Two Phase 3 Trials of Baricitinib for Alopecia Areata.

BACKGROUND: Alopecia areata is an autoimmune condition characterized by rapid hair loss in the scalp, eyebrows, and eyelashes, for which treatments are limited. Baricitinib, an oral, selective, reversible inhibitor of Janus kinases 1 and 2, may interrupt cytokine signaling implicated in the pathogenesis of alopecia areata. METHODS: We conducted two randomized, placebo-controlled, phase 3 trials (BRAVE-AA1 and BRAVE-AA2) involving adults with severe alopecia areata with a Severity of Alopecia Tool (SALT) score of 50 or higher (range, 0 [no scalp hair loss] to 100 [complete scalp hair loss]). Patients were randomly assigned in a 3:2:2 ratio to receive once-daily baricitinib at a dose of 4 mg, baricitinib at a dose of 2 mg, or placebo. The primary outcome was a SALT score of 20 or less at week 36. RESULTS: We enrolled 654 patients in the BRAVE-AA1 trial and 546 in the BRAVE-AA2 trial. The estimated percentage of patients with a SALT score of 20 or less at week 36 was 38.8% with 4-mg baricitinib, 22.8% with 2-mg baricitinib, and 6.2% with placebo in BRAVE-AA1 and 35.9%, 19.4%, and 3.3%, respectively, in BRAVE-AA2. In BRAVE-AA1, the difference between 4-mg baricitinib and placebo was 32.6 percentage points (95% confidence interval [CI], 25.6 to 39.5), and the difference between 2-mg baricitinib and placebo was 16.6 percentage points (95% CI, 9.5 to 23.8) (P<0.001 for each dose vs. placebo). In BRAVE-AA2, the corresponding values were 32.6 percentage points (95% CI, 25.6 to 39.6) and 16.1 percentage points (95% CI, 9.1 to 23.2) (P<0.001 for each dose vs. placebo). Secondary outcomes for baricitinib at a dose of 4 mg but not at a dose of 2 mg generally favored baricitinib over placebo. Acne, elevated levels of creatine kinase, and increased levels of low- and high-density lipoprotein cholesterol were more common with baricitinib than with placebo. CONCLUSIONS: In two phase 3 trials involving patients with severe alopecia areata, oral baricitinib was superior to placebo with respect to hair regrowth at 36 weeks. Longer trials are required to assess the efficacy and safety of baricitinib for alopecia areata. (Funded by Eli Lilly under license from Incyte; BRAVE-AA1 and BRAVE-AA2 ClinicalTrials.gov numbers, NCT03570749 and NCT03899259.).

Palmitoylation is required for Sept8-204 and Sept5 to form vesicle-like structure and colocalize with synaptophysin.

Sept8 is a vesicle associated protein and there are two typical transcriptional variants (Sept8-204 and Sept8-201) expressed in mice brain. Interestingly, the coexpression of Sept8-204/Sept5 induces the formation of small sized vesicle-like structure, while that of the Sept8-201/Sept5 produces large puncta. Sept8 is previously shown to be palmitoylated. Here it was further revealed that protein palmitoylation is required for Sept8-204/Sept5 to maintain small sized vesicle-like structure and colocalize with synaptophysin, since either the expression of nonpalmitoylated Sept8-204 mutant (Sept8-204-3CA) or inhibiting Sept8-204 palmitoylation by 2-BP with Sept5 produces large puncta, which barely colocalizes with synaptophysin (SYP). Moreover, it was shown that the dynamic palmitoylation of Sept8-204 is controlled by ZDHHC17 and PPT1, loss of ZDHHC17 decreases Sept8-204 palmitoylation and induces large puncta, while loss of PPT1 increases Sept8-204 palmitoylation and induces small sized vesicle-like structure. Together, these findings suggest that palmitoylation is essential for the maintenance of the small sized vesicle-like structure for Sept8-204/Sept5, and may hint their important roles in synaptic functions.

Systematic calibration of epitranscriptomic maps using a synthetic modification-free RNA library.

Recent years have witnessed rapid progress in the field of epitranscriptomics. Functional interpretation of the epitranscriptome relies on sequencing technologies that determine the location and stoichiometry of various RNA modifications. However, contradictory results have been reported among studies, bringing the biological impacts of certain RNA modifications into doubt. Here, we develop a synthetic RNA library resembling the endogenous transcriptome but without any RNA modification. By incorporating this modification-free RNA library into established mapping techniques as a negative control, we reveal abundant false positives resulting from sequence bias or RNA structure. After calibration, precise and quantitative mapping expands the understanding of two representative modification types, N6-methyladenosine (m6A) and 5-methylcytosine (m5C). We propose that this approach provides a systematic solution for the calibration of various RNA-modification mappings and holds great promise in epitranscriptomic studies.

Associations between long-term ozone exposure and small airways function in Chinese young adults: a longitudinal cohort study.

BACKGROUND: Increasing evidence is appearing that ozone has adverse effects on health. However, the association between long-term ozone exposure and lung function is still inconclusive. OBJECTIVES: To investigate the associations between long-term exposure to ozone and lung function in Chinese young adults. METHODS: We conducted a prospective cohort study among 1594 college students with a mean age of 19.2 years at baseline in Shandong, China from September 2020 to September 2021. Lung function indicators were measured in September 2020 and September 2021, including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), forced expiratory flow at the 25th, 50th, and 75th percentile of the FVC (FEF25, FEF50, and FEF75) and mean flow rate between 25% and 75% of the FVC (FEF25-75) were measured. Daily 10 km×10 km ozone concentrations come from a well-validated data-fusion approach. The time-weighted average concentrations in 12 months before the lung function test were defined as the long-term ozone exposure. The associations between long-term ozone exposure and lung function indicators in Chinese young adults were investigated using a linear mixed effects model, followed by stratified analyses regarding sex, BMI and history of respiratory diseases. RESULTS: Each interquartile range (IQR) (8.9 µg/m3) increase in long-term ozone exposure were associated with a -204.3 (95% confidence interval (CI): -361.6, -47.0) ml/s, -146.3 (95% CI: -264.1, -28.4) ml/s, and - 132.8 (95% CI: -239.2, -26.4) ml/s change in FEF25, FEF50, and FEF25-75, respectively. Stronger adverse associations were found in female participants or those with BMI ≥ 24 kg/m2 and history of respiratory diseases. CONCLUSION: Long-term exposure to ambient ozone is associated with impaired small airway indicators in Chinese young adults. Females, participants with BMI ≥ 24 kg/m2 and a history of respiratory disease have stronger associations.

Zwitterionic Aqua Palladacycles with Noncovalent Interactions for meta-Selective Suzuki Coupling of 3,4-Dichlorophenol and 3,4-Dichlorobenzyl Alcohol in Water.

The site-selective reaction of substrates with multiple reactive sites has been a focus of the current synthetic chemistry. The use of attractive noncovalent interactions between the catalyst and substrate is emerging as a versatile approach to address site-selectivity challenges. Herein, we designed and synthesized a series of palladacycles, to control meta-selective Suzuki coupling of 3,4-dichlorophenol and 3,4-dichlorobenzyl alcohol. Noncovalent interactions directed zwitterionic aqua palladacycles catalyzed meta-selective Suzuki couplings of 3,4-dichloroarenes bearing hydroxyl in water have been developed. Experiments and density functional theory (DFT) calculations demonstrated that the electrostatic interactions play a critical role in meta-selective coupling of 3,4-dichlorophenol, while meta-selective coupling of 3,4-dichlorobenzyl alcohol arises due to the hydrogen-bonding interactions.

Molecular Structures, Dipole Moments, and Electronic Properties of ß-HMX under External Electric Field from First-Principles Calculations.

In order to investigate the impact of an external electric field on the sensitivity of ß-HMX explosives, we employ first-principles calculations to determine the molecular structure, dipole moment, and electronic properties of both ß-HMX crystals and individual ß-HMX molecules under varying electric fields. When the external electric field is increasing along the [100], [010], and [001] crystallographic directions of ß-HMX, the calculation results indicate that an increase in the bond length (N1-N3/N1'-N3') of the triggering bond, an increase in the main Qnitro (N3, N3') value, an increase in the minimum surface electrostatic potential, and a decrease in band gap all contribute to a reduction in its stability. Among these directions, the [010] direction exhibits the highest sensitivity, which can be attributed to the significantly smaller effective mass along the [010] direction compared with the [001] and [100] directions. Moreover, the application of an external electric field along the Y direction of the coordinate system on individual ß-HMX molecules reveals that the strong polarization effect induced by the electric field enhances the decomposition of the N1-N3 bonds. In addition, due to the periodic potential energy of ß-HXM crystal, the polarization effect of ß-HMX crystal caused by an external electric field is much smaller than that of a single ß-HXM molecule.

CircRNAs regulate the crosstalk between inflammation and tumorigenesis: The bilateral association and molecular mechanisms.

Inflammation, a hallmark of cancer, has been associated with tumor progression, transition into malignant phenotype and efficacy of the chemotherapeutic agents in cancer. Chronic inflammation provides a favorable environment for tumorigenesis by inducing immunosuppression, whereas acute inflammation prompts tumor suppression by generating anti-tumor immune responses. Inflammatory factors derived from interstitial cells or tumor cells can stimulate cell proliferation and survival by modulating oncogenes and/or tumor suppressors. Recently, a new class of RNAs, i.e., circular RNAs (circRNAs), has been implicated in inflammatory diseases. Although there are reports on circRNAs imparting functions in inflammatory insults, whether these circularized transcripts hold the potential to regulate inflammation-induced cancer or tumor-related inflammation, and modulate the interactions between tumor microenvironment (TME) and the inflammatory stromal/immune cells, awaits further elucidation. Contextually, the current review describes the molecular association between inflammation and cancer, and spotlights the regulatory mechanisms by which circRNAs can moderate TME in response to inflammatory signals/triggers. We also present comprehensive information about the immune cell(s)-specific expression and functions of the circRNAs in TME, modulation of inflammatory signaling pathways to drive tumorigenesis, and their plausible roles in inflammasomes and tumor development. Moreover, the therapeutic potential of these circRNAs in harnessing inflammatory responses in cancer is also discussed.

Does the utilization of fluoroscopy affect the accuracy of prosthesis position in patients undergoing hip replacement surgery via the direct anterior approach compared to the posterolateral approach for an experienced surgeon? A single-center retrospective study.

BACKGROUND: The direct anterior approach (DAA) for total hip arthroplasty (THA) has gained popularity due to perceived advantages in achieving better early outcomes. However, the theoretical benefits such as precise implant positioning and accurate leg length restoration are still inconsistent. In this study, we compared implant position and leg length discrepancy (LLD) of the DAA and posterolateral approach (PLA) conducted by a single surgeon who had mastered both approaches. METHODS: This study retrospectively reviewed the medical records and radiographic images of 244 patients who underwent THA between 2012 and 2021 by a single experienced surgeon using either the DAA (n = 120) or PLA (n = 124). Postoperative pelvic anteroposterior radiographs at 6 months follow-up were used to assess acetabular component inclination and anteversion, as well as LLD. Mann-Whitney U tests and Chi-squared test were performed to compare outcomes between the two approaches. RESULTS: No significant differences were observed in patient demographics between the two groups. The DAA group demonstrated significantly lower postoperative LLD (0.00 mm) compared to the PLA group (5.00 mm, p < 0.0001). No significant difference was observed in the Lewinnek zone for cup anteversion and inclination angles between the two groups. CONCLUSIONS: For experienced surgeons in other approaches, our findings suggest transferring to the DAA may not substantially improve cup positioning, but it might slightly enhance limb length measurement. For surgeons already proficient in other approaches and deciding to maintain those approaches, their primary concern for optimal THA outcome should be striving for leg length equivalence.

Blood chromium and lung function among Chinese young adults: A comprehensive analysis based on epidemiology and metabolomics.

Chromium (Cr) exposure is associated with various respiratory system diseases, but there are limited studies investigating its impact on lung function in young adults. The Cr exposure-related metabolomic changes are not well elucidated. This study recruited 608 students from a university in Shandong Province, China in 2019. We used cohort design fitted with linear mixed-effects models to assess the association between blood Cr concentration and lung function. In addition, we performed metabolomic and lipidomic analyses of baseline serum samples (N = 582) using liquid chromatography-mass spectrometry. Two-step statistical analysis (analysis of variance and mixed-linear effect model) was used to evaluate the effect of blood Cr exposure on metabolites. We found that blood Cr was associated with decreased lung function in young adults. Each 2-fold increase in blood Cr concentrations was significantly associated with decreased FEV1 and FVC by 35.26 mL (95 % CI: -60.75, -9.78) and 38.56 mL (95 % CI: -66.60, -10.51), respectively. In the metabolomics analysis, blood Cr exposure was significantly associated with 14 key metabolites. The changed metabolites were mainly enriched in six pathways including lipid metabolism, amino acid metabolism, and cofactor vitamin metabolism. Blood Cr may affect lung function through oxidative stress and inflammation related pathways.

Impact of radish seeds (Semen Raphani) on the absorption and transportation of ginsenosides in the Caco-2 cell model: a UPLC-ESI-MS analysis.

This study examined the impact of Semen raphani on the absorption of ginsenosides from Panax ginseng C.A. Meyer (ginseng) using a Caco-2 cell model and Ultra-High-Performance Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry (UPLC-ESI-MS). Six primary ginsenosides (Rg1, Re, Rb1, Rb2, Rc, Rd) were quantified. Results showed that Semen Raphani increased the efflux rate of ginsenosides, particularly at higher concentrations, suggesting it inhibits their absorption. The research elucidates the intestinal absorption process of ginsenosides and the antagonistic mechanism of Semen Raphani against ginseng.

Smart Phototheranostics based on Carbon Nanohorns for Precise Imaging-Guided Post-PDT toward Residual Tumor Cells after Initial Phototherapy.

As promising photonic material, phototheranostics can be activated in the laser irradiation range of tumor with sensitivity and spatiotemporal precision. However, it is difficult to completely eradicate solid tumors due to their irregularity and limited laser irradiation area. Herein, multi-stimulus responsive HA-Ce6@SWNHs were constructed with single-walled carbon nanohorns (SWNHs) and chlorine e6 (Ce6) modified hyaluronic acid (HA) via non-covalent binding. This SWNHs-based phototheranostics not only exhibited water dispersion but also could target tumor and be activated by near-infrared light for photodynamic therapy (PDT) and photothermal therapy (PTT). Additionally, HA-Ce6@SWNHs could be degraded by hyaluronidase in residual tumor cells, causing HA-Ce6 to fall off the SWNHs surfaces to restore autofluorescence, thus precisely guiding the programmed photodynamic treatments for residual tumor cells after the initial phototherapy. Thus, this work provides a rationally designed multiple-stimulus-response strategy to develop smart SWNHs-based phototheranostics for precise PDT/PTT and post-treatment imaging-guided PDT of residual tumor cells.

Efficacy and safety of baricitinib in combination with topical corticosteroids in paediatric patients with moderate-to-severe atopic dermatitis with an inadequate response to topical corticosteroids: results from a phase III, randomized, double-blind, placebo-controlled study (BREEZE-AD PEDS).

BACKGROUND: Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, is approved in many countries for moderate-to-severe atopic dermatitis (AD) in adults who are candidates for systemic therapy. OBJECTIVES: To evaluate the efficacy and safety of three doses of baricitinib in combination with low-to-moderate potency topical corticosteroids in paediatric patients with moderate-to-severe AD. METHODS: Patients (aged 2 to < 18 years) were randomized (1 : 1 : 1 : 1) to once-daily baricitinib low dose (1 mg equivalent), medium dose (2 mg equivalent), high dose (4 mg equivalent) or placebo for 16 weeks. The primary endpoint was the proportion of patients achieving a validated Investigator Global Assessment® (vIGA-AD) of 0/1 with a ≥ 2-point improvement at week 16. Key secondary endpoints included the proportions of patients achieving ≥ 75% and ≥ 90% improvement in the Eczema Area and Severity Index (EASI-75 and EASI-90, respectively), ≥ 75% improvement in the SCORing Atopic Dermatitis (SCORAD 75), mean change from baseline in EASI score and proportion of patients achieving a 4-point improvement in the Itch Numeric Rating scale (NRS) for patients aged ≥ 10 years. Primary and key secondary efficacy analyses were conducted on the intent-to-treat population and adjusted for multiplicity. Safety analyses included all randomized patients who received ≥ 1 dose of study treatment. RESULTS: A total of 483 patients were randomized (mean age 12 years). The baricitinib 4 mg equivalent achieved a statistically significant (P < 0.05) improvement vs. placebo on all 16-week endpoints (vIGA 0/1 with ≥ 2-point improvement, EASI-75, EASI-90, SCORAD 75, mean change in EASI score and Itch NRS 4-point improvement for patients aged ≥ 10 years). Improvement (P < 0.05, non-multiplicity adjusted) was also observed for baricitinib 4 mg equivalent vs. placebo in the ability to fall asleep and in reduction of topical corticosteroid use. Few patients discontinued due to adverse events (1.6% for placebo and 0.6% for those treated with baricitinib). There were no deaths, venous thromboembolic events, arterial thrombotic events, major adverse cardiovascular events, malignancies, gastrointestinal perforations or opportunistic infections seen. CONCLUSIONS: The results indicate that baricitinib offers a potential therapeutic option with a favourable benefit-risk profile for paediatric patients with moderate-to-severe AD who are candidates for systemic therapies.

Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials.

BACKGROUND: Baricitinib, an oral, selective, reversible Janus kinase (JAK)1/JAK2 inhibitor, is an approved treatment for adults with severe alopecia areata (AA) in the USA, European Union and Japan. OBJECTIVES: To report safety data for baricitinib in patients with severe AA from two clinical trials including long-term extension periods. METHODS: This analysis includes pooled patient-level safety data from two trials, an adaptive phase II/III trial (BRAVE-AA1) and a phase III trial (BRAVE-AA2) (ClinicalTrials.gov, NCT03570749 and NCT03899259). Data are reported in three datasets: (i) the placebo-controlled dataset (up to week 36): baricitinib 2 mg and 4 mg vs. placebo; (ii) the extended dataset (up to the data cutoff): patients remaining on continuous treatment with baricitinib 2 mg or 4 mg from baseline; and (iii) the all-baricitinib dataset (all-BARI, up to the data cutoff): all patients receiving any dose of baricitinib at any time during the trials. Safety outcomes include treatment-emergent adverse events (TEAEs), adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IR) were calculated. RESULTS: Data were collected for 1303 patients who were given baricitinib, reflecting 1868 patient-years of exposure (median 532 days). The most frequently reported TEAEs during the placebo-controlled period (based on the baricitinib 4-mg group) were upper respiratory tract infection, nasopharyngitis, headache, acne and elevated blood creatine phosphokinase (CPK). During the placebo-controlled period, the frequency of acne was higher with baricitinib than placebo, and elevated CPK was higher with baricitinib 4 mg than placebo and baricitinib 2 mg. In all-BARI, the IR of serious infections was low (n = 16, IR 0.8). There was one opportunistic infection (IR 0.1), and 34 cases of herpes zoster (IR 1.8). There was one positively adjudicated major adverse cardiovascular event (myocardial infarction) (IR 0.1), one pulmonary embolism (IR 0.1), three malignancies other than nonmelanoma skin cancer (IR 0.2) and one gastrointestinal perforation (IR 0.1). No deaths were reported. CONCLUSIONS: This integrated safety analysis in patients with severe AA is consistent with the overall safety profile of baricitinib. Some differences with atopic dermatitis were noted that may be attributable to the disease characteristics of AA.

When to expect scalp hair regrowth during treatment of severe alopecia areata with baricitinib: insights from trajectories analyses of patients enrolled in two phase III trials.

BACKGROUND: Baricitinib is approved for the treatment of adults with severe alopecia areata (AA). In the absence of robust data on the patterns of regrowth during treatment of severe AA, there is a gap in the knowledge regarding treatment expectations. OBJECTIVES: To examine whether different clinical response subgroups could be identified in baricitinib-treated patients with severe AA and factors that contribute to these subgroups. METHODS: The BRAVE-AA1 and BRAVE-AA2 phase III trials enrolled patients with severe AA [Severity of Alopecia Tool (SALT) score ≥ 50 (≥ 50% scalp hair loss)]. Patients randomized to baricitinib 4 mg or 2 mg retained their treatment allocation for 52 weeks. Based on patterns identified through growth mixture modelling (GMM), patients were categorized into responder subgroups according to when they first achieved ≥ 30% improvement from baseline in SALT score (SALT30). For each responder subgroup, trajectories of response (i.e. achievement of a SALT score ≤ 20, SALT score ≤ 10 and ≥ 50% change from baseline in SALT score) and baseline disease characteristics are reported. RESULTS: Respectively, 515 and 340 patients were randomized to once-daily baricitinib 4 mg and 2 mg at baseline; 69% and 51%, respectively, achieved SALT30 at least once by week 52. Based on GMM findings, we identified three responder subgroups: early (SALT30 by week 12), gradual (SALT30 after week 12-week 36) and late (SALT30 after week 36-week 52). The proportions of early, gradual and late responders and nonresponders were, respectively, 33%, 28%, 8% and 31% among patients treated with baricitinib 4 mg, and 20%, 23%, 9% and 49%, respectively, among those treated with baricitinib 2 mg. Early responders had a shorter trajectory to maximal clinical outcomes (e.g. > 78% achieved a SALT score ≤ 20 by week 36) vs. gradual or late responders. Early responders were more frequent among patients with baseline severe AA (SALT score 50 to < 95) vs. very severe AA (SALT score 95-100). Overall, responders (early to late) were more frequent in patients with short (< 4 years) episodes of hair loss. CONCLUSIONS: These analyses identified early, gradual and late responder subgroups for scalp hair regrowth in baricitinib-treated patients with severe AA, and that these subgroups are influenced by baseline characteristics. Findings from these analyses will help to inform treatment expectations for scalp hair regrowth.

Environmental trade-offs and externalities of electrochemical-based batteries: Quantitative analysis between lithium-ion and vanadium redox flow units.

This study aims to increase the scientific knowledge of the environmental impacts and externalities of two promising electrochemical-based techniques for large-scale stationary energy storage: lithium nickel cobalt manganese (NCM) and vanadium redox flow (VRF) batteries. The global warming potential (GWP) and cumulative energy demand (CED) for NCM and VRF batteries are 28 kg CO2eq and 410 MJ and 186 kg CO2eq and 3080 MJ, respectively, for the provision of 1 MWh of electricity. While the trend of the environmental externality results is proportional to the environmental impact results, the environmental costs from GWP and terrestrial ecotoxicity impacts contribute the largest share of the total environmental costs for both batteries. Overall, NCM batteries have favorable environmental performance in terms of their impact values and externalities but still show relatively higher contributions in human toxicity and ozone layer depletion impacts, based on their high resource uses. The VRF batteries, on the other hand, report higher impacts in abiotic depletion, GWP and terrestrial ecotoxicity, mainly due to their great mass of the electrolyte. Our results highlight the importance of substituting the active metals with low-impact metals or carefully considering the origin of key materials while also taking advantage of the properties of the battery to carefully assess possible advancements in battery design. The environmental externality results also provide essential information for the future development of battery industries for stationary applications with energy and environmental benefits.

The nucleolar protein SAHY1 is involved in pre-rRNA processing and normal plant growth.

Although the nucleolus is involved in ribosome biogenesis, the functions of numerous nucleolus-localized proteins remain unclear. In this study, we genetically isolated Arabidopsis thaliana salt hypersensitive mutant 1 (sahy1), which exhibits slow growth, short roots, pointed leaves, and sterility. SAHY1 encodes an uncharacterized protein that is predominantly expressed in root tips, early developing seeds, and mature pollen grains and is mainly restricted to the nucleolus. Dysfunction of SAHY1 primarily causes the accumulation of 32S, 18S-A3, and 27SB pre-rRNA intermediates. Coimmunoprecipitation experiments further revealed the interaction of SAHY1 with ribosome proteins and ribosome biogenesis factors. Moreover, sahy1 mutants are less sensitive to protein translation inhibitors and show altered expression of structural constituents of ribosomal genes and ribosome subunit profiles, reflecting the involvement of SAHY1 in ribosome composition and ribosome biogenesis. Analyses of ploidy, S-phase cell cycle progression, and auxin transport and signaling indicated the impairment of mitotic activity, translation of auxin transport carrier proteins, and expression of the auxin-responsive marker DR5::GFP in the root tips or embryos of sahy1 plants. Collectively, these data demonstrate that SAHY1, a nucleolar protein involved in ribosome biogenesis, plays critical roles in normal plant growth in association with auxin transport and signaling.

Moonlighting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein of Lactobacillus gasseri attenuates allergic asthma via immunometabolic change in macrophages.

BACKGROUND: The extra-intestinal effects of probiotics for preventing allergic diseases are well known. However, the probiotic components that interact with host target molecules and have a beneficial effect on allergic asthma remain unknown. Lactobacillus gasseri attenuates allergic airway inflammation through the activation of peroxisome proliferator- activated receptor γ (PPARγ) in dendritic cells. Therefore, we aimed to isolate and investigate the immunomodulatory effect of the PPARγ activation component from L. gasseri. METHODS: Culture supernatants of L. gasseri were fractionated and screened for the active component for allergic asthma. The isolated component was subjected to in vitro functional assays and then cloned. The crystal structure of this component protein was determined using X-ray crystallography. Intrarectal inoculation of the active component-overexpressing Clear coli (lipopolysaccharide-free Escherichia coli) and intraperitoneal injection of recombinant component protein were used in a house dust mite (HDM)-induced allergic asthma mouse model to investigate the protective effect. Recombinant mutant component proteins were assayed, and their structures were superimposed to identify the detailed mechanism of alleviating allergic inflammation. RESULTS: A moonlighting protein, glycolytic glyceraldehyde 3-phosphate dehydrogenase (GAPDH), LGp40, that has multifunctional effects was purified from cultured L. gasseri, and the crystal structure was determined. Both intrarectal inoculation of LGp40-overexpressing Clear coli and intraperitoneal administration of recombinant LGp40 protein attenuated allergic inflammation in a mouse model of allergic asthma. However, CDp40, GAPDH isolated from Clostridium difficile did not possess this anti-asthma effect. LGp40 redirected allergic M2 macrophages toward the M1 phenotype and impeded M2-prompted Th2 cell activation through glycolytic activity that induced immunometabolic changes. Recombinant mutant LGp40, without enzyme activity, showed no protective effect against HDM-induced airway inflammation. CONCLUSIONS: We found a novel mechanism of moonlighting LGp40 in the reversal of M2-prompted Th2 cell activation through glycolytic activity, which has an important immunoregulatory role in preventing allergic asthma. Our results provide a new strategy for probiotics application in alleviating allergic asthma.

Phosphine-Mediated Morita-Baylis-Hillman-Type/Wittig Cascade: Access to E-Configured 3-Styryl- and 3-(Benzopyrrole/furan-2-yl) Quinolinones.

A phosphine-mediated, well-designed Morita-Baylis-Hillman-type/Wittig cascade for the rapid assembly of a quinolinone framework from benzaldehyde derivatives is developed for the first time. By rationally combining I2/NIS-mediated cyclization, biologically relevant 3-(benzopyrrole/furan-2-yl) quinolinones were facilely synthesized in a one-pot process by starting from 3-styryl-quinolinones bearing an o-hydroxy/amino group, significantly expanding the chemical space of this privileged skeleton. Further utility of this protocol is illustrated by successfully performing this transformation in a catalytic manner through in situ reduction of phosphine oxide by phenylsilane.

Exogenous glutathione exerts a therapeutic effect in ischemic stroke rats by interacting with intrastriatal dopamine.

We previously showed that oral administration of exogenous glutathione (GSH) exerted a direct and/or indirect therapeutic effect on ischemic stroke rats, but the underlying mechanisms remain elusive. In the current study, we conducted a quantitative proteomic analysis to explore the pathways mediating the therapeutic effect of GSH in cerebral ischemia/reperfusion (I/R) model rats. Rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. The rats were treated with GSH (250 mg/kg, ig) or levodopa (L-dopa, 100 mg/kg, ig) plus carbidopa (10 mg/kg, ig). Neurologic deficits were assessed, and the rats were sacrificed at 24 h after cerebral I/R surgery to measure brain infarct sizes. We conducted a proteomic analysis of the lesion side striatum samples and found that tyrosine metabolism and dopaminergic synapse were involved in the occurrence of cerebral stroke and the therapeutic effect of GSH. Western blot assay revealed that tyrosine hydroxylase (TH) mediated the occurrence of I/R-induced ischemic stroke and the therapeutic effect of GSH. We analyzed the regulation of GSH on endogenous small molecule metabolites and showed that exogenous GSH had the most significant effect on intrastriatal dopamine (DA) in I/R model rats by promoting its synthesis and inhibiting its degradation. To further explore whether DA-related alterations were potential targets of GSH, we investigated the therapeutic effect of DA accumulation on ischemic brain injury. The combined administration of the precursor drugs of DA (L-dopa and carbidopa) significantly ameliorated neurological deficits, reduced infarct size, and oxidative stress, and decreased pro-inflammatory cytokines levels in the striatum of I/R injury rats. More interestingly, exogenous L-dopa/carbidopa could also greatly enhance the exposure of intracerebral GSH by upregulating GSH synthetases and enhancing homocysteine (HCY) levels in the striatum. Thus, administration of exogenous GSH exerts a therapeutic effect on ischemic stroke by increasing intrastriatal DA, and the accumulated DA can, in turn, enhance the exposure of GSH and its related substances, thus promoting the therapeutic effect of GSH.

Two-Photon-Near Infrared-II Antimicrobial Graphene-Nanoagent for Ultraviolet-Near Infrared Imaging and Photoinactivation.

Nitrogen doping and amino group functionalization through chemical modification lead to strong electron donation. Applying these processes to a large π-conjugated system of graphene quantum dot (GQD)-based materials as electron donors increases the charge transfer efficiency of nitrogen-doped amino acid-functionalized GQDs (amino-N-GQDs), resulting in enhanced two-photon absorption, post-two-photon excitation (TPE) stability, TPE cross-sections, and two-photon luminescence through the radiative pathway when the lifetime decreases and the quantum yield increases. Additionally, it leads to the generation of reactive oxygen species through two-photon photodynamic therapy (PDT). The sorted amino-N-GQDs prepared in this study exhibited excitation-wavelength-independent two-photon luminescence in the near-infrared region through TPE in the near-infrared-II region. The increase in size resulted in size-dependent photochemical and electrochemical efficacy, increased photoluminescence quantum yield, and efficient two-photon PDT. Therefore, the sorted amino-N-GQDs can be applicable as two-photon contrast probes to track and localize analytes in in-depth two-photon imaging executed in a biological environment along with two-photon PDT to eliminate infectious or multidrug-resistant microbes.