PIM1 signaling in immunoinflammatory diseases: an emerging therapeutic target.

PIM1, the proviral integration site for Moloney murine leukemia virus, is a member of the serine/threonine protein kinase family. It is involved in many biological events, such as cell survival, cell cycle progression, cell proliferation, and cell migration, and has been widely studied in malignant diseases. However, recent studies have shown that PIM1 plays a prominent role in immunoinflammatory diseases, including autoimmune uveitis, inflammatory bowel disease, asthma, and rheumatoid arthritis. PIM1 can function in inflammatory signal transduction by phosphorylating multiple inflammatory protein substrates and mediating macrophage activation and T lymphocyte cell specification, thus participating in the development of multiple immunoinflammatory diseases. Moreover, the inhibition of PIM1 has been demonstrated to ameliorate certain immunoinflammatory disorders. Based on these studies, we suggest PIM1 as a potential therapeutic target for immunoinflammatory diseases and a valid candidate for future research. Herein, for the first time, we provide a detailed review that focuses on the roles of PIM1 in the pathogenesis of immunoinflammatory diseases.

Lnc-Pim1 Promotes Neurite Outgrowth and Regeneration of Neuron-Like Cells Following ACR-Induced Neuronal Injury.

Decreased regenerative capacity of central nervous system neurons is the main cause for failure of damaged neuron regeneration and functional recovery. Long noncoding RNAs (lncRNAs) are abundant in mammalian transcriptomes, and many time- and tissue-specific lncRNAs are thought to be closely related to specific biological functions. The promoting effect of Pim-1 gene on neural differentiation and regeneration has been documented, but the effect and mechanism of its neighbor gene Lnc-Pim1 in regulating the response of central neurons to injury remain unclear. RT-PCR in this study demonstrated that the expression of Lnc-Pim1 was upregulated in acrylamide (ACR)-induced neuronal injury. FISH and nucleus-cytoplasmic assay demonstrated that Lnc-Pim1 was mainly expressed in the neuron cytoplasm, with a small amount in the nucleus. Western blot analysis proved that Lnc-Pim1 overexpression induced by the lentivirus vector could promote neurite outgrowth in Neuro-2a cells by activating the Erk1/2 signal pathway, and improve neurite regeneration of injured neurons by upregulating GAP-43 and ß-Ⅲ tubulin protein expression. However, silencing Lnc-Pim1 expression by interfering RNA could effectively downregulate the GAP-43 and ß-Ⅲ tubulin protein expression, and inhibit neurite growth of neurons. In addition, CHIRP-MS was performed to identify several potential targets of Lnc-Pim1 involved in the regulation of neurite regeneration of injured neurons. In conclusion, our study demonstrated that Lnc-Pim1 is a potential lnc-RNA, playing an important role in regulating central nerve regeneration.

Thermal desorption-photoionization ion mobility-electronic nose (TD-PIM-Nose) with distance-probability joint decision SVM algorithm: A novel system for Daqu Grade identification.

Electronic nose is a bionic technology that uses sensor arrays and pattern recognition algorithms to mimic the human olfactory system. This study developed a thermal desorption-photoionization ion mobility-electronic nose (TD-PIM-Nose) system, employing thermal desorption for direct sampling and humidity control, with a photoionization ion mobility tube as virtual sensor array for component separation and detection, and pattern recognition algorithms for signal processing to differentiate and identify samples. Furthermore, it was applied to assess four quality grades of Daqu samples ("Excellent+", "Excellent", "Grade I", and "Grade II") determined by the Check-All-That-Apply (CATA) method. Characteristic compound differences among these grades were identified using fingerprint spectra and reduced mobility values. A distance-probability joint decision support vector machine (SVM) algorithm model was established, validated against sensory CATA standards. Results showed identification accuracies: 90 %, 90 %, 96.88 %, and 100 % for respective grades. These findings demonstrated the promising potential of the TD-PIM-Nose system in Daqu quality grading.

New Insights on Y, La, Nd, and Sm Extraction with Bifunctional Ionic Liquid Cyphos IL 104 Incorporated in a Polymer Inclusion Membrane.

In this study, an ionic liquid-based polymer inclusion membrane (IL-PIM) made of (50% polymer-50% CyphosIL104) was used to extract and separate the rare earth elements (REEs) Y, La, Nd, and Sm in chloride solutions. The effect of extraction time and pH was studied to optimize the extraction and separation conditions. The four REEs were effectively extracted at pH 4-5 from both single and mixed metals solutions. However, at pH 2, only Y was extracted. The recovery of the extracted REEs from the loaded PIM was achieved using HNO3 and H2SO4. In the case of La, it was quantitatively back-extracted with H2SO4 after a contact time of 1 h, while up to 4 h was necessary to recover 70% of the extracted Y, Sm, and Nd. Extraction isotherms were studied, and the Freundlich isotherm model was the most adequate to describe the interaction between the PIM and the REEs. Finally, the developed PIM was investigated for the extraction of REEs from mixtures containing other metals, which showed great selectivity for the REEs.

Identification of indole-grafted pyrazolopyrimidine and pyrazolopyridine derivatives as new anti-cancer agents: Synthesis, biological assessments, and molecular modeling insights.

In the current medical era, developing new PIM-1 inhibitors stands as a significant approach to cancer management due to the pivotal role of PIM-1 kinase in promoting cell survival, proliferation, and drug resistance in various cancers. This study involved designing and synthesizing new derivatives of pyrazolo[1,5-a]pyrimidines (6a-i) and pyrazolo[3,4-b]pyridines (10a-i) as potential anti-cancer agents targeting PIM-1 kinase. The cytotoxicity was screened on three cancer cell lines: A-549 (lung), PANC-1 (pancreatic), and A-431 (skin), alongside MRC5 normal lung cells to assess selectivity. Several pyrazolo[1,5-a]pyrimidines (6b, 6c, 6g, 6h, and 6i) and pyrazolo[3,4-b]pyridine (10f) demonstrated notable anticancer properties, particularly against A-549 lung cancer cells (IC50 range: 1.28-3.52 µM), also they exhibited significantly lower toxicity towards MRC5 normal cells. Thereafter, the compounds were evaluated for their inhibitory activity against PIM-1 kinase. Notably, 10f, bearing a 4-methoxyphenyl moiety, demonstrated good inhibition of PIM-1 with an IC50 of 0.18 µM. Additionally, 10f induced apoptosis and arrested cell cycle progression in A-549 cells. Molecular docking and dynamics simulations provided insights into the binding interactions and compounds' stability with PIM-1 kinase. The results highlight these compounds, especially 10f, as promising selective anticancer agents targeting PIM-1 kinase.

PIM Kinase Inhibitors as Novel Promising Therapeutic Scaffolds in Cancer Therapy.

Cancer involves the uncontrolled, abnormal growth of cells and affects other tissues. Kinase has an impact on proliferating the cells and causing cancer. For the purpose of treating cancer, PIM kinase is a potential target. The pro-viral Integration site for moloney murine leukaemia virus (PIM) kinases is responsible for the tumorigenesis, by phosphorylating the proteins that control the cell cycle and cell proliferation. PIM-1, PIM-2, and PIM-3 are the three distinct isoforms of PIM kinases. The JAK/STAT pathway is essential for controlling how PIM genes are expressed. PIM kinase is also linked withPI3K/AKT/mTOR pathway in various types of cancers. The overexpression of PIM kinase will cause cancer. Currently, there are significant efforts being made in medication design and development to target its inhibition. A few small chemical inhibitors (E.g., SGI-1776, AZD1208, LGH447) that specifically target the PIM proteins' adenosine triphosphate (ATP)-binding domain have been identified. PIM kinase antagonists have a remarkable effect on different types of cancer. Despite conducting clinical trials on SGI-1776, the first PIM inhibitory agent, was prematurely withdrawn, making it unable to generate concept evidence. On the other hand, in recent years, it has aided in hastening the identification of multiple new PIM inhibitors. Cyanopyridines and Pyrazolo[1,5-a]pyrimidinecan act as potent PIM kinase inhibitors for cancer therapy. We explore the involvement of oncogenic transcription factor c-Mycandmi-RNA in relation to PIM kinase. In this article, we highlight the oncogenic effects, and structural insights into PIM kinase inhibitors for the treatment of cancer.

The NRF2 inducer CDDO-2P-Im provokes a reduction in amyloid ß levels in Alzheimer's disease model mice.

Alzheimer's disease (AD) is the most common etiology of dementia. The transcription factor NF-E2-related factor 2 (NRF2) induces the expression of genes encoding phase II detoxification and antioxidant genes. NRF2 is regulated by Kelch-like ECH-associated protein 1 (KEAP1), and the KEAP1-NRF2 system is the key regulatory system involved in cytoprotection. To examine whether pharmacological induction of NRF2 expression alleviates AD phenotypes in vivo, we employed two AD mouse models, i.e., App  NL-G-F/NL-G-F (AppNLGF) and APPV717I::TAUP301L (APP/TAU) mice. As the synthetic oleanane triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11-dien-28-oyl)] (CDDO)-4(-pyridin-2-yl)-imidazole (CDDO-2P-Im) exhibits strong NRF2-inducing activity, we treated AD model mice with CDDO-2P-Im. We found that Aß42 levels were markedly greater in the brains of AppNLGF mice than in those of APP/TAU mice. CDDO-2P-Im treatment significantly decreased Aß42 levels, but not Aß40 levels, in APP/TAU mice. Consequently, CDDO-2P-Im also decreased the ratio of Aß42/Aß40, a vital marker of amyloid plaque formation. LC-MS/MS analyses revealed that CDDO-2P-Im was delivered to the brains of the APP/TAU mice. CDDO-2P-Im induced the expression of detoxification and antioxidant gene targets of NRF2 and elevated reduced glutathione (GSH) levels in the mouse brain. These results support the notion that CDDO-2P-Im ameliorates AD-related pathologic changes.

Regulation of cagA-Helicobacter on gastric PIM2 expression in gastric cancer.

BACKGROUND: The association between infection with cagA-positive H. pylori and an elevated susceptibility to gastric cancer has been firmly established. PIM2 is known to be overexpressed in various types of cancers; however, the specific mechanism by which cagA influences the regulation of PIM2 expression in gastric cancer remains unidentified at present. MATERIALS AND METHODS: A mutant NCTC11637ΔcagA strain of H. pylori and the eukaryotic expression vector pcDNA-cagA were constructed for evaluating PIM2 expression levels in gastric cancer cells (HGC27, SGC7901, and AG) co-cultured with the NCTC11637 and NCTC11637ΔcagA strain, as well as pcDNA-cagA and the empty vector pcDNA3.1 (+). RESULTS: Co-culturing gastric cancer cells with NCTC11637 significantly increased PIM2 expression levels (P< 0.001) compared to the negative control group. Additionally, the expression of PIM2 in cells co-cultured with NCTC11637 was higher than that co-cultured with NCTC11637ΔcagA (P< 0.001). Furthermore, successful construction of the eukaryotic expression vector pcDNA-cagA resulted in a significant increase in PIM2 mRNA expression levels after its transfection into gastric cancer cells compared to the control group after 48 hours. CONCLUSIONS: The findings indicate that H. pylori/cagA A could be one of the key factors in regulating PIM2 expression levels, potentially influencing the progression of H. pylori-related Gastric Cancer.

Multi-Objectives Optimization of Plastic Injection Molding Process Parameters Based on Numerical DNN-GA-MCS Strategy.

An intelligent optimization technique has been presented to enhance the multiple structural performance of PA6-20CF carbon fiber-reinforced polymer (CFRP) plastic injection molding (PIM) products. This approach integrates a deep neural network (DNN), Non-dominated Sorting Genetic Algorithm II (NSGA-II), and Monte Carlo simulation (MCS), collectively referred to as the DNN-GA-MCS strategy. The main objective is to ascertain complex process parameters while elucidating the intrinsic relationships between processing methods and material properties. To realize this, a numerical study on the PIM structural performance of an automotive front engine hood panel was conducted, considering fiber orientation tensor (FOT), warpage, and equivalent plastic strain (PEEQ). The mold temperature, melt temperature, packing pressure, packing time, injection time, cooling temperature, and cooling time were employed as design variables. Subsequently, multiple objective optimizations of the molding process parameters were employed by GA. The utilization of Z-score normalization metrics provided a robust framework for evaluating the comprehensive objective function. The numerical target response in PIM is extremely intricate, but the stability offered by the DNN-GA-MCS strategy ensures precision for accurate results. The enhancement effect of global and local multi-objectives on the molded polymer-metal hybrid (PMH) front hood panel was verified, and the numerical results showed that this strategy can quickly and accurately select the optimal process parameter settings. Compared with the training set mean value, the objectives were increased by 8.63%, 6.61%, and 9.75%, respectively. Compared to the full AA 5083 hood panel scenario, our design reduces weight by 16.67%, and achievements of 92.54%, 93.75%, and 106.85% were obtained in lateral, longitudinal, and torsional strain energy, respectively. In summary, our proposed methodology demonstrates considerable potential in improving the, highlighting its significant impact on the optimization of structural performance.

Benzohydroxamate and nitrobenzohydroxamate affect membrane order: Correlations between spectroscopic and molecular dynamics to approach tuberculosis.

This work correlates the effects of benzohydroxamate (BH) and nitrobenzohydroxamate (NBH) anions in two membrane models which may be used for anti-tuberculosis (anti-TB) spectroscopic studies and/or computational studies. Firstly, the BH and NBH influence in the physico-chemical properties of soy asolectin (ASO)-based large multilamellar vesicles (MLVs) were evaluated by spectroscopic and calorimetric studies. In parallel, the BH and NBH interaction with a Mycobacterium tuberculosis (Mtb) inner membrane model, composed of phosphatidyl-myo-inositol-dimannoside (PIM2), was investigated by molecular dynamics (MD) simulations. Spectroscopic data showed a localization of BH close to the lipid phosphate group, while NBH was found close to the choline region. The BH ordered the ASO choline, phosphate and carbonyl regions and disrupted the acyl methylenes, reducing the membrane packing of the lipid hydrophobic region. On the other hand, NBH showed an ordering effect in all the lipid groups (polar, interface and hydrophobic ones). By MD studies, it was found that NBH enhanced the stability of the PIM2 membrane more than BH, while also being positioned closer to its mannosyl oxygens. As in ASO MLVs, BH was localized close to the PIM2 phosphate group and disrupted its acyl chains. However, higher values of lateral diffusion were observed for NBH than BH. Despite this, BH and NBH increased the membrane thickness by 35 %, which suggests a global ordering effect of both drugs. Findings of this work reinforce the accordance and complementarity between MLVs based on ASO and the PIM2 MD model results to study the drug effects in Mtb membrane properties.

Racial and ethnic disparities in potentially inappropriate medication use in patients with dementia.

INTRODUCTION: Racial and ethnic disparities in potentially inappropriate medication (PIM) use among older adults with dementia are unclear. METHODS: Data were drawn from the baseline visits of participants who were ≥60 years old and diagnosed with dementia in the National Alzheimer's Coordinating Center Uniform Data Set (NACCUDS) recruited from National Institute on Aging (NIA)-funded Alzheimer's Disease Research Centers (ADCs) throughout the United States. PIM utilization was evaluated using the 2019 American Geriatrics Society Beers Criteria for PIM Use in Older Adults. We estimated the association between race and ethnicity and the following outcomes and estimation models: (1) any PIM use, any PIM in each drug class, and any PIM best avoided in dementia patients using logistic regression models, (2) total number of medications, total number of PIMs, and anticholinergic burden scale (ACBS) using Poisson or negative binomial regression models, and (3) proportion of total medications that were PIMs using generalized linear models (GLM). RESULTS: Compared to White participants, Black, Hispanic, and Asian participants reported taking fewer total medications (incidence rate ratio [IRR] ± standard error[SE] = 0.903 ± 0.017, 0.875 ± 0.021, and 0.912 ± 0.041, respectively, all p < 0.01). Asian participants were less likely to be exposed to any PIM (odds ratio [OR] ± SE = 0.619 ± 0.118, p < 0.05). Compared to White participants, Black participants were less likely to be exposed to benzodiazepine (OR ± SE = 0.609 ± 0.094, p < 0.01) and antidepressant (OR ± SE = 0.416 ± 0.103, p < 0.001) PIMs, but greater antipsychotic (OR ± SE = 1.496 ± 0.204, p < 0.01), cardiovascular (OR ± SE = 2.193 ± 0.255, p < 0.001), and skeletal muscle relaxant (OR ± SE = 2.977 ± 0.860, p < 0.001) PIMs. Hispanic participants were exposed to greater skeletal muscle relaxant PIMs and had lower anticholinergic burden. Asian participants were exposed to fewer benzodiazepine PIMs. DISCUSSION: Significant racial and ethnic disparities in exposure to PIMs and PIMs by medication category in dementia research participants who have access to dementia experts found in the study suggest that disparities may be wider in the larger community.

Pediatric Critical Care Illness Severity Toolkit: Stata Commands for Calculation of Pediatric Index of Mortality and Pediatric Logistic Organ Dysfunction Scores.

Introduction: Illness severity scoring tools, such as PRISM III/IV, PIM-3, and PELOD-2, are widely used in pediatric critical care research. However, their application is hindered by complex calculation processes, privacy concerns with third-party online calculators, and challenges in accurate implementation within statistical packages. Methods: We have developed a comprehensive, open-source toolkit for implementing the PIM-3, Simplified PIM-3, and PELOD-2 scores. The toolkit includes the pim3 and pelod2 commands and is compatible with Stata versions 12 and above. It features robust data validation, error messaging, a graphical interface, and support for SI and Imperial units. The toolkit's accuracy was validated through unit testing and synthetic data, comparing results with existing implementations. Results: In performance tests, the toolkit exhibited a median processing time of 21.82 seconds for PELOD-2, 14.06 seconds for PIM-3, and 9.74 seconds for Simplified PIM-3, when applied to datasets of 10,000,000 records. It consistently achieved 100% accuracy in both synthetic data tests and manual spot checks. Conclusion: The toolkit decreases processing time and improves accuracy in calculating pediatric critical care severity scores such as PELOD-2, PIM-3, and Simplified PIM-3. Its application in large datasets and validation highlights its utility as a tool for streamlining pediatric critical care research.

Risk of falls or fall-related injuries associated with potentially inappropriate medication use among older adults with dementia.

BACKGROUND: Potentially inappropriate medications (PIMs) are prevalent in older adults with dementia and subsequent falls or fall-related injuries. The present study determined the risk of falls or fall-related injuries associated with PIM use in older adults with dementia. METHODS: The National Health Insurance Service-Elderly Cohort Database 2.0 (NHIS-ECDB 2.0) was used for this self-controlled case series (SCCS) study. This study included 1430 participants who went through exposure and non-exposure periods of PIM application among patients with dementia and experienced outcome events of falls or fall-related injuries between January 2016 and December 2019. The incidence of falls or fall-related injuries during the exposure and post-exposure periods was compared with that during the non-exposure period. Beers Criteria were used to define PIMs in patients with dementia. Negative binomial regression was conducted. The incidence rate ratio (IRR) was used to determine the risk of falls or fall-related injuries. RESULTS: During the exposure periods in which falls or fall-related injuries occurred, the mean number of PIMs among patients with dementia was 3.76 (SD = 2.99), and the most commonly used PIMs among patients with dementia were first-generation antihistamines (n = 283; 59.1%). Compared to the non-exposure period, the adjusted IRR during the exposure period was 1.57 (95% CI = 1.39-1.76). The risk of falls or fall-related injuries was increased when PIM use in patients with dementia was initiated (1-14 days: IRR = 2.76, 95% CI = 2.31-3.28; 15-28 days: IRR = 1.95, 95% CI = 1.48-2.56; ≥ 29 days: IRR = 1.17, 95% CI = 1.01-1.35). Especially, an increased risk of falls or fall-related injuries was associated with greater PIM use among patients with dementia. CONCLUSION: Among older adults with dementia, PIMs significantly increase the risk of falls and fall-related injuries. Therefore, strategies should be developed to manage PIM prescriptions in patients with dementia to prevent falls.

The role of Pim-1 kinases in inflammatory signaling pathways.

OBJECTIVE AND DESIGN: This observational study investigated the regulatory mechanism of Pim-1 in inflammatory signaling pathways. MATERIALS: THP-1, RAW 264.7, BV2, and Jurkat human T cell lines were used. TREATMENT: None. METHODS: Lipopolysaccharide (LPS) was used to induce inflammation, followed by PIM1 knockdown. Western blot, immunoprecipitation, immunofluorescence, and RT-PCR assays were used to assess the effect of PIM1 knockdown on LPS-induced inflammation. RESULTS: PIM1 knockdown in macrophage-like THP-1 cells suppressed LPS-induced upregulation of pro-inflammatory cytokines, inducible nitric oxide synthase, cyclooxygenase-2, phosphorylated Janus kinase, signal transducer and activator of transcription 3, extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, and nuclear factor kappa B p65 (NF-κB p65). It also suppressed upregulation of inhibitor of NF-κB kinase α/ß and enhanced the nuclear translocation of NF-κB p65. Moreover, it inhibited the upregulation of Nod-like receptor family pyrin domain-containing 3 (NLRP3) and cleavage of caspase-1 induced by co-treatment of LPS with adenosine triphosphate. Additionally, p-transforming growth factor-ß-activated kinase 1 (TAK1) interacted with Pim-1. All three members of Pim kinases (Pim-1, Pim-2, and Pim-3) were required for LPS-mediated inflammation in macrophages; however, unlike Pim-1 and Pim-3, Pim-2 functioned as a negative regulator of T cell activity. CONCLUSIONS: Pim-1 interacts with TAK1 in LPS-induced inflammatory responses and is involved in MAPK/NF-κB/NLRP3 signaling pathways. Additionally, considering the negative regulatory role of Pim-2 in T cells, further in-depth studies on their respective functions are needed.

PIM1-HDAC2 axis modulates intestinal homeostasis through epigenetic modification.

The mucosal barrier is crucial for intestinal homeostasis, and goblet cells are essential for maintaining the mucosal barrier integrity. The proviral integration site for Moloney murine leukemia virus-1 (PIM1) kinase regulates multiple cellular functions, but its role in intestinal homeostasis during colitis is unknown. Here, we demonstrate that PIM1 is prominently elevated in the colonic epithelia of both ulcerative colitis patients and murine models, in the presence of intestinal microbiota. Epithelial PIM1 leads to decreased goblet cells, thus impairing resistance to colitis and colitis-associated colorectal cancer (CAC) in mice. Mechanistically, PIM1 modulates goblet cell differentiation through the Wnt and Notch signaling pathways. Interestingly, PIM1 interacts with histone deacetylase 2 (HDAC2) and downregulates its level via phosphorylation, thereby altering the epigenetic profiles of Wnt signaling pathway genes. Collectively, these findings investigate the unknown function of the PIM1-HDAC2 axis in goblet cell differentiation and ulcerative colitis/CAC pathogenesis, which points to the potential for PIM1-targeted therapies of ulcerative colitis and CAC.

National patterns of paroxetine use among US Medicare patients from 2015-2020.

Introduction: Paroxetine is an older "selective" serotonin reuptake inhibitor (SSRI) that is notable for its lack of selectivity, resulting in an anticholinergic adverse-effect profile, especially among older adults (65+). Methods: Paroxetine prescription rates and costs per state were ascertained from the Medicare Specialty Utilization and Payment Data. States' annual prescription rate, corrected per thousand Part D enrollees, outside a 95% confidence interval were considered significantly different from the average. Results: Nationally, there was a steady decrease in population-corrected paroxetine prescriptions (-34.52%) and spending (-29.55%) from 2015-2020 but a consistent, five-fold state-level difference. From 2015-2020, Kentucky (194.9, 195.3, 182.7, 165.1, 143.3, 132.5) showed significantly higher prescriptions rates relative to the national average, and Hawaii (42.1, 37.9, 34.3, 31.7, 27.7, 26.6) showed significantly lower prescription rates. North Dakota was often a frequently elevated prescriber of paroxetine (2016: 170.7, 2018: 143.3), relative to the average. Neuropsychiatry and geriatric medicine frequently prescribed the most paroxetine, relative to the number of providers in that specialty, from 2015-2020. Discussion: Despite the American Geriatrics Society's prohibition against paroxetine use in older adults and many effective treatment alternatives, paroxetine was still commonly used in the US in this population, especially in Kentucky and North Dakota and by neuropsychiatry and geriatric medicine. These findings provide information on the specialty types and states where education and policy reform would likely have the greatest impact on improving adherence to the paroxetine prescription recommendations.

Facile Polymer of Intrinsic Microporosity-Modified Separator with Quite-Low Loading for Enhanced-Performance Lithium Metal Batteries.

Lithium metal batteries (LMBs) using Li metals as anodes are conspicuous for high-energy-density energy-storage devices. However, the nonuniform deposition of Li+ ions leading to uncontrolled Li dendrite growth, which adversely affects electrochemical performance and safety, has impeded the practical application of lithium metal batteries (LMBs). Herein, PIM-1, a type of polymer of intrinsic microporosity (PIM), was utilized for surface engineering of conventional polyolefin separators. This process resulted in the formation of a continuous and homogeneous coating across the separator, facilitating uniform Li+ ion flux and deposition, and consequently reducing dendrite formation. Notably, the loading mass was quite low (0.6 g/m2) through the convenient dipping method. The intrinsic micropores and polar groups (cyano and ether groups) of PIM-1 greatly improved the electrolyte wettability and ionic conductivity of commercial polypropylene (PP) separators. And the PIM-1 coating guided Li+ flux to achieve uniform Li deposition. Moreover, the polar groups (cyano and ether groups) of PIM-1 are beneficial to the desolvation of Li+-solvates. As a result, the synergetic effect of uniform Li+ flux, desolvation, and enhanced mechanical strength of separators brings about considerable improvement in cycle life, suppression of Li dendrite, and Coulombic efficiency for LMBs. As this surface engineering is simple, relatively low-cost, and effective, this work provides fresh insights into separators for LMBs.

High rate of potentially inappropriate medication use in older people: a case-control study.

Annually, 172 million fall events cause temporary or permanent impairment in older adults, and this number is increasing. Contributing factors that increase the risk for falls include age, polypharmacy, and malnutrition. This study evaluated medications mainly included in the EU(7)-PIM (potentially inappropriate medication) list. From March 21, 2022, to July 6, 2022, 945 patients who experienced a fall and visited the Department of Emergency Medicine at the Albert Szent-Györgyi Health Centre of the University of Szeged in Hungary. Data from 886 patients were collected (study group). The control group included 1364 patient data collected from three general practice in Hungary. The use of ≥ 2 EU(7)-PIM drugs was found to be associated with increased risk for falls (adjusted odds ratio [AOR], 1.38; 95% confidence interval [CI] 1.01-1.88). Piracetam (AOR, 1.81; 95% CI, 1.28-2.57) and trimetazidine (AOR, 1.62; 95% CI, 1.17-2.24) were associated with increased risk for falls. Doxazosin was associated with a low risk for falls (AOR, 0.59; 95% CI, 0.41-0.86). Tiapride (AOR, 3.54; 95% CI, 1.75-7.17), gliclazide (AOR, 1.57; 95% CI, 1.02-2.43), and vinpocetine (AOR, 1.95; 95% CI, 1.29-2.95) are not included in the EU(7)-PIM list; however, they are associated with increased risk for falls. Long-acting benzodiazepines (AOR, 1.79; 95% CI, 1.20-2.68), antidepressants (AOR, 1.89; 95% 95% CI, 1.37-2.61), serotonin-norepinephrine reuptake inhibitor (AOR, 2.82; 95% CI, 1.41-5.67; p < 0.01), and selective serotonin reuptake inhibitor (AOR, 1.88; 95% CI, 1.24-2.85) were also associated with increased risk for falls. However, Z-drugs were associated with a low risk for falls (AOR, 0.57; 95% CI, 0.36-0.92). With the help of this tool, trimetazidine and piracetam are filtered as EU(7)-PIM drugs associated with increased risk for falls.

Targeting prostate cancer via therapeutic targeting of PIM-1 kinase by Naringenin and Quercetin.

PIM-1 kinase belongs to the Ser/Thr kinases family, an attractive therapeutic target for prostate cancer. Here, we screened about 100 natural substances to find potential PIM-1 inhibitors. Two natural compounds, Naringenin and Quercetin, were finally selected based on their PIM-1 inhibitory potential and binding affinities. The docking score of Naringenin and Quercetin with PIM-1 is -8.4 and - 8.1 kcal/mol, respectively. Fluorescence binding studies revealed a strong affinity (Ka values, 3.1 × 104 M-1 and 4.6 × 107 M-1 for Naringenin and Quercetin, respectively) with excellent IC50 values for Naringenin and Quercetin (28.6 µM and 34.9 µM, respectively). Both compounds inhibited the growth of prostate cancer cells (LNCaP) in a dose-dependent manner, with the IC50 value of Naringenin at 17.5 µM and Quercetin at 8.88 µM. To obtain deeper insights into the PIM-1 inhibitory effect of Naringenin and Quercetin, we performed extensive molecular dynamics simulation studies, which provided insights into the binding mechanisms of PIM-1 inhibitors. Finally, Naringenin and Quercetin were suggested to serve as potent PIM-1 inhibitors, offering targeted treatments of prostate cancer. In addition, our findings may help to design novel Naringenin and Quercetin derivatives that could be effective in therapeutic targeting of prostate cancer.

Pim Kinase Inhibition Disrupts CXCR4 Signalling in Megakaryocytes and Platelets by Reducing Receptor Availability at the Surface.

A key step in platelet production is the migration of megakaryocytes to the vascular sinusoids within the bone marrow. This homing is mediated by the chemokine CXCL12 and its receptor CXCR4. CXCR4 is also a positive regulator of platelet activation and thrombosis. Pim-1 kinase has been shown to regulate CXCR4 signalling in other cell types, and we have previously described how Pim kinase inhibitors attenuate platelet aggregation to CXCL12. However, the mechanism by which Pim-1 regulates CXCR4 signalling in platelets and megakaryocytes has yet to be elucidated. Using human platelets, murine bone marrow-derived megakaryocytes, and the megakaryocyte cell line MEG-01, we demonstrate that pharmacological Pim kinase inhibition leads to reduced megakaryocyte and platelet function responses to CXCL12, including reduced megakaryocyte migration and platelet granule secretion. Attenuation of CXCL12 signalling was found to be attributed to the reduced surface expression of CXCR4. The decrease in CXCR4 surface levels was found to be mediated by rapid receptor internalisation, in the absence of agonist stimulation. We demonstrate that pharmacological Pim kinase inhibition disrupts megakaryocyte and platelet function by reducing constitutive CXCR4 surface expression, decreasing the number of receptors available for agonist stimulation and signalling. These findings have implications for the development and use of Pim kinase inhibitors for the treatment of conditions associated with elevated circulating levels of CXCL12/SDF1α and increased thrombotic risk.