Enhanced High-Temperature Cycling Stability of Garnet-Based All Solid-State Lithium Battery Using a Multi-Functional Catholyte Buffer Layer.

The pursuit of safer and high-performance lithium-ion batteries (LIBs) has triggered extensive research activities on solid-state batteries, while challenges related to the unstable electrode-electrolyte interface hinder their practical implementation. Polymer has been used extensively to improve the cathode-electrolyte interface in garnet-based all-solid-state LIBs (ASSLBs), while it introduces new concerns about thermal stability. In this study, we propose the incorporation of a multi-functional flame-retardant triphenyl phosphate additive into poly(ethylene oxide), acting as a thin buffer layer between LiNi0.8Co0.1Mn0.1O2 (NCM811) cathode and garnet electrolyte. Through electrochemical stability tests, cycling performance evaluations, interfacial thermal stability analysis and flammability tests, improved thermal stability (capacity retention of 98.5% after 100 cycles at 60 °C, and 89.6% after 50 cycles at 80 °C) and safety characteristics (safe and stable cycling up to 100 °C) are demonstrated. Based on various materials characterizations, the mechanism for the improved thermal stability of the interface is proposed. The results highlight the potential of multi-functional flame-retardant additives to address the challenges associated with the electrode-electrolyte interface in ASSLBs at high temperature. Efficient thermal modification in ASSLBs operating at elevated temperatures is also essential for enabling large-scale energy storage with safety being the primary concern.

Serum amyloid A and mitochondrial DNA in extracellular vesicles are novel markers for detecting traumatic brain injury in a mouse model.

This study investigates the potential use of circulating extracellular vesicles' (EVs) DNA and protein content as biomarkers for traumatic brain injury (TBI) in a mouse model. Despite an overall decrease in EVs count during the acute phase, there was an increased presence of exosomes (CD63+ EVs) during acute and an increase in microvesicles derived from microglia/macrophages (CD11b+ EVs) and astrocytes (ACSA-2+ EVs) in post-acute TBI phases, respectively. Notably, mtDNA exhibited an immediate elevation post-injury. Neuronal (NFL) and microglial (Iba1) markers increased in the acute, while the astrocyte marker (GFAP) increased in post-acute TBI phases. Novel protein biomarkers (SAA, Hp, VWF, CFD, CBG) specific to different TBI phases were also identified. Biostatistical modeling and machine learning identified mtDNA and SAA as decisive markers for TBI detection. These findings emphasize the importance of profiling EVs' content and their dynamic release as an innovative diagnostic approach for TBI in liquid biopsies.

Perovskite-Based Electrocatalysts for Cost-Effective Ultrahigh-Current-Density Water Splitting in Anion Exchange Membrane Electrolyzer Cell.

Development of cost-effective water splitting technology that allows low-overpotential operation at high current density with non-precious catalysts is the key for large-scale hydrogen production. Herein, it is demonstrated that the versatile perovskite-based oxides, usually applied for operating at low current density and room temperature in alkaline solution, can be developed into low-cost, highly active and durable electrocatalysts for operating at high current densities in a zero-gap anion exchange membrane electrolyzer cell (AEMEC). The composite perovskite with mixed phases of Ruddlesden-Popper and single perovskite is applied as the anode in AEMEC and exhibits highly promising performance with an overall water-splitting current density of 2.01 A cm-2 at a cell voltage of only 2.00 V at 60 °C with stable performance. The elevated temperature to promote anion diffusion in membrane boosts oxygen evolution kinetics by enhancing lattice-oxygen participation. The bifunctionality of perovskites further promises the more cost-effective symmetrical AEMEC configuration, and a primary cell with the composite perovskite as both electrodes delivers 3.00 A cm-2 at a cell voltage of only 2.42 V. This work greatly expands the use of perovskites as robust electrocatalysts for industrial water splitting at high current density with great practical application merit.

Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor.

KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.

Oxidative stress induces Z-DNA-binding protein 1-dependent activation of microglia via mtDNA released from retinal pigment epithelial cells.

Oxidative stress, inflammation, and aberrant activation of microglia in the retina are commonly observed in ocular pathologies. In glaucoma or age-related macular degeneration, the chronic activation of microglia affects retinal ganglion cells and photoreceptors, respectively, contributing to gradual vision loss. However, the molecular mechanisms that cause activation of microglia in the retina are not fully understood. Here we show that exposure of retinal pigment epithelial (RPE) cells to chronic low-level oxidative stress induces mitochondrial DNA (mtDNA)-specific damage, and the subsequent translocation of damaged mtDNA to the cytoplasm results in the binding and activation of intracellular DNA receptor Z-DNA-binding protein 1 (ZBP1). Activation of the mtDNA/ZBP1 pathway triggers the expression of proinflammatory markers in RPE cells. In addition, we show that the enhanced release of extracellular vesicles (EVs) containing fragments of mtDNA derived from the apical site of RPE cells induces a proinflammatory phenotype of microglia via activation of ZBP1 signaling. Collectively, our report establishes oxidatively damaged mtDNA as an important signaling molecule with ZBP1 as its intracellular receptor in the development of an inflammatory response in the retina. We propose that this novel mtDNA-mediated autocrine and paracrine mechanism for triggering and maintaining inflammation in the retina may play an important role in ocular pathologies. Therefore, the molecular mechanisms identified in this report are potentially suitable therapeutic targets to ameliorate development of ocular pathologies.

Therapy Processes Associated With Sudden Gains in Cognitive Therapy for Depression: Exploring Therapeutic Changes in the Sessions Surrounding the Gains.

Background: The frequency and clinical impact of Sudden Gains-large symptom improvements during a single between-session interval-in psychotherapy for depression have been well established. However, there have been relatively few efforts to identify the processes that lead to sudden gains. Aim: To explore therapy processes associated with sudden gains in cognitive therapy for depression by examining changes in the sessions surrounding the gains, and the session preceding the gain in particular. Methods: Using ratings of video-recordings (n = 36), we assessed the content, frequency and magnitude of within-session cognitive-, behavioral-, and interpersonal change, as well as the quality of the therapeutic alliance in the session prior to the gain (pre-gain session), the session after the gain (post-gain session) and a control session. After that, we contrasted scores in the pre-gain session with those in the control session. In addition, we examined changes that occurred between the pre- and post-gain session (between-session changes) and explored patients' attributions of change. Results: Although not statistically significant, within-session changes were more frequent and stronger in the pre-gain session compared to the control session. The largest difference between the pre-gain and control session was found in the behavioral domain, and reached the level of trend-significance. There were more, and more impactful between-session changes in the interval during which the gain occurred as compared to a control interval. Exploratory analysis of attributions of change revealed eight subcategories, all corresponding with the cognitive-, behavioral- and interpersonal- domain. The quality of the therapeutic alliance was high and almost identical in all sessions. Conclusion: In spite of its small sample size, our study provides relevant descriptive information about potential precipitants of, themes related to, and attributions given for sudden gains. Furthermore, our study provides clear suggestions for future research. A better understanding of session content in the sessions surrounding sudden gains may provide insight into the mechanisms of change in psychotherapy, hereby suggesting treatment-enhancing strategies. We encourage researchers to conduct research that could clarify the nature of these mechanisms, and believe the methods used in this study could serve as a framework for further work in this area.

Inhibition of bacterial adherence to biomaterials by coating antimicrobial peptides with anionic surfactant.

Medical devices are widely used in modern medicine, but their utilities are often limited by the biofilm formation of bacteria that are tolerant to most antibiotics. In this report, antimicrobial peptides (AMPs) were coated onto biomaterials by the aid of surfactant through hydrophobic interactions. To increase the coating efficiency, stability of AMPs in body fluids and spectrum of antimicrobial activity, pairs of AMPs were coated simultaneously onto various substrates, such as silicone, polyurethane and titanium, which are commonly used components of biomedical devices. These coated AMPs exhibited very low cytotoxicity and hemolytic activities because they were gradually released into urine or serum. The AMP pairs, such as T9W + SAAP159 and T9W + RRIKA, coated onto the silicone discs were able to inhibit in vitro bacterial adherence in urine. Most importantly, AMP pairs coated onto the silicone tubing by surfactant SDBS could prevent bacterial adherence to mouse bladder and the silicone tubing implanted within it. These results provide a promising approach towards circumventing urinary catheter-associated infections caused by bacterial adherence.

Role of zinc transporter ZIP12 in susceptibility-weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function.

Brain zinc dysregulation is linked to many neurological disorders. However, the mechanisms regulating brain zinc homeostasis are poorly understood. We performed secondary analyses of brain MRI GWAS and exome sequencing data from adults in the UK Biobank. Coding ZIP12 polymorphisms in zinc transporter ZIP12 (SLC39A12) were associated with altered brain susceptibility weighted MRI (swMRI). Conditional and joint association analyses revealed independent GWAS signals in linkage disequilibrium with 2 missense ZIP12 polymorphisms, rs10764176 and rs72778328, with reduced zinc transport activity. ZIP12 rare coding variants predicted to be deleterious were associated with similar impacts on brain swMRI. In Neuro-2a cells, ZIP12 deficiency by short hairpin RNA (shRNA) depletion or CRISPR/Cas9 genome editing resulted in impaired mitochondrial function, increased superoxide presence, and detectable protein carbonylation. Inhibition of Complexes I and IV of the electron transport chain reduced neurite outgrowth in ZIP12 deficient cells. Transcriptional coactivator PGC-1α, mitochondrial superoxide dismutase (SOD2), and chemical antioxidants α-tocopherol, MitoTEMPO, and MitoQ restored neurite extension impaired by ZIP12 deficiency. Mutant forms of α-synuclein and tau linked to familial Parkinson's disease and frontotemporal dementia, respectively, reduced neurite outgrowth in cells deficient in ZIP12. Zinc and ZIP12 may confer resilience against neurological diseases or premature aging of the brain.

Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.

Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.

Anionic Surfactant-Facilitated Coating of Antimicrobial Peptide and Antibiotic Reduces Biomaterial-Associated Infection.

Medical devices are widely used in modern medicine, but the high prevalence of biomaterial-associated infections still presents a major problem. Especially problematic is the formation of biofilms that are tolerant to most antibiotics. In this report, antimicrobial peptides (AMPs) were driven into an amphipathic structure by anionic surfactant. To increase the coating efficacy and spectrum of antimicrobial activity, the AMPs were coated simultaneously with antibiotic, Polymyxin B, by surfactant onto polystyrene, silicone, polyurethane, and titanium which are commonly used with biomedical devices. These coated antimicrobials stably adhered to the substrate and were gradually released into urine and serum. They exhibited high bactericidal activity, but low cytotoxicity and hemolytic activity. Most importantly, the antimicrobials coated onto silicone tubing inhibited the planktonic growth of E. coli in mouse urine and also markedly prevented bacterial adherence to the bladder and the silicone tubing implanted in the bladder. These results provide a promising approach to circumvent catheter-associated infections due to bacterial adherence.

Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair.

BACKGROUND: The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated. METHODS: To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI. RESULTS: Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate. CONCLUSIONS: Gut microbiota-derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.

Prostaglandin E2 Receptor 2 Modulates Macrophage Activity for Cardiac Repair.

Background Prostaglandin E2 has long been known to be an immune modulator. It is released after tissue injury and plays a role in modulating macrophage activities, which are essential for tissue regeneration. However, the involvement of prostaglandin E2 receptor 2 ( EP 2)-dependent regulation of macrophages in postischemic heart is unclear. This study aims to evaluate the role of EP 2 in damaged heart. Methods and Results The effect of EP 2 in postischemic heart was evaluated using EP 2-deficient transgenic mice. We demonstrated that cardiac function was worse after myocardial injury on loss of EP 2. Furthermore, EP 2 deficiency also altered proinflammatory response and resulted in a defect in macrophage recruitment to the injured myocardium. Transcriptome analysis revealed that the expression of erythroid differentiation regulator 1 ( Erdr1) was significantly induced in EP 2-deficient macrophages. Knocking down Erdr1 expression restored migration ability of EP 2-deficient cells both in vitro and in vivo. By using a genetic fate-mapping approach, we showed that abolishment of EP 2 expression effectively attenuated cell replenishment. Conclusions The EP 2-dependent signaling pathway plays a critical role in regulating macrophage recruitment to the injured myocardium, thereby exerting a function in modulating the inflammatory microenvironment for cardiac repair.

Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity.

KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted.

Harnessing the early post-injury inflammatory responses for cardiac regeneration.

Cardiac inflammation is considered by many as the main driving force in prolonging the pathological condition in the heart after myocardial infarction. Immediately after cardiac ischemic injury, neutrophils are the first innate immune cells recruited to the ischemic myocardium within the first 24 h. Once they have infiltrated the injured myocardium, neutrophils would then secret proteases that promote cardiac remodeling and chemokines that enhance the recruitment of monocytes from the spleen, in which the recruitment peaks at 72 h after myocardial infarction. Monocytes would transdifferentiate into macrophages after transmigrating into the infarct area. Both neutrophils and monocytes-derived macrophages are known to release proteases and cytokines that are detrimental to the surviving cardiomyocytes. Paradoxically, these inflammatory cells also play critical roles in repairing the injured myocardium. Depletion of either neutrophils or monocytes do not improve overall cardiac function after myocardial infarction. Instead, the left ventricular function is further impaired and cardiac fibrosis persists. Moreover, the inflammatory microenvironment created by the infiltrated neutrophils and monocytes-derived macrophages is essential for the recruitment of cardiac progenitor cells. Recent studies also suggest that treatment with anti-inflammatory drugs may cause cardiac dysfunction after injury. Indeed, clinical studies have shown that traditional ant-inflammatory strategies are ineffective to improve cardiac function after infarction. Thus, the focus should be on how to harness these inflammatory events to either improve the efficacy of the delivered drugs or to favor the recruitment of cardiac progenitor cells.

Discovery of dual positive allosteric modulators (PAMs) of the metabotropic glutamate 2 receptor and CysLT1 antagonists for treating migraine headache.

Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu2 receptor. The hydroxyacetophenone scaffold is a second series of mGlu2 PAMs we have identified. This series of molecules are potent mGlu2 potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold.

Specific Pharmacological Effects of Paroxetine Comprise Psychological but Not Somatic Symptoms of Depression.

BACKGROUND: Meta-analyses of placebo-controlled trials of SSRIs suggest that only a small portion of the observable change in depression may be attributed to "true" pharmacological effects. But depression is a multidimensional construct, so treatment effects may differ by symptom cluster. We tested the hypothesis that SSRIs uniquely alter psychological rather than somatic symptoms of depression and anxiety. METHOD: Outpatients with moderate to severe MDD were randomly assigned to receive paroxetine (n = 120) or placebo (n = 60). RESULTS: Paroxetine significantly outperformed placebo on all psychological subscales of the syndrome measures, but not on any of the somatic subscales. The difference in score reduction between paroxetine and placebo was more than twice as great for the psychological symptoms compared to the somatic symptoms. CONCLUSIONS: Paroxetine appears to have a "true" pharmacological effect on the psychological but not on the somatic symptoms of depression and anxiety. Paroxetine's influence on somatic symptoms appears to be mostly duplicated by placebo.

Review of the regulations for clinical research in herbal medicines in USA.

In 2012, USA Food and Drug Administration (FDA) approved 39 new drugs, however, there are only two botanical drugs (one topical and one oral) approved by FDA since the publication of the FDA's industry guidelines for the botanical drug product in June 2004. The approval shows the Western guideline can be used for herbal medicines, authors investigate current regulation on herbal medicine clinical research, identify challenges conducting clinical trials, and seek to produce some guidance for potential investigators and sponsors considering a clinical trial in this area. Key words were formulated for searching on Medline and FDA website to locate relevant regulations for clinical research in herbal medicines to understand current environment for herbal medicine usage and examine the barriers affecting herbal medicine in clinical trials. Authors critically explore case study of the 1st FDA approved botanical drugs, Veregen (sinecatechins), green tea leaves extract, a topical cream for perianal and genital condyloma. In consideration of current regulation environment in USA, based on the findings and analysis through the literature review and Veregen case study, authors produce and propose a Checklist for New Drug Application of Herbal Medicines for potential investigators and sponsors considering in a herbal medicine clinical trial.

Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists.

In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.

Discovery of 7-tetrahydropyran-2-yl chromans: ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid ß-protein (Aß) in the central nervous system.

In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2' sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aß1-40 production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (Cfree,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of Aß1-40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.

Design, synthesis, and structure-activity relationships of dihydrofuran-2-one and dihydropyrrol-2-one derivatives as novel benzoxazin-3-one-based mineralocorticoid receptor antagonists.

Dihydrofuran-2-one and dihydropyrrol-2-one derivatives were identified as novel, potent and selective mineralocorticoid receptor (MR) antagonists by the structure-based drug design approach utilizing the crystal structure of MR/compound complex. Introduction of lipophilic substituents directed toward the unfilled spaces of the MR and identification of a new scaffold, dihydropyrrol-2-one ring, led to potent in vitro activity. Among the synthesized compounds, dihydropyrrol-2-one 11i showed an excellent in vitro activity (MR binding IC50=43nM) and high selectivity over closely related steroid receptors such as the androgen receptor (AR), progesterone receptor (PR) and glucocorticoid receptor (GR) (>200-fold for AR and PR, 100-fold for GR).