Podocyte SIRPα reduction aggravates lupus nephritis via promoting T cell inflammatory responses.

Signal-regulatory protein alpha (SIRPα) has recently been found to be highly expressed in podocytes and is essential for maintaining podocyte function. However, its immunoregulatory function in podocytes remains elusive. Here, we report that SIRPα controls podocyte antigen presentation in specific T cell activation via inhibiting spleen tyrosine kinase (Syk) phosphorylation. First, podocyte SIRPα under lupus nephritis (LN) conditions is strongly downregulated. Second, podocyte-specific deletion of SIRPα exacerbates renal disease progression in lupus-prone mice, as evidenced by an increase in T cell infiltration. Third, SIRPα deletion or knockdown enhances podocyte antigen presentation, which activates specific T cells, via enhancing Syk phosphorylation. Supporting this, Syk inhibitor GS-9973 prevents podocyte antigen presentation, resulting in a decrease of T cell activation and mitigation of renal disease caused by SIRPα knockdown or deletion. Our findings reveal an immunoregulatory role of SIRPα loss in promoting podocyte antigen presentation to activate specific T cell immune responses in LN.

BnaPLDα1-BnaMPK6 Involved in NaCl-Mediated Overcoming of Self-Incompatibility in Brassica napus L.

Self-incompatibility (SI) is an important genetic mechanism exploited by numerous angiosperm species to prevent inbreeding. This mechanism has been widely used in the breeding of SI trilinear hybrids of Brassica napus. The SI responses in these hybrids can be overcome by using a salt (NaCl) solution, which is used for seed propagation in SI lines. However, the mechanism underlying the NaCl-induced breakdown of the SI response in B. napus remains unclear. Here, we investigated the role of two key proteins, BnaPLDα1 and BnaMPK6, in the breakdown of SI induced by NaCl. Pollen grain germination and seed set were reduced in BnaPLDα1 triple mutants following incompatible pollination with NaCl treatment. Conversely, SI responses were partially abolished by overexpression of BnaC05.PLDα1 without salt treatment. Furthermore, we observed that phosphatidic acid (PA) produced by BnaPLDα1 bound to B. napus BnaMPK6. The suppression and enhancement of the NaCl-induced breakdown of the SI response in B. napus were observed in BnaMPK6 quadruple mutants and BnaA05.MPK6 overexpression lines, respectively. Moreover, salt-induced stigmatic reactive oxygen species (ROS) accumulation had a minimal effect on the NaCl-induced breakdown of the SI response. In conclusion, our results demonstrate the essential role of the BnaPLDα1-PA-BnaMPK6 pathway in overcoming the SI response to salt treatment in SI B. napus. Additionally, our study provides new insights into the relationship between SI signaling and salt stress response. SIGNFICANCE STATEMENT: A new molecular mechanism underlying the breakdown of the NaCl-induced self-incompatibility (SI) response in B. napus has been discovered. It involves the induction of BnaPLDα1 expression by NaCl, followed by the activation of BnaMPK6 through the production of phosphatidic acid (PA) by BnaPLDα1. Ultimately, this pathway leads to the breakdown of SI. The involvement of the BnaPLDα1-PA-BnaMPK6 pathway in overcoming the SI response following NaCl treatment provides new insights into the relationship between SI signalling and the response to salt stress.

Catalysts for C-N coupling in urea electrosynthesis under ambient conditions from carbon dioxide and nitrogenous species.

Urea is an indispensable nitrogen-containing organic compound in modern human life. However, the current industrial synthesis of urea involves ammonia, which is produced through the Haber-Bosch process under harsh reaction conditions, causing huge energy consumption and heavy environmental pollution. Electrochemical reduction of carbon dioxide (CO2) and nitrogenous species (N2, NOx- and NO) have achieved significant progress, offering a promising approach for the electrochemical C-N coupling to produce urea under ambient conditions. Urea synthesis driven by renewable electricity represents a suitable alternative to the traditional process, contributing to the goal of carbon neutrality and nitrogen cycles. However, challenges such as low yield rate, poor selectivity and unveiled reaction mechanisms still need to be addressed. This review provides a summary of the latest catalysts utilized in urea electrosynthesis, aiming to provide guidance and prospects for the development of high-performance catalysts.

Discovery of Oral AMP-Activated Protein Kinase Activators for Treating Hyperlipidemia.

Activation of AMP-activated protein kinase (AMPK) is proposed to alleviate hyperlipidemia. With cordycepin and N6-(2-hydroxyethyl) adenosine (HEA) as lead compounds, a series of adenosine-based derivatives were designed, synthesized, and evaluated on activation of AMPK. Finally, compound V1 was identified as a potent AMPK activator with the lipid-lowering effect. Molecular docking and circular dichroism indicated that V1 exerted its activity by binding to the γ subunit of AMPK. V1 markedly decreased the serum low-density lipoprotein cholesterol levels in C57BL/6 mice, golden hamsters, and rhesus monkeys. V1 was selected as the clinical compound and concluded Phase 1 clinical trials. A single dose of V1 (2000 mg) increased AMPK activation in human erythrocytes after 5 and 12 h of treatment. RNA sequencing data suggested that V1 downregulated expression of genes involved in regulation of apoptotic process, lipid metabolism, endoplasmic reticulum stress, and inflammatory response in liver by activating AMPK.

A simple method to prepare anion exchange membrane by PVA/EVOH/MIDA for acid recovery by diffusion dialysis.

Given the substantial environmental pollution from industrial expansion, environmental protection has become particularly important. Nowadays, anion exchange membranes (AEMs) are widely used in wastewater treatment. With the use of polyvinyl alcohol (PVA), ethylene-vinyl alcohol (EVOH) copolymer, and methyl iminodiacetic acid (MIDA), a series of cross-linked AEMs were successfully prepared using the solvent casting technique, and the network structure was formed in the membranes due to the cross-linking reaction between PVA/EVOH and MIDA. Fourier transform infrared spectrometer, X-ray photoelectron spectroscopy, scanning electron microscopy, and transmission electron microscopy were used to analyze the prepared membranes. At the same time, its comprehensive properties which include water uptake, linear expansion rate, ion exchange capacity, thermal stability, chemical stability, and mechanical stability were thoroughly researched. In addition, diffusion dialysis performance in practical applications was also studied in detail. The acid dialysis coefficient (UH+) ranged from 10.2 to 35.6 × 10-3 m/h. Separation factor (S) value ranged from 25 to 38, which were all larger than that of the commercial membrane DF-120 (UH+: 8.5 × 10-3 m/h, S: 18.5). The prepared membranes had potential application value in acid recovery.

Systematic Review and Meta-Analysis: Pharmacological and Nonpharmacological Interventions for Disruptive Mood Dysregulation Disorder.

Objectives: Disruptive mood dysregulation disorder (DMDD) is a relatively new diagnosis that comprises severe, nonepisodic irritability and recurrent outbursts of emotional instability in adolescents. This meta-analysis examined the efficacy of the available pharmacological and nonpharmacological interventions for DMDD. Methods: Literature searches were conducted in July 2023. To determine relevant articles, 330 abstracts were reviewed, and 39 articles were identified for full review. A random-effects model was used for the meta-analysis, and a subgroup analysis was performed to assess the effects of study design and intervention type. Results: Eleven studies were reviewed, including six pharmacological and five nonpharmacological. Despite high heterogeneity in effects (I2 = 85%), we showed statistically significant improvements in irritability symptoms following intervention. We showed statistically significant enhancements in symptoms of irritability following the intervention. The subgroup analysis revealed that, compared with randomized controlled trials (RCTs), open trials showed significant improvements in irritability. In addition, drug intervention significantly improved irritability compared to nondrug interventions. Atomoxetine (ATX), optimized stimulants, and stimulants combined with other drugs and behavioral therapy effectively improved irritability. Conclusions: With research indicating potential benefits for irritability from a combination of pharmacological interventions and therapy, including ATX, stimulants in conjunction with antipsychotic or antidepressant medications, and cognitive-behavioral techniques such as Dialectical Behavior Therapy for Children. Future large-scale RCTs are essential to further explore and refine these treatment approaches, especially focusing on the efficacy of combining pharmacological with effective nonpharmacological to improve irritability and overall outcomes in this population.

Development of an efficient liposomal DOX delivery formulation for HCC therapy by targeting CK2α.

Hepatocellular carcinoma (HCC) is a digestive tract cancer with high mortality and poor prognosis, especially in China. Current chemotherapeutic drugs lead to poor prognosis, low efficacy, and high side effects due to weak targeting specificity and rapidly formed multidrug resistance (MDR). Based on the previous studies on the doxorubicin (DOX) formulation for cancer targeting therapy, we developed a novel DOX delivery formulation for the targeting chemotherapy of HCC and DOX resistant HCC. HCSP4 was previously screened and casein kinase 2α (CK2α) was predicted as its specific target on HCC cells in our lab. In the study, miR125a-5p was firstly predicted as an MDR inhibiting miRNA, and then CK2α was validated as the target of HCSP4 and miR125a-5p using CK2α-/-HepG2 cells. Based on the above, an HCC targeting and MDR inhibiting DOX delivery liposomal formulation, HCSP4/Lipo-DOX/miR125a-5p was synthesized and tested for its HCC therapeutic efficacy in vitro. The results showed that the liposomal DOX delivery formulation targeted to HCC cells specifically and sensitively, and presented the satisfied therapeutic efficacy for HCC, particularly for DOX resistant HCC. The potential therapeutic mechanism of the DOX delivery formulation was explored, and the formulation inhibited the expression of MDR-relevant genes including ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein), ATP-binding cassette subfamily C member 5 (ABCC5), enhancer of zeste homolog 2 (EZH2), and ATPase Na+/K+ transporting subunit beta 1 (ATP1B1). Our study presents a novel targeting chemotherapeutic drug formulation for the therapy of HCC, especially for drug resistant HCC, although it is primarily and needs further study in vivo, but provided a new strategy for the development of novel anticancer drugs.

Knocking out FAM20C in pre-osteoblasts leads to up-regulation of osteoclast differentiation to affect long bone development.

Family with sequence similarity 20 member C (FAM20C) is a Golgi casein kinase that phosphorylates extracellularly-secreted regulatory proteins involved in bone development and mineralization, but its specific role in bone development is still largely unknown. In this study, to examine the specific mechanisms that FAM20C influences bone development, we cross-bred Osx-Cre with FAM20Cflox/flox mice to establish a Osx-Cre; FAM20Cflox/flox knockout (oKO) mouse model; FAM20C was KO in pre-osteoblasts. oKO development was examined at 1-10 weeks, in which compared to control FAM20Cflox/flox, they had lower body weights and bone tissue mineralization. Furthermore, oKO had lower bone volume fractions, thickness, and trabecular numbers, along with higher degrees of trabecular separation. These mice also had decreased femoral metaphyseal cartilage proliferation layer, along with thickened hypertrophic layer and increased apoptotic cell counts. Transcriptomic analysis found that differentially-expressed genes in oKO were concentrated in the osteoclast differentiation pathway, in line with increased osteoclast presence. Additionally, up-regulation of osteoclast-related, and down-regulation of osteogenesis-related genes, were identified, in which the most up-regulated genes were signal regulatory protein ß-1 family (Sirpb1a-c) and mitogen-activated protein kinase 13. Overall, FAM20C KO in pre-osteoblasts leads to abnormal long bone development, likely due to subsequent up-regulation of osteoclast differentiation-associated genes.

The Effect of Pixel Design and Operation Conditions on Linear Output Range of 4T CMOS Image Sensors.

We analyze several factors that affect the linear output range of CMOS image sensors, including charge transfer time, reset transistor supply voltage, the capacitance of integration capacitor, the n-well doping of the pinned photodiode (PPD) and the output buffer. The test chips are fabricated with 0.18 µm CMOS image sensor (CIS) process and comprise six channels. Channels B1 and B2 are 10 µm pixels and channels B3-B6 are 20 µm pixels, with corresponding pixel arrays of 1 × 2560 and 1 × 1280 respectively. The floating diffusion (FD) capacitance varies from 10 fF to 23.3 fF, and two different designs were employed for the n-well doping in PPD. The experimental results indicate that optimizing the FD capacitance and PPD design can enhance the linear output range by 37% and 32%, respectively. For larger pixel sizes, extending the transfer gate (TG) sampling time leads to an increase of over 60% in the linear output range. Furthermore, optimizing the design of the output buffer can alleviate restrictions on the linear output range. The lower reset voltage for noise reduction does not exhibit a significant impact on the linear output range. Furthermore, these methods can enhance the linear output range without significantly amplifying the readout noise. These findings indicate that the linear output range of pixels is not only influenced by pixel design but also by operational conditions. Finally, we conducted a detailed analysis of the impact of PPD n-well doping concentration and TG sampling time on the linear output range. This provides designers with a clear understanding of how nonlinearity is introduced into pixels, offering valuable insight in the design of highly linear pixels.

Tyrosine kinase inhibitors in patients with advanced anaplastic thyroid cancer: an effective analysis based on real-world retrospective studies.

Background: Tyrosine kinase inhibitors (TKIs) contribute to the treatment of patients with anaplastic thyroid cancer (ATC). Although prospective clinical studies of TKIs exhibit limited efficacy, whether ATC patients benefit from TKI treatment in real-world clinical practice may enlighten future explorations. Therefore, we conducted this effective analysis based on real-world retrospective studies to illustrate the efficacy of TKI treatment in ATC patients. Methods: We systematically searched the online databases on September 03, 2023. Survival curves were collected and reconstructed to summarize the pooled curves. Responses were analyzed by using the "meta" package. The primary endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Results: 12 studies involving 227 patients were enrolled in the study. Therapeutic strategies included: anlotinib, lenvatinib, dabrafenib plus trametinib, vemurafenib, pembrolizumab plus dabrafenib and trametinib, pembrolizumab plus lenvatinib, pembrolizumab plus trametinib, and sorafenib. The pooled median OS and PFS were 6.37 months (95% CI 4.19-10.33) and 5.50 months (95% CI 2.17-12.03). The integrated ORR and DCR were 32% (95% CI 23%-41%) and 40% (95% CI 12%-74%). Conclusion: In real-world clinical practice, ATC patients could benefit from TKI therapy. In future studies, more basic experiments and clinical explorations are needed to enhance the effects of TKIs in the treatment of patients with ATC.

A multifunctional fluorescent probe for sequential detection of hydrogen sulfide and pH in foodstuffs, living cells and mice.

BACKGROUND: Cancer as a leading cause of premature death worldwide has become a major threat to human health due to the high incidence and mortality. Monitoring tumor markers are reliable and significantly important for early detection of cancers. In complex biological systems, it is of great urgency but still remains challenging to conceive a fluorescent probe with multiple tumor markers detection property. Hydrogen sulfide (H2S) and pH are two target biomarkers for diagnosis of early cancer. The preparation of a novel probe with H2S and pH dual detection functions is highly anticipated. RESULTS: Herein, a novel sequential detection probe HTPQ-HS for H2S and pH has been developed. In this system, HPQ (2-(2 -hydroxyphenyl)-4(3H)-quinazolinone) structure combined with triphenylamine is applied as the fluorophore, and 2, 4-dinitrophenylsulfonyl group is used as the recognition group. In the presence of H2S, HTPQ-HS is transformed into product HTPQ-OH which shows fluorescence enhancement (29-fold) at 525 nm in less than 4 min and further displays repeatable acid-base responsive ability. HTPQ-HS is able to sequentially response to H2S and pH in living cells and does not react directly with pH. Owing to the low cytotoxicity, HTPQ-HS is able to detect exogenous and endogenous H2S in colon cancer cells and mice, monitor H2S in inflammation model and in foodstuffs. As the environment changes from acidic to alkaline, the fluorescence intensity ratio (I470/I530) of product HTPQ-OH changes remarkably, illustrating the ratiometric fluorescent responsiveness to pH. SIGNIFICANCE AND NOVELTY: A multifunctional fluorescent probe HTPQ-HS for sequential detection of H2S and pH is synthesized. Probe HTPQ-OH realizes the monitoring of dynamic changes in intracellular pH and displays prospective application in security printing. We expect that our work could offer an important guidance on the development of multifunctional fluorescent probes for visualizing H2S and pH in biology and environment.

Lithium Borohydride Nanorods: Self-Assembling Growth and Remarkable Hydrogen Cycling Properties.

Nanostructured metal hydrides with unique morphology and improved hydrogen storage properties have attracted intense interests. However, the study of the growth process of highly active borohydrides remains challenging. Herein, for the first time the synthesis of LiBH4 nanorods through a hydrogen-assisted one-pot solvothermal reaction is reported. Reaction of n-butyl lithium with triethylamine borane in n-hexane under 50 bar of H2 at 40-100 °C gives rise to the formation of the [100]-oriented LiBH4 nanorods with 500-800 nm in diameter, whose growth is driven by orientated attachment and ligand adsorption. The unique morphology enables the LiBH4 nanorods to release hydrogen from ≈184 °C, 94 °C lower than the commercial sample (≈278 °C). Hydrogen release amounts to 13 wt% within 40 min at 450 °C with a stable cyclability, remarkably superior to the commercial LiBH4 (≈9.1 wt%). More importantly, up to 180 °C reduction in the onset temperature of hydrogenation is successfully attained by the nanorod sample with respect to the commercial counterpart. The LiBH4 nanorods show no foaming during dehydrogenation, which improves the hydrogen cycling performance. The new approach will shed light on the preparation of nanostructured metal borohydrides as advanced functional materials.

Investigating the synergy of Shikonin and Valproic acid in inducing apoptosis of osteosarcoma cells via ROS-mediated EGR1 expression.

BACKGROUND: Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy. PURPOSE: This study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism. METHODS/STUDY DESIGN: CCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism. RESULTS: The combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma. CONCLUSION: The combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.

Relationship between hepatic surgical margins of colorectal cancer liver metastases and prognosis: A review.

Colorectal cancer (CRC) remains a significant global health concern, as characterized by its high mortality rate ranking second among all the leading causes of death. The liver serves as the primary site of CRC metastasis, and the occurrence of liver metastasis is a significant contributor to mortality among patients diagnosed with CRC. The survival rate of patients with colorectal liver metastasis has significantly increased with the advancement of comprehensive tumor therapy. However, radical surgery remains the key factor. Since there are frequently multiple liver metastases, which are prone to recurrence after surgery, it is crucial to preserve as much liver parenchyma as possible without affecting the prognosis. The issue of surgical margins plays a crucial role in this regard. In this review, we begin by examining the occurrence of positive surgical margins in liver metastases of patients diagnosed with CRC. We aim to define positive margins in hepatic surgery, examine the relationship between margins and prognosis and establish a foundation for future research in this field.

Genomic and epigenetic characterization of the arsenic-induced oncogenic microRNA-21.

As one of the first identified oncogenic microRNAs, the precise details concerning the transcriptional regulation and function of microRNA-21 (miR-21) are still not completely established. The miR-21 gene is situated on chromosome 17q23.2, positioned at the 3'-UTR of the gene that encodes vacuole membrane protein-1 (VMP1). In this current study, we presented evidence indicating that miR-21 possesses its own gene promoter, which can be found in the intron 10 of the VMP1 gene. Chromatin immunoprecipitation followed by global DNA sequencing (ChIP-seq) revealed the presence of a broad H3K4me3 peak spanning the entire gene body of the primary miR-21 and the existence of super-enhancer clusters in the close proximity to both the miR-21 gene promoter and the transcription termination site in arsenic (As3+)-induced cancer stem-like cells (CSCs) and human induced pluripotent stem cells (hiPSCs). In non-transformed human bronchial epithelial cells (BEAS-2B), As3+ treatment enhanced Nrf2 binding to both the host gene VMP1 of miR-21 and the miR-21 gene. Knockout of Nrf2 inhibited both the basal and As3+-induced expressions of miR-21. Furthermore, the As3+-enhanced Nrf2 peaks in ChIP-seq fully overlap with these super-enhancers enriched with H3K4me1 and H3K27ac in the miR-21 gene, suggesting that Nrf2 may coordinate with other transcription factors through the super-enhancers to regulate the expression of miR-21 in cellular response to As3+. These findings demonstrate the unique genetic and epigenetic characteristics of miR-21 and may provide insights into understanding the novel mechanisms linking environmental As3+ exposure and human cancers.

A lysosome-targeted fluorescent probe based on a BODIPY structure for Cys/Hcy detection.

Cysteine (Cys) and homocysteine (Hcy) are important biothiols in living organisms. They play important roles in a variety of physiological and pathological processes. Therefore, it is very important to design an optical probe for the selective detection of Cys/Hcy. Herein, we report the design and synthesis of a fluorescent probe NBD-B-T based on a boron-dipyrromethene (BODIPY) structure, which showed an excellent lysosome targeting ability and an outstanding Cys/Hcy detection capacity. For NBD-B-T, the sensing group 7-nitro-2,1,3-benzoxadiazole (NBD) and the lysosomal targeting group morpholine were introduced. The results show that the NBD-B-T probe can detect Cys/Hcy with fluorescence emission turn-on performance. The low detection limits of this probe are about 76.0 nM for Hcy and 97.6 nM for Cys, respectively. The NBD-B-T probe has a low detection limit, high stability, and excellent selectivity and sensitivity. More importantly, the NBD-B-T can target lysosome, and simultaneously detect the Cys/Hcy in living cells.

Discovery and druggability evaluation of pyrrolamide-type GyrB/ParE inhibitor against drug-resistant bacterial infection.

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity. The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC50 = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC50 = 1.513 µmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 µg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 (5) and AZD5099 (6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 (6) as well as excellent therapeutic indexes and pharmacokinetic properties. At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 µg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure-activity relationships of the compounds were also studied.

Rhesus monkeys exhibiting spontaneous ritualistic behaviors resembling obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic and debilitating psychiatric disorder that affects ∼2%-3% of the population globally. Studying spontaneous OCD-like behaviors in non-human primates may improve our understanding of the disorder. In large rhesus monkey colonies, we found 10 monkeys spontaneously exhibiting persistent sequential motor behaviors (SMBs) in individual-specific sequences that were repetitive, time-consuming and stable over prolonged periods. Genetic analysis revealed severely damaging mutations in genes associated with OCD risk in humans. Brain imaging showed that monkeys with SMBs had larger gray matter (GM) volumes in the left caudate nucleus and lower fractional anisotropy of the corpus callosum. The GM volume of the left caudate nucleus correlated positively with the daily duration of SMBs. Notably, exposure to a stressor (human presence) significantly increased SMBs. In addition, fluoxetine, a serotonergic medication commonly used for OCD, decreased SMBs in these monkeys. These findings provide a novel foundation for developing better understanding and treatment of OCD.

Assessment of the Purity of IMM-H014 and Its Related Substances for the Treatment of Metabolic-Associated Fatty Liver Disease Using Quantitative Nuclear Magnetic Resonance Spectroscopy.

An accurate, rapid, and selective quantitative nuclear magnetic resonance method was developed and validated to assess the purity of IMM-H014, a novel drug for the treatment of metabolic-associated fatty liver disease (MAFLD), and four related substances (impurities I, II, III, and IV). In this study, we obtained spectra of IMM--H014 and related substances in deuterated chloroform using dimethyl terephthalate (DMT) as the internal standard reference. Quantification was performed using the 1H resonance signals at δ 8.13 ppm for DMT and δ 6.5-7.5 ppm for IMM-H014 and its related substances. Several key experimental parameters were investigated and optimized, such as pulse angle and relaxation delay. Methodology validation was conducted based on the International Council for Harmonization guidelines and verified with satisfactory specificity, precision, linearity, accuracy, robustness, and stability. In addition, the calibration results of the samples were consistent with those obtained from the mass balance method. Thus, this research provides a reliable and practical protocol for purity analysis of IMM-H014 and its critical impurities and contributes to subsequent clinical quality control research.

Holographic imaging platform for particle discrimination based on simultaneous mass density and refractive index measurements.

Real-time detection, classification and identification of aerosol particles is crucial in various industries and public health areas. In order to circumvent the limitations of existing particle analysis methods for efficient discrimination, we demonstrate a compact digital in-line holographic microscopy platform with an inertial spectrometer for simultaneous measurement of two independent fingerprint parameters at single species level. In particular, by interrogating the particle location and size captured with the platform, particle mass density can be estimated. Furthermore, by employing Monte Carlo fitting to the Lorenz-Mie theory, the refractive index of each particle can also be extracted from the interference patterns. It is demonstrated that the combination of mass density and optical density characterization unambiguously enhances the discriminatory power of the system, especially when dealing with particles that exhibit similar mass densities but distinctive refractive indices or vice versa. This innovative approach represents a significant advancement in particle characterization and composition identification, with potential applications in various industrial, scientific, and research domains. An iOS-based app interface is then customized for wireless controlling of the CMOS imager, image acquisition, reconstruction, and data analysis. The imaging platform proposed in this work has prominent advantages including compactness, accuracy, efficiency, high throughput, and remote sensing capability, which is especially relevant for applications where on-site/remote metrology and identification of particles is required.