Prevalence and associated factors of low bone mineral density in people living with HIV: a cross-sectional study.

This study examined low bone mineral density (BMD) prevalence and associated factors among Chinese people living with HIV (PLWH), uncovering a persistent high BMD risk in older individuals, even after adjusting for age and body mass index (BMI). Notably, lopinavir/ritonavir (LPV/r) therapy was linked to reduced BMD, highlighting the imperative need for regular BMD monitoring and interventions in older PLWH. PURPOSE: HIV infection and antiretroviral therapy (ART) have been shown to contribute to lower BMD, resulting in an increased susceptibility to osteopenia and osteoporosis. However, there is limited knowledge about the prevalence of reduced BMD and its associated factors among Chinese PLWH. In this cross-sectional study, we aimed to investigate the prevalence and factors associated with low BMD among PLWH in China. METHODS: We retrospectively enrolled PLWH and non-HIV volunteers who underwent dual-energy X-ray absorptiometry (DXA) scans to measure bone density. Demographic information, laboratory test results, ART regimens, and treatment duration were collected. Univariate and multiple regression analyses were performed to identify factors influencing abnormal bone mass in PLWH. RESULTS: A total of 829 individuals were included in this study, comprising the HIV group (n = 706) and the non-HIV group (n = 123). The prevalence of low BMD among all PLWH was found to be 13.88% (98 out of 706). However, among PLWH aged 50 years and above, the prevalence increased to 65.32% (81 out of 124). In contrast, control subjects in the same age group had a prevalence of 38.21% (47 out of 123). After adjusting for age and BMI, older PLWH still demonstrated a higher prevalence of low BMD compared to the non-HIV group (68.24% vs 34.94%, P < 0.001). Multivariate analysis revealed that older age was strongly associated with a higher risk of low BMD among PLWH, with an odds ratio (OR) of 6.28 for every 10-year increase in age in the ART-naïve population (95% confidence intervals [CIs], 3.12-12.65; P < 0.001) and OR of 4.83 in the ART-experienced population (3.20-7.29, P < 0.001). Within the ART-experienced group, current LPV/r treatment was associated with an increased risk of low BMD (OR = 3.55, 1.24-10.14, P < 0.05), along with lower BMI (OR = 0.84, 0.75-0.95, P < 0.05), and elevated alkaline phosphatase (OR = 1.02, 1.01-1.03, P < 0.01). CONCLUSION: The prevalence of low BMD is higher among PLWH aged 50 years and above compared to non-HIV individuals. The use of LPV/r for ART is associated with reduced BMD. These findings emphasize the importance of regular monitoring of BMD in older PLWH and the need for appropriate interventions to mitigate the risks of osteopenia and osteoporosis in this population.

Shaping school for childhood myopia: the association between floor area ratio of school environment and myopia in China.

AIM: To investigate the association of floor area ratio (FAR), an indicator of built environments, and myopia onset. METHODS: This prospective cohort study recruited 136 753 children aged 6-10 years from 108 schools in Shenzhen, China at baseline (2016-2017). Refractive power was measured with non-cycloplegic autorefraction over a 2-year follow-up period. FAR was objectively evaluated using geographical information system technology. Mixed-effects logistic regression models were constructed to examine the association of FAR with a 2-year cumulative incidence of myopia among individuals without baseline myopia; multiple linear regression model, with a 2-year cumulative incidence rate of myopia at each school. RESULTS: Of 101 624 non-myopic children (56.3% boys; mean (SE) age, 7.657±1.182 years) included in the study, 26 391 (26.0%) of them developed myopia after 2 years. In the individual-level analysis adjusting for demographic, socioeconomic and greenness factors, an IQR in FAR was associated with a decreased risk of 2-year myopia incidence (OR 0.898, 95% CI 0.866 to 0.932, p<0.001). Similar findings were observed in the analysis additionally adjusted for genetic and behavioural factors (OR 0.821, 95% CI 0.766 to 0.880, p<0.001). In the school-level, an IQR increase in FAR was found to be associated with a 2.0% reduction in the 2-year incidence rate of myopia (95% CI 1.3% to 2.6%, p<0.001). CONCLUSIONS: Exposure to higher FAR was associated with a decreased myopia incidence, providing insights into myopia prevention through school built environments in China.

Development of an effective meropenem/KPC-2 inhibitor combination to combat infections caused by carbapenem-resistant K. pneumoniae.

The global public health threat of bacterial antibiotic resistance continues to escalate and necessitates the implementation of urgent measures to expand our arsenal of antimicrobial drugs. In this study, we identified a benzoxaborane compound, namely 5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2178), which can effectively inhibit the catalytic activity of the Klebsiella pneumoniae carbapenemase (KPC-2) enzyme. The efficacy of AN2718 as an inhibitor for the KPC-2 enzyme was verified through various assays, including enzyme activity assays and isothermal titration calorimetry. Results of multiple biochemical assays, minimum inhibitory concentration assay, and time-killing assay also showed that binding of AN2718 to KPC-2 enabled the restoration of the bactericidal effect of meropenem. The survival rate of mice infected by carbapenem-resistant, high-virulence strains increased significantly upon treatment with this agent. Most importantly, the meropenem and AN2718 combination is effective on KPC-2 mutations such as KPC-33 that were clinically evolved and exhibited resistance to ceftazidime-avibactam upon the clinical uses of this drug for a couple of years. Comprehensive safety tests both in vitro and in vivo, such as cytotoxicity, haemolytic activity, and cytochrome P450 inhibition assays demonstrated that AN2718 was safe for clinical use. These promising data indicate that AN2718 has a high potential for being approved for the treatment of drug resistant bacterial infections, including those caused by the Ceftazidime-Avibactam resistant strains. To conclude, the compound AN2718 can be regarded as a valuable addition to the current antimicrobial armamentarium and a promising tool to combat antimicrobial resistance.

Eosin Y Post-Decorated Metal-Organic Framework as a Selectivity Regulator for the Alcohols Oxidation.

The selective oxidation of alcohols into aldehydes is a basic and significant procedure, with great potential for scientific research and industrial applications. However, as an important factor in the C(sp3)-H activation process, high selectivity is generally difficult to achieve due to the fact that the more easily activated properties of aldehydes are compared to alcohols. Herein, by the ingenious decoration of eosin Y into a Zr-based metal-organic framework (MOF-808), EY@MOF-808 was prepared as a selectivity regulator for the aerobic oxidation of the benzyl alcohols into corresponding aldehydes, possessing applicability for the benzylic alcohols with various substituents. By anchoring eosin Y on Zr6O4(OH)4 clusters of MOF-808 and maintaining open metal nodes with selective binding effects, the benzyl alcohol substrates were selectively coordinated to the unsaturated metal clusters adjacent to eosin Y, which ensured that the excited eosin Y rapidly activated substrates to generate carbon radicals by the hydrogen atom transfer (HAT) process. The rapid electron transfer (ET) simultaneously produced reactive oxygen species (O2•-) and then a combination of both to further promote the generation of benzaldehydes. The weak interaction of benzaldehydes with the skeleton allowed it to dissociate rapidly, thus preventing overoxidation. Under the catalysis of EY@MOF-808, the selectivity of various benzaldehydes was more than 99%. In contrast, eosin Y gave only benzoic acid products under the same conditions, which demonstrated the superiority of regulatory selectivity of EY@MOF-808. Taking advantage of the heterogeneity of the MOF, EY@MOF-808 was recycled four times without a decrease in its selectivity and avoided the quenching effect of eosin Y. The organic functional units postdecorated MOF-based photocatalyst strategy exhibits a promising new perspective approach to sustainably regulating the selectivity of inert oxidation.

Immune mediated support of metastasis: Implication for bone invasion.

Bone is a common organ affected by metastasis in various advanced cancers, including lung, breast, prostate, colorectal, and melanoma. Once a patient is diagnosed with bone metastasis, the patient's quality of life and overall survival are significantly reduced owing to a wide range of morbidities and the increasing difficulty of treatment. Many studies have shown that bone metastasis is closely related to bone microenvironment, especially bone immune microenvironment. However, the effects of various immune cells in the bone microenvironment on bone metastasis remain unclear. Here, we described the changes in various immune cells during bone metastasis and discussed their related mechanisms. Osteoblasts, adipocytes, and other non-immune cells closely related to bone metastasis were also included. This review also summarized the existing treatment methods and potential therapeutic targets, and provided insights for future studies of cancer bone metastasis.

Employing unnatural promiscuity of sortase to construct peptide macrocycle libraries for ligand discovery.

With the increasing attention paid to macrocyclic scaffolds in peptide drug development, genetically encoded peptide macrocycle libraries have become invaluable sources for the discovery of high-affinity peptide ligands targeting disease-associated proteins. The traditional phage display technique of constructing disulfide-tethered macrocycles by cysteine oxidation has the inherent drawback of reduction instability of the disulfide bond. Chemical macrocyclization solves the problem of disulfide bond instability, but the involved highly electrophilic reagents are usually toxic to phages and may bring undesirable side reactions. Here, we report a unique Sortase-mediated Peptide Ligation and One-pot Cyclization strategy (SPLOC) to generate peptide macrocycle libraries, avoiding the undesired reactions of electrophiles with phages. The key to this platform is to mine the unnatural promiscuity of sortase on the X residue of the pentapeptide recognition sequence (LPXTG). Low reactive electrophiles are incorporated into the X-residue side chain, enabling intramolecular cyclization with the cysteine residue of the phage-displayed peptide library. Utilizing the genetically encoded peptide macrocycle library constructed by the SPLOC platform, we found a high-affinity bicyclic peptide binding TEAD4 with a nanomolar KD value (63.9 nM). Importantly, the binding affinity of the bicyclic peptide ligand is 102-fold lower than that of the acyclic analogue. To our knowledge, this is the first time to mine the unnatural promiscuity of ligases to generate peptide macrocycles, providing a new avenue for the construction of genetically encoded cyclic peptide libraries.

Total Syntheses of Streptamidine and Klebsazolicin Using Biomimetic On-Resin Ring-Closing Amidine Formation.

Diketopiperazine (DKP) derived cyclic amidine structures widely exist in peptide natural products according to the genome mining result. The largely unknown bioactivity and mode of action are partially caused by the poor availability of the compounds via microbiological and chemical approaches. To tackle this challenge, in this work, we have developed the on-resin ring-closing amidine formation strategy to synthesize peptides containing N-terminal DKP derived cyclic amidine structure, in which the 6-exo-trig cyclization mediated by HgCl2 activation of thioamides was the key step. Leveraging from this new strategy, we finished the total syntheses of streptamidine and klebsazolicin. Meanwhile, eleven klebsazolicin analogues were synthesized for its structure-activity relationship study.

Tsunami Squares: Leapfrog scheme implementation and benchmark study on wave-shore interaction of solitary waves.

Impulse waves are generated by rapid subaerial mass movements including landslides, avalanches and glacier break-offs, which pose a potential risk to public facilities and residents along the shore of natural lakes or engineered reservoirs. Therefore, the prediction and assessment of impulse waves are of considerable importance to practical engineering. Tsunami Squares, as a meshless numerical method based on a hybrid Eulerian-Lagrangian algorithm, have focused on the simulation of landslide-generated impulse waves. An updated numerical scheme referred to as Tsunami Squares Leapfrog, was developed which contains a new smooth function able to achieve space and time convergence tests as well as the Leapfrog time integration method enabling second-order accuracy. The updated scheme shows improved performance due to a lower wave decay rate per unit propagation distance compared to the original implementation of Tsunami Squares. A systematic benchmark testing of the updated scheme was conducted by simulating the run-up, reflection and overland flow of solitary waves along a slope for various initial wave amplitudes, water depths and slope angles. For run-up, the updated scheme shows good performance when the initial relative wave amplitude is smaller than 0.4. Otherwise, the model tends to underestimate the run-up height for mild slopes, while an overestimation is observed for steeper slopes. With respect to overland flow, the prediction error of the maximum flow height can be limited to ± 50% within a 90% confidence interval. However, the prediction of the front propagation velocity can only be controlled to ± 100% within a 90% confidence interval. Furthermore, a sensitivity analysis of the dynamic friction coefficient of water was performed and a suggested range from 0.01 to 0.1 was given for reference.

A Bibliometric Analysis of the Spatial Transcriptomics Literature from 2006 to 2023.

In recent years, spatial transcriptomics (ST) research has become a popular field of study and has shown great potential in medicine. However, there are few bibliometric analyses in this field. Thus, in this study, we aimed to find and analyze the frontiers and trends of this medical research field based on the available literature. A computerized search was applied to the WoSCC (Web of Science Core Collection) Database for literature published from 2006 to 2023. Complete records of all literature and cited references were extracted and screened. The bibliometric analysis and visualization were performed using CiteSpace, VOSviewer, Bibliometrix R Package software, and Scimago Graphica. A total of 1467 papers and reviews were included. The analysis revealed that the ST publication and citation results have shown a rapid upward trend over the last 3 years. Nature Communications and Nature were the most productive and most co-cited journals, respectively. In the comprehensive global collaborative network, the United States is the country with the most organizations and publications, followed closely by China and the United Kingdom. The author Joakim Lundeberg published the most cited paper, while Patrik L. Ståhl ranked first among co-cited authors. The hot topics in ST are tissue recognition, cancer, heterogeneity, immunotherapy, differentiation, and models. ST technologies have greatly contributed to in-depth research in medical fields such as oncology and neuroscience, opening up new possibilities for the diagnosis and treatment of diseases. Moreover, artificial intelligence and big data drive additional development in ST fields.

SAMSGL: Series-aligned multi-scale graph learning for spatiotemporal forecasting.

Spatiotemporal forecasting in various domains, like traffic prediction and weather forecasting, is a challenging endeavor, primarily due to the difficulties in modeling propagation dynamics and capturing high-dimensional interactions among nodes. Despite the significant strides made by graph-based networks in spatiotemporal forecasting, there remain two pivotal factors closely related to forecasting performance that need further consideration: time delays in propagation dynamics and multi-scale high-dimensional interactions. In this work, we present a Series-Aligned Multi-Scale Graph Learning (SAMSGL) framework, aiming to enhance forecasting performance. In order to handle time delays in spatial interactions, we propose a series-aligned graph convolution layer to facilitate the aggregation of non-delayed graph signals, thereby mitigating the influence of time delays for the improvement in accuracy. To understand global and local spatiotemporal interactions, we develop a spatiotemporal architecture via multi-scale graph learning, which encompasses two essential components: multi-scale graph structure learning and graph-fully connected (Graph-FC) blocks. The multi-scale graph structure learning includes a global graph structure to learn both delayed and non-delayed node embeddings, as well as a local one to learn node variations influenced by neighboring factors. The Graph-FC blocks synergistically fuse spatial and temporal information to boost prediction accuracy. To evaluate the performance of SAMSGL, we conduct experiments on meteorological and traffic forecasting datasets, which demonstrate its effectiveness and superiority.

Mass Balance, Metabolic Pathways, Absolute Bioavailability, and Pharmacokinetics of Giredestrant in Healthy Subjects.

Giredestrant is a potent and selective small-molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination, and metabolite profile of [14C]giredestrant. In part 1 (mass balance), a single 30.8-mg oral dose of [14C]giredestrant (105 µCi) was administered to women of nonchildbearing potential (WNCBP; n = 6). The mean recovery of total radioactivity in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized, with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In part 2 (aBA), WNCBP (n = 10) received an oral (30-mg capsule) or intravenous (30-mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant. SIGNIFICANCE STATEMENT: This study provides definitive insight into the absorption, distribution, metabolism, and excretion of giredestrant in humans. The results show that giredestrant exhibits low clearance, a high volume of distribution, and moderate oral bioavailability in humans. In addition, the data show that oxidative metabolism followed by excretion in feces is the primary elimination route of giredestrant in humans. These results will be used to further inform the clinical development of giredestrant.

Impact of P-gp inhibition on systemic exposure of pralsetinib and dosing considerations.

A study to determine the impact of cyclosporine (Neoral), an inhibitor of P-gp, on the pharmacokinetics of pralsetinib (trade name GAVRETO®) was conducted in 15 healthy adult volunteers. A single 200 mg dose of pralsetinib was administered orally alone and in combination with cyclosporine with a 9-day washout between treatments. Co-administration with cyclosporine resulted in a clinically relevant increase in pralsetinib maximum plasma concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) with associated geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of 148% (109, 201) and 181% (136, 241), respectively. These findings provide insight into concomitant dosing of pralsetinib with inhibitors of P-gp given the increases in pralsetinib exposure observed when administered with cyclosporine. Based on these results, co-administration of pralsetinib with P-gp inhibitors is not recommended. In the event that co-administration cannot be avoided, it is recommended that the dose of pralsetinib be reduced.

Acupoint Autohemotherapy Attenuates DNCB-Induced Atopic Dermatitis and Activates Regulatory T Cells in BALB/c Mice.

Purpose: Acupoint autohemotherapy (A-AHT) has been proposed as an alternative and complementary treatment for atopic dermatitis (AD), yet the exact role of its blood component in terms of therapeutic efficacy and mechanism of action is still largely unknown. Methods: This study aimed to evaluate the therapeutic efficacies and action mechanisms of intramuscular injections of autologous whole blood (AWB) and mouse immunoglobulin G (IgG) (autologous or heterologous) at acupoints on 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse models. Serum levels of total immunoglobulin E (IgE), IgG, interleukin-10 (IL-10), and interferon-gamma (IFN-γ) were measured, as well as mRNA expression levels of Forkhead box P3 (FoxP3), IL-10 and IFN-γ in dorsal skin lesions, and IL-10+, IFN-γ+ and FoxP3+CD4+T cells in murine spleen. Results: It showed that repeated acupoint injection of AWB, autologous total IgG (purified from autologous blood in AD mice) or heterologous total IgG (purified from healthy blood in normal mice) effectively reduced the severity of AD symptoms and decreased epidermal and dermal thickness as well as mast cells in skin lesions. Additionally, AWB acupoint injection was found to upregulate FoxP3+, IL-10+ and IFN-γ+ CD4+T cells in murine spleen, suppressing the production of IgE antibodies and increasing that of IgG antibodies in the serum. Furthermore, both AWB and autologous total IgG administrations significantly elevated FoxP3 expression, mRNA levels of IL-10 and IFN-γ in dorsal skin lesions. However, acupoint injection of heterologous total IgG had no effect on regulatory T (Treg) and Th1 cells modulation. Conclusion: These findings suggest that the therapeutic effects of A-AHT on AD are mediated by IgG-induced activation of Treg cells.

Real-world clinical effectiveness of nonsurgical treatments for female with POP-Q stage II cystocele: a retrospective analysis of therapeutic efficacy.

Background: Patients with cystocele of pelvic organ prolapse quantification (POP-Q) stage II and below can be treated conservatively, but there are few reports on non-surgical treatment for these patients. This study aimed to present the real-world clinical effectiveness of nonsurgical treatment, including pelvic floor muscle training (PFMT), PFMT combined with pessary (PFMT + P), or non-ablative radiofrequency (PFMT + RF) for female with POP-Q stage II cystocele. Methods: We retrospectively analyzed females with POP-Q stage II cystocele between January 2020 and January 2022 who received PFMT, PFMT + P, or PFMT + RF treatment and were followed up for 12 months. Clinical parameters including Pelvic Floor Distress Inventory-20 questionnaire (PFDI-20), Persian version urinary incontinence quality of life questionnaire (I-QOL), POP-Q, pelvic floor Glazer evaluation, and trans-labial ultrasound at different time points were analyzed. Results: There were 147 participants enrolled. PFDI-20 and I-QOL scores were improved in all groups, but the mean decrement in the PFDI-20 scores (-14.28±8.57 and -9.78±8.25) was higher in the PFMT + P group than in the PFMT group and PFMT + RF group at both 6 and 12 months (P<0.05), and the mean I-QOL score (3.82±23.43 and 3.47±22.06) was higher in the PFMT + RP group at both 6 months and 12 months (P<0.05). The PFMT + P group also showed higher improvement rate (43.3%, P=0.03) in terms of changing the severity of cystocele (point Ba) and delta bladder neck-symphyseal distance (ΔBSD) (P<0.05) than the other 2 groups at 12 months. No statistical difference was found in the type-I and type-II myofiber function-based Glazer assessment among 3 groups. Conclusions: The combination of 2 treatment strategies seems to be superior to PFMT only for stage-II cystocele. Specific prolapse-related symptoms and objective indicators did improve more in the PFMT + P group, whereas stress urinary incontinence (SUI) symptoms and quality of life were improved in the PFMT + RP group.

Transmission of reduced levels of miR-34/449 from sperm to preimplantation embryos is a key step in the transgenerational epigenetic inheritance of the effects of paternal chronic social instability stress.

The transgenerational effects of exposing male mice to chronic social instability (CSI) stress are associated with decreased sperm levels of multiple members of the miR-34/449 family that persist after their mating through preimplantation embryo (PIE) development. Here we demonstrate the importance of these miRNA changes by showing that restoring miR-34c levels in PIEs derived from CSI stressed males prevents elevated anxiety and defective sociability normally found specifically in their adult female offspring. It also restores, at least partially, levels of sperm miR-34/449 normally reduced in their male offspring who transmit these sex-specific traits to their offspring. Strikingly, these experiments also revealed that inducing miR-34c levels in PIEs enhances the expression of its own gene and that of miR-449 in these cells. The same induction of embryo miR-34/449 gene expression likely occurs after sperm-derived miR-34c is introduced into oocytes upon fertilization. Thus, suppression of this miRNA amplification system when sperm miR-34c levels are reduced in CSI stressed mice can explain how a comparable fold-suppression of miR-34/449 levels can be found in PIEs derived from them, despite sperm containing ~50-fold lower levels of these miRNAs than those already present in PIEs. We previously found that men exposed to early life trauma also display reduced sperm levels of miR-34/449. And here we show that miR-34c can also increase the expression of its own gene, and that of miR-449 in human embryonic stem cells, suggesting that human PIEs derived from men with low sperm miR-34/449 levels may also contain this potentially harmful defect.

Enhancing resistance, but not virulence attributed to the high mortality caused by carbapenem-resistant Klebsiella pneumoniae.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a global threat due to its high mortality in clinical patients. However, the specific mechanisms underlying this increased mortality remain unclear. The objective of this study is to investigate how the development of a resistance phenotype contributes to the significantly higher mortality associated with this pathogen. To achieve this, a collection of isogeneic strains was generated. The clinical carbapenem-susceptible K. pneumoniae (CSKP) strain HKU3 served as the control isolate, while HKU3-KPC was created through conjugation with a blaKPC-2-bearing plasmid and served as clinical CRKP strain. Using a sepsis model, it was demonstrated that both HKU3 and HKU3-KPC exhibited similar levels of virulence. Flow cytometry, RNA-seq, and ELISA analysis were employed to assess immune cell response, M1 macrophage polarization, and cytokine storm induction, revealing that both strains elicited comparable types and levels of these immune responses. Subsequently, meropenem was utilized to treat K. pneumoniae infection, and it was found that meropenem effectively reduced bacterial load, inhibited M1 macrophage polarization, and suppressed serum cytokine production during HKU3 (CSKP) infection. However, these effects were not observed in the case of HKU3-KPC (CRKP) infection. These findings provide evidence that the high mortality associated with CRKP is attributed to its enhanced survival within the host during antibiotic treatment, resulting in a cytokine storm and subsequent host death. The development of an effective therapy for CRKP infections could significantly reduce the mortality caused by this pathogen.

Membrane-assisted tariquidar access and binding mechanisms of human ATP-binding cassette transporter P-glycoprotein.

The human multidrug transporter P-glycoprotein (P-gp) is physiologically essential and of key relevance to biomedicine. Recent structural studies have shed light on the mode of inhibition of the third-generation inhibitors for human P-gp, but the molecular mechanism by which these inhibitors enter the transmembrane sites remains poorly understood. In this study, we utilized all-atom molecular dynamics (MD) simulations to characterize human P-gp dynamics under a potent inhibitor, tariquidar, bound condition, as well as the atomic-level binding pathways in an explicit membrane/water environment. Extensive unbiased simulations show that human P-gp remains relatively stable in tariquidar-free and bound states, while exhibiting a high dynamic binding mode at either the drug-binding pocket or the regulatory site. Free energy estimations by partial nudged elastic band (PNEB) simulations and Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method identify two energetically favorable binding pathways originating from the cytoplasmic gate with an extended tariquidar conformation. Interestingly, free tariquidar in the lipid membrane predominantly adopts extended conformations similar to those observed at the regulatory site. These results suggest that membrane lipids may preconfigure tariquidar into an active ligand conformation for efficient binding to the regulatory site. However, due to its conformational plasticity, tariquidar ultimately moves toward the drug-binding pocket in both pathways, explaining how it acts as a substrate at low concentrations. Our molecular findings propose a membrane-assisted mechanism for the access and binding of the third-generation inhibitors to the binding sites of human P-gp, and offer deeper insights into the molecule design of more potent inhibitors against P-gp-mediated drug resistance.

Study on Influence Factors of H2O2 Generation Efficiency on Both Cathode and Anode in a Diaphragm-Free Bath.

Electrosynthesis of H2O2 via both pathways of anodic two-electron water oxidation reaction (2e-WOR) and cathodic two-electron oxygen reduction reaction (2e-ORR) in a diaphragm-free bath can not only improve the generation rate and Faraday efficiency (FE), but also simplify the structure of the electrolysis bath and reduce the energy consumption. The factors that may affect the efficiency of H2O2 generation in coupled electrolytic systems have been systematically investigated. A piece of fluorine-doped tin oxide (FTO) electrode was used as the anode, and in this study, its catalytic performance for 2e-WOR in Na2CO3/NaHCO3 and NaOH solutions was compared. Based on kinetic views, the generation rate of H2O2 via 2e-WOR, the self-decomposition, and the oxidative decomposition rate of the generated H2O2 during electrolysis in carbonate electrolytes were investigated. Furthermore, by choosing polyethylene oxide-modified carbon nanotubes (PEO-CNTs) as the catalyst for 2e-ORR and using its loaded electrode as the cathode, the coupled electrolytic systems for H2O2 generation were set up in a diaphragm bath and in a diaphragm-free bath. It was found that the generated H2O2 in the electrolyte diffuses and causes oxidative decomposition on the anode, which is the main influent factor on the accumulated concentration in H2O2 in a diaphragm-free bath.

Exploring the Impact of Hepatic Impairment on Pralsetinib Pharmacokinetics.

Pralsetinib is a kinase inhibitor indicated for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer. Pralsetinib is primarily eliminated by the liver and hence hepatic impairment (HI) is likely alter its pharmacokinetics (PK). Mild HI has been shown to have minimal impact on the PK of pralsetinib. This hepatic impairment study aimed to determine the pralsetinib PK, safety and tolerability in subjects with moderate and severe HI, as defined by the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification systems, in comparison to subjects with normal hepatic function. Based on the Child-Pugh classification, subjects with moderate and severe HI had similar systemic exposure (area under the plasma concentration time curve from time 0 to infinity [AUC0-∞]) to pralsetinib, with AUC0-∞ geometric mean ratios (GMR) of 1.12 and 0.858, respectively, compared to subjects with normal hepatic function. Results based on the NCI-ODWG classification criteria were comparable; the AUC0-∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.