Programmable liquid crystal display based noise reduced dynamic synthetic coded aperture imaging camera (NoRDS-CAIC).

Besides traditional lens-based imaging techniques, coded aperture imaging (CAI) can also provide target images but without using any optical lenses, therefore it is another solution in imaging applications. Most CAI methods reconstruct target image only from a single-shot coded image using a fixed coding mask; however, the collected partial information inevitably deteriorates the reconstruction quality. Though multi-exposure CAI methods are designed, these existed algorithms can hardly improve reconstruction signal-to-noise ratio (SNR) and spatial resolution simultaneously; additionally, dynamic coding mask display still requires expensive devices and complicated systems. In order to reconstruct target image with both enhanced spatial resolution and SNR but using cost-effective devices and a simple system, we design a noise reduced dynamic synthetic coded aperture imaging camera (NoRDS-CAIC) in this paper. The NoRDS-CAIC only consists of a programmable liquid crystal display (LCD) and an image recorder, and both of them are integrated with a three-dimensional printed shell with the compact size of 19 cm × 15 cm × 16 cm and controlled by our designed software to automatically realize coding mask display, coded image recording and target image reconstruction. When using the NoRDS-CAIC, the optimized coding mask is first sent to the programmable LCD and displayed, then the corresponding coded image is automatically captured using the image recorder. Next, cycle the above procedures to capture enough coded images with previously known coding masks and measured point spread functions (PSFs), and the target image can be finally reconstructed using our designed NoRDS-CAIC decoding algorithm, which is shown with better noise suppression capability and higher reconstruction resolution compared to other classical CAI algorithms. According to the experimental verifications, the NoRDS-CAIC can reach the high resolution of 99.2 µm and the high SNR of 19.43 dB, proving that the designed NoRDS-CAIC can be potentially used for lensless imaging in practical applications.

Serendipitous discovery of aryl boronic acids as ß-lactamase inhibitors.

High throughput screening for ß-lactamase inhibitors afforded biphenyl hits such as 1. Hit confirmation and X-ray soaking experiments with Pseudomonas Aeruginosa AmpC enzyme led to the identification of an aryl boronic acid-serine complex 4, which was formed from phenyl boronic acid 8 (an impurity in compound 1) and ethylene glycol (the cryoprotectant in the soaking experiment).

Discovery of potent wall teichoic acid early stage inhibitors.

The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current ß-lactam antibiotics and created an urgent need for novel treatment options. Using an S. aureus phenotypic screening strategy, we have identified small molecule early stage wall teichoic acid (WTA) pathway-specific inhibitors predicted to be chemically synergistic with ß-lactams. These previously disclosed inhibitors, termed tarocins, demonstrate by genetic and biochemical means inhibition of TarO, the first step in WTA biosynthesis. Tarocins demonstrate potent bactericidal synergy in combination with broad spectrum ß-lactam antibiotics across diverse clinical isolates of methicillin-resistant Staphylococci. The synthesis and structure-activity relationships (SAR) of a tarocin series will be detailed. Tarocins and other WTA inhibitors may provide a rational strategy to develop Gram-positive bactericidal ß-lactam combination agents active against methicillin-resistant Staphylococci.

Benzimidazole analogs as WTA biosynthesis inhibitors targeting methicillin resistant Staphylococcus aureus.

A series of benzimidazole analogs have been synthesized to improve the profile of the previous lead compounds tarocin B and 1. The syntheses, structure-activity relationships, and selected biochemical data of these analogs are described. The optimization efforts allowed the identification of 21, a fluoro-substituted benzimidazole, exhibiting potent TarO inhibitory activity and typical profile for a wall teichoic acid (WTA) biosynthesis inhibitor. Compound 21 displayed a potent synergistic and bactericidal effect in combination with imipenem against diverse methicillin-resistant Staphylococci.

Bioavailable pyrrolo-benzo-1,4-diazines as Na(v)1.7 sodium channel blockers for the treatment of pain.

A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 µM.

Discovery of pyrrolo-benzo-1,4-diazines as potent Na(v)1.7 sodium channel blockers.

A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.

Prevention and treatment of antibiotics-associated adverse effects through the use of probiotics: A review.

BACKGROUND: The human gut hosts a diverse microbial community, essential for maintaining overall health. However, antibiotics, commonly prescribed for infections, can disrupt this delicate balance, leading to antibiotic-associated diarrhea, inflammatory bowel disease, obesity, and even neurological disorders. Recognizing this, probiotics have emerged as a promising strategy to counteract these adverse effects. AIM OF REVIEW: This review aims to offer a comprehensive overview of the latest evidence concerning the utilization of probiotics in managing antibiotic-associated side effects. KEY SCIENTIFIC CONCEPTS OF REVIEW: Probiotics play a crucial role in preserving gut homeostasis, regulating intestinal function and metabolism, and modulating the host immune system. These mechanisms serve to effectively alleviate antibiotic-associated adverse effects and enhance overall well-being.

Human Breast Milk: The Role of Its Microbiota and Metabolites in Infant Health.

This review explores the role of microorganisms and metabolites in human breast milk and their impact on neonatal health. Breast milk serves as both a primary source of nutrition for newborns and contributes to the development and maturation of the digestive, immunological, and neurological systems. It has the potential to reduce the risks of infections, allergies, and asthma. As our understanding of the properties of human milk advances, there is growing interest in incorporating its benefits into personalized infant nutrition strategies, particularly in situations in which breastfeeding is not an option. Future infant formula products are expected to emulate the composition and advantages of human milk, aligning with an evolving understanding of infant nutrition. The long-term health implications of human milk are still under investigation.

General requirements for the production of extracellular vesicles derived from human stem cells.

'General requirements for the production of extracellular vesicles derived from human stem cells' is the first guideline for stem cells derived extracellular vesicles in China, jointly drafted and agreed upon by experts from the Chinese Society for Stem Cell Research. This standard specifies the general requirements, process requirements, packaging and labelling requirements and storage requirements for preparing extracellular vesicles derived from human stem cells, which is applicable to the research and production of extracellular vesicles derived from stem cells. It was originally released by the China Society for Cell Biology on 30 August 2022. We hope that the publication of this guideline will promote institutional establishment, acceptance and execution of proper protocols, and accelerate the international standardisation of extracellular vesicles derived from human stem cells.

Structure Guided Discovery of Novel Pan Metallo-ß-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration.

The use of ß-lactam (BL) and ß-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-ß-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates.

Molecular characterizations of genes in chloroplast genomes of the genus Arachis L. (Fabaceae) based on the codon usage divergence.

Studies on the molecular characteristics of chloroplast genome are generally important for clarifying the evolutionary processes of plant species. The base composition, the effective number of codons, the relative synonymous codon usage, the codon bias index, and their correlation coefficients of a total of 41 genes in 21 chloroplast genomes of the genus Arachis were investigated to further perform the correspondence and clustering analyses, revealing significantly higher variations in genomes of wild species than those of the cultivated taxa. The codon usage patterns of all 41 genes in the genus Arachis were AT-rich, suggesting that the natural selection was the main factor affecting the evolutionary history of these genomes. Five genes (i.e., ndhC, petD, atpF, rpl14, and rps11) and five genes (i.e., atpE, psbD, psaB, ycf2, and rps12) showed higher and lower base usage divergences, respectively. This study provided novel insights into our understanding of the molecular evolution of chloroplast genomes in the genus Arachis.

A portable Raspberry Pi-based spectrometer for on-site spectral testing.

We designed a portable Raspberry Pi-based spectrometer, which mainly consists of a white LED acting as the wide-spectrum source, a reflection grating for light dispersion, and a CMOS imaging chip aiming at spectral recording. All the optical elements and Raspberry Pi were integrated using 3-D printing structures with a size of 118 mm × 92 mm × 84 mm, and home-built software was also designed for spectral recording, calibration, analysis, and display implemented with a touch LCD. Additionally, the portable Raspberry Pi-based spectrometer was equipped with an internal battery, thus supporting on-site applications. Tested by a series of verifications and applications, the portable Raspberry Pi-based spectrometer could reach a spectral resolution of 0.065 nm per pixel within the visible band and provide spectral detection with high accuracy. Therefore, it can be used for on-site spectral testing in various fields.

Ezetimibe inhibits triple-negative breast cancer proliferation and promotes cell cycle arrest by targeting the PDGFR/AKT pathway.

Cholesterol levels were strongly associated with tumor progression and metastasis. Targeted cholesterol metabolism has broad prospects in tumor treatment. Ezetimibe, the only FDA-approved inhibitor of cholesterol absorption, has been reported to be able to inhibit angiogenesis in liver cancer. However, the efficacy and specific mechanisms of Ezetimibe in the treatment of Triple-Negative Breast Cancer (TNBC)have not been reported. Our research shows Ezetimibe inhibits TNBC cell proliferation and blocks the cell cycle in the G1 phase. Mechanistically, Ezetimibe inhibits the activation of PDGFRß/AKT pathway, thereby promoting cell cycle arrest and inhibiting cell proliferation. By overexpressing PDGFRß in TNBC cells, we found that PDGFRß significantly reduced the inhibitory effect of Ezetimibe on TNBC cell proliferation and the cell cycle. Similarly, SC79, an AKT agonist, can reduce the proliferation inhibitory and cycle-blocking effects of Ezetimibe on TNBC cells. Furthermore, the AKT inhibitor MK2206 enhanced the inhibitory effect of Ezetimibe on the cell cycle and proliferation ability of TNBC cells overexpressing PDGFRß. In xenograft tumor models, we also found that Ezetimibe inhibited TNBC growth, an effect that can be blocked by overexpression of PDGFR or activation of AKT. In summary, we have demonstrated that EZ inhibits the PDGFR/AKT pathway, thereby halting TNBC cycle progression and tumor growth.

Pyrazoloquinolines as PDE10A inhibitors: discovery of a tool compound.

A series of pyrazoloquinolines, possessing (hetero)arylhydroxymethyl substituents at the quinoline C-4 position were evaluated as PDE10A inhibitors. Among these, methylpyrimidyl analogue 15 was identified as having good rodent and monkey exposure, and a MED of 10 mg/kg in an in vivo model.

Discovery of orally active pyrazoloquinolines as potent PDE10 inhibitors for the management of schizophrenia.

A series of pyrazoloquinoline analogs have been synthesized and shown to bind to PDE10 with high affinity. From the SAR study and our lead optimization efforts, compounds 16 and 27 were found to possess potent oral antipsychotic activity in the MK-801 induced hyperactive rat model.

The discovery of potent, selective, and orally active pyrazoloquinolines as PDE10A inhibitors for the treatment of Schizophrenia.

High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a ∼6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.

Molecular elimination of Br2 in photodissociation of CH2BrC(O)Br at 248 nm using cavity ring-down absorption spectroscopy.

The primary elimination channel of bromine molecule in one-photon dissociation of CH(2)BrC(O)Br at 248 nm is investigated using cavity ring-down absorption spectroscopy. By means of spectral simulation, the ratio of nascent vibrational population in v = 0, 1, and 2 levels is evaluated to be 1:(0.5 ± 0.1):(0.2 ± 0.1), corresponding to a Boltzmann vibrational temperature of 581 ± 45 K. The quantum yield of the ground state Br(2) elimination reaction is determined to be 0.24 ± 0.08. With the aid of ab initio potential energy calculations, the obtained Br(2) fragments are anticipated to dissociate on the electronic ground state, yielding vibrationally hot Br(2) products. The temperature-dependence measurements support the proposed pathway via internal conversion. For comparison, the Br(2) yields are obtained analogously from CH(3)CHBrC(O)Br and (CH(3))(2)CBrC(O)Br to be 0.03 and 0.06, respectively. The trend of Br(2) yields among the three compounds is consistent with the branching ratio evaluation by Rice-Ramsperger-Kassel-Marcus method. However, the latter result for each molecule is smaller by an order of magnitude than the yield findings. A non-statistical pathway so-called roaming process might be an alternative to the Br(2) production, and its contribution might account for the underestimate of the branching ratio calculations.

Rapid Evolution of a Fragment-like Molecule to Pan-Metallo-Beta-Lactamase Inhibitors: Initial Leads toward Clinical Candidates.

With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.

Structure-activity relationships of 2,4-diphenyl-1H-imidazole analogs as CB2 receptor agonists for the treatment of chronic pain.

A series of 2,4-diphenyl-1H-imidazole analogs have been synthesized and displayed potent human CB2 agonist activity. Many of these analogs showed high functional selectivity over human CB1 receptors. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described.

Microwave Sintering and Microwave Dielectric Properties of (1-x)Ca0.61La0.26TiO3-xNd(Mg0.5Ti0.5)O3 Ceramics.

The (1-x)Ca0.61La0.26TiO3-xNd(Mg0.5Ti0.5)O3 [(1-x)CLT-xNMT, x = 0.35~0.60] ceramics were prepared via microwave sintering. The effects of sintering temperature and composition on the phase formation, microstructure, and microwave dielectric properties were investigated. The results show that the microwave sintering process requires a lower sintering temperature and shorter sintering time of (1-x)CLT-xNMT ceramics than conventional heating methods. All of the (1-x)CLT-xNMT ceramics possess a single perovskite structure. With the increase of x, the dielectric constant (ε) shows a downward trend; the quality factor (Qf) drops first and then rises significantly; the resonance frequency temperature coefficient (τf ) keeps decreasing. With excellent microwave dielectric properties (ε = 51.3, Qf = 13,852 GHz, τf = -1.9 × 10-6/°C), the 0.65CLT-0.35NMT ceramic can be applied to the field of mobile communications.