the current gold standard.     

Environmental effects on the strength and impact damage resistance of alumina based oxide/oxide ceramic matrix composites

In this study the effects of high temperature and moisture on the impact damage resistance and mechanical strength of Nextel 610/alumina silicate ceramic matrix composites were experimentally evaluated. Composite laminates were exposed to either a 1050°C isothermal furnace-based environment for 30 consecutive days at 6 h a day, or 95% relative humidity environment for 13 consecutive days at 67°C. Low velocity impact, tensile and short beam strength tests were performed on both ambient and environmentally conditioned laminates and damage was characterized using a combination of non-destructive and destructive techniques. High temperature and humidity environmental exposure adversely affected the impact resistance of the composite laminates. For all the environments, planar internal damage area was greater than the back side dent area, which in turn was greater than the impactor side dent area. Evidence of environmental embrittlement through a stiffer tensile response was noted for the high temperature exposed laminates while the short beam strength tests showed greater propensity for interlaminar shear failure in the moisture exposed laminates. Destructive evaluations exposed larger, more pronounced delaminations in the environmentally conditioned laminates in comparison to the ambient ones. External damage metrics of the impactor side dent depth and area directly influenced the post-impact tensile strength of the laminates while no such trend between internal damage area and residual strength could be ascertained.     

Rational Design of Potent Inhibitors of a Metallohydrolase Using a Fragment-Based Approach

Metallohydrolases form a large group of enzymes that have fundamental importance in a broad range of biological functions. Among them, the purple acid phosphatases (PAPs) have gained attention due to their crucial role in the acquisition and use of phosphate by plants and also as a promising target for novel treatments of bone-related disorders and cancer. To date, no crystal structure of a mammalian PAP with drug-like molecules bound near the active site is available. Herein, we used a fragment-based design approach using structures of a mammalian PAP in complex with the Maybridge^TM fragment CC063346, the amino acid L-glutamine and the buffer molecule HEPES, as well as various solvent molecules to guide the design of highly potent and efficient mammalian PAP inhibitors. These inhibitors have improved aqueous solubility when compared to the clinically most promising PAP inhibitors available to date. Furthermore, drug-like fragments bound in newly discovered binding sites mapped out additional scaffolds for further inhibitor discovery, as well as scaffolds for the design of inhibitors with novel modes of action.     

SaBRe: load-time selective binary rewriting

Binary rewriting consists in disassembling a program to modify its instructions. However, existing solutions suffer from shortcomings in terms of soundness and performance. We present SaBRe, a load-time system for selective binary rewriting. SaBRe rewrites specific constructs—particularly system calls and functions—when the program is loaded into memory, and intercepts them using plugins through a simple API. We also discuss the theoretical underpinnings of disassembling and rewriting. We developed two backends—for x86_64 and RISC-V—which were used to implement three plugins: a fast system call tracer, a multi-version executor, and a fault injector. Our evaluation shows that SaBRe imposes little overhead, typically below 3%.