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.

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.

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.

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.

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.

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.

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.

Why is the labor epidural rate low and cesarean delivery rate high? A survey of Chinese perinatal care providers.

OBJECTIVE: China has a high cesarean delivery (CD) and low labor epidural analgesia (LEA) rate. This online survey was conducted to explore the reasons behind this phenomenon and potential solutions. METHODS: A voluntary, anonymous survey was distributed via both WeChat and professional websites for 4 months amongst groups of Chinese perinatal professionals. Data was collected and analyzed using a Chi-square test and presented as percentages of respondents. RESULTS: 1412 respondents were recorded (43% anesthesiologists, 35% obstetricians, 15.5% midwives or labor and delivery nurses, and 6.5% others), and 1320 respondents were care providers. It was found that 82.7% (1092/1320) of the provider respondents used CD per patient request in fear of lawsuits or yinao/yibao and 63.4% (837/1320) used CD for respecting superstitious culture. The number one reason (noted by 60.2% (795/1320) of all the three specialties) for low LEA use was lack of anesthesia manpower without statistical difference among specialties. The most recommended solution was increasing the anesthesia workforce, proposed by 79.8% (1053/1320) of the three specialties. However, the top solution provided by the two non-anesthesia specialties is different from the one proposed by anesthesiologists. The later (83%, 504/606) suggested increasing the incentive to provide the service is more effective. The answers to questions related to medical knowledge about CD and LEA, and unwillingness of anesthesiologists, parturients and their family members to LEA were similar for the most part, while the opinions regarding low LEA use related to poor experiences and unwillingness of obstetricians and hospital administrators were significantly divided among the three specialties. In the providers' point of view, the unwillingness to LEA from parturient's family members was the most salient (26.1%, 345/1320), which is more than all care providers, hospital administrators, and parturients themselves (16.8%, 222/1320). CONCLUSION: The reasons for high CD rate and low LEA use are multifactorial. The sociological issues (fear of yinao/yibao and superstitious culture) were the top two contributing factors for the high CD rate in China, while lack of anesthesia manpower was the top response for the low LEA use, which contributes to its being the most recommended solution overall from the three specialties. An incentive approach to providers is a short-term solution while training more perinatal care providers (especially among anesthesiologists and midwives), improving billing systems, and reforming legal systems are 3 systemic approaches to tackling this problem in the long-term.

Sensitive antibody fluorescence immunosorbent assay (SAFIA) for rapid on-site detection on avian influenza virus H9N2 antibody.

Avian influenza virus (AIV) is a serious zoonotic disease causing severe damages to both poultry industry and human health. To rapidly detect AIV on-site with high sensitivity and accuracy, we design sensitive antibody fluorescence immunosorbent assay (SAFIA) on AIV H9N2 antibody. In SAFIA, hemagglutinin (HA1) protein coated sample chamber specifically binds targets but remarkably reduces non-specific absorption; Protein L coated polystyrene microsphere captures target through secondary antibody to significantly amplify the fluorescence signal; and a portable fluorescence counter automatically measures the fluorescence spot density for AIV H9N2 antibody detection. Proved by practical applications, SAFIA could probe AIV H9N2 antibody in high sensitivity and selectivity, and distinguish positive and negative serum samples in high accuracy. Additionally, SAFIA can rapidly detect AIV H9N2 antibody at room temperature only requiring simple operations as well as cost-effective and compact devices. Therefore, SAFIA is a potential new-generation tool in rapid on-site testing for agricultures.

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.

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).

[Effect of deep and shallow electroacupuncture stimulation at "Huantiao"(GB30) on expression of phosphorylated-p38 and phosphorylated-p53 proteins and apoptosis in dorsal root ganglia in sciatic nerve injury rats].

OBJECTIVE: To observe the effect of deep electroacupuncture (EA) stimulation at "Huantiao"(GB30) on hindlimb motor function and expression of p38 mitogen-activated protein kinase (p38 MAPK ) and p53 proteins in dorsal root ganglia (DRG) in rats with chronic constrictive injury (CCI) of sciatic nerve. METHODS: Forty-eight SD rats (half male and half female) were randomly divided into control, model, shallow EA (SEA) stimulation and deep EA (DEA) stimulation groups (n=12 in each group). The CCI model was constructed by implanting a silicone tube close to the sciatic nerve of the left hind limb. For DEA group and SEA group, filiform acupuncture needles were inserted into GB30 about 12-14 mm deep and 5-8 mm deep (monitored by using a high-frequency ultrasound device), respectively, followed by electrical stimulation (2 Hz/100 Hz, 1 mA) using an EA stimulator. The intervention was conducted for 15 min every time, once daily for 14 days. The sciatic nerve function index (SFI) calculated to assess the motor function status. Histopathological changes of the sciatic nerve were displayed by H.E. staining. The expression levels of phosphorylated-p38 MAPK (p-p38) and phosphorylated-tumor protein p53 (p-p53) in DRGs of L4-L5 on the affected side were observed by immunohistochemical staining. RESULTS: Following modeling, the SFI were significantly decreased (P<0.01), and the expression levels of p-p38 and p-p53 proteins of L4-L5 DRGs were considerably increased in the model group (P<0.05). After the intervention, the SFI were obviously increased, and the expression levels of p-p38 and p-p53 proteins notably down-regulated in both DEA and SEA groups relevant to the model group (P<0.01, P<0.05). The therapeutic effect of DEA was significantly superior to that of SEA in raising SFI and down-regulating expression le-vels of p-p38 and p-p53 proteins (P<0.01, P<0.05). H.E. staining showed disordered arrangement of the sciatic nerve fibers and myelin, disaggregation of the myelin and axons with deformity and vacuolation in some of them and with an increase of Schwann cells in the model group, which was relatively milder in both DEA and SEA groups. CONCLUSION: Both DEA and SEA at GB30 can obviously improve the motor function in CCI rats, which may be associated with its function in down-regulating the expression of p-p38 and p-p53 proteins in L4-L5 DRGs, restraining p38 MAPK signaling. The therapeutic effect of DEA is evidently better than that of SEA.

Freestanding Three-Dimensional CuO/NiO Core-Shell Nanowire Arrays as High-Performance Lithium-Ion Battery Anode.

We demonstrate significant improvement of CuO nanowire arrays as anode materials for lithium ion batteries by coating with thin NiO nanosheets conformally. The NiO nanosheets were designed two kinds of morphologies, which are porous and non-porous. By the NiO nanosheets coating, the major active CuO nanowires were protected from direct contact with the electrolyte to improve the surface chemical stability. Simultaneously, through the observation and comparison of TEM results of crystalline non-porous NiO nanosheets, before and after lithiation process, we clearly prove the effect of expected protection of CuO, and clarify the differences of phase transition, crystallinity change, ionic conduction and the mechanisms of the capacity decay further. Subsequently, the electrochemical performances exhibit lithiation and delithiation differences of the porous and non-porous NiO nanosheets, and confirm that the presence of the non-porous NiO coating can still effectively assist the diffusion of Li+ ions into the CuO nanowires, maintaining the advantage of high surface area, and improves the cycle performance of CuO nanowires, leading to enhanced battery capacity. Optimally, the best structure is validated to be non-porous NiO nanosheets, in contrary to the anticipated porous NiO nanosheets. In addition, considering the low cost and facile fabrication process can be realized further for practical applications.

Can We Make Small Molecules Lean? Optimization of a Highly Lipophilic TarO Inhibitor.

We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO, an early stage enzyme in the biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC50 of 125 nM in an enzyme assay and possessed very high lipophilicity (clogP = 7.1) with no measurable solubility in PBS buffer. Structure-activity relationship (SAR) studies resulted in a series of compounds with improved lipophilic ligand efficiency (LLE) consistent with the reduction of clogP. From these efforts, analog 9 was selected for our initial in vivo study, which in combination with subefficacious dose of imipenem (IPM) robustly lowered the bacterial burden in a neutropenic Staphylococci murine infection model. Concurrent with our in vivo optimization effort using 9, we further improved LLE as exemplified by a much more druglike analog 26.

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.

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.

TarO-specific inhibitors of wall teichoic acid biosynthesis restore ß-lactam efficacy against methicillin-resistant staphylococci.

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 new treatment options. We report an S. aureus phenotypic screening strategy involving chemical suppression of the growth inhibitory consequences of depleting late-stage wall teichoic acid biosynthesis. This enabled us to identify early-stage pathway-specific inhibitors of wall teichoic acid biosynthesis predicted to be chemically synergistic with ß-lactams. We demonstrated by genetic and biochemical means that each of the new chemical series discovered, herein named tarocin A and tarocin B, inhibited the first step in wall teichoic acid biosynthesis (TarO). Tarocins do not have intrinsic bioactivity but rather demonstrated potent bactericidal synergy in combination with broad-spectrum ß-lactam antibiotics against diverse clinical isolates of methicillin-resistant staphylococci as well as robust efficacy in a murine infection model of MRSA. Tarocins and other inhibitors of wall teichoic acid biosynthesis may provide a rational strategy to develop Gram-positive bactericidal ß-lactam combination agents active against 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.