HIGH PLOIDY2-mediated SUMOylation of transcription factor ARR1 controls two-component signaling in Arabidopsis.

Cytokinins regulate plant growth, development, and responses to environmental stresses such as cold via phosphorelay from cytokinin receptors to the ARABIDOPSIS RESPONSE REGULATORs (ARRs). However, the molecular mechanisms underlying the activation of type-B ARR transcriptional activity in Arabidopsis (Arabidopsis thaliana) remain unclear. Here, we show that the E3 SUMO ligase HIGH PLOIDY2 SUMOylates ARR1, a type-B ARR, at K236, triggering its activation. Cold- or cytokinin-induced phosphorylation of ARR1 at D89 is crucial for its interaction with HPY2. Lysine 236 is critical for ARR1's transactivation without compromising its DNA-binding ability, while D89 is crucial for ARR1's binding to target gene promoters. Cytokinin enhances ARR1's chromatin binding, but cold does not. ARR1 K236 plays a critical role in promoting histone H3 acetylation in response to both cytokinin and cold without affecting chromatin binding. The K236R mutation in ARR1 reduces target gene expression and alters cytokinin and cold response phenotypes. This study unveils a mechanism of ARR1 activation wherein phosphorylated ARR1 interacts with HPY2 and binds to chromatin in response to cytokinin. Cold triggers a phosphorelay targeting chromatin-bound ARR1. HPY2 then catalyzes ARR1 SUMOylation at K236, enhancing histone H3 acetylation and leading to transcriptional activation of ARR1 in response to both cold and cytokinin.

Cation-eutaxy-enabled III-V-derived van der Waals crystals as memristive semiconductors.

Novel two-dimensional semiconductor crystals can exhibit diverse physical properties beyond their inherent semiconducting attributes, making their pursuit paramount. Memristive properties, as exemplars of these attributes, are predominantly manifested in wide-bandgap materials. However, simultaneously harnessing semiconductor properties alongside memristive characteristics to produce memtransistors is challenging. Herein we prepared a class of semiconducting III-V-derived van der Waals crystals, specifically the HxA1-xBX form, exhibiting memristive characteristics. To identify candidates for the material synthesis, we conducted a systematic high-throughput screening, leading us to 44 prospective III-V candidates; of these, we successfully synthesized ten, including nitrides, phosphides, arsenides and antimonides. These materials exhibited intriguing characteristics such as electrochemical polarization and memristive phenomena while retaining their semiconductive attributes. We demonstrated the gate-tunable synaptic and logic functions within single-gate memtransistors, capitalizing on the synergistic interplay between the semiconducting and memristive properties of our two-dimensional crystals. Our approach guides the discovery of van der Waals materials with unique properties from unconventional crystal symmetries.

Tumor-intrinsic role of ICAM-1 in driving metastatic progression of triple-negative breast cancer through direct interaction with EGFR.

Triple-negative breast cancer (TNBC), the most aggressive subtype, presents a critical challenge due to the absence of approved targeted therapies. Hence, there is an urgent need to identify effective therapeutic targets for this condition. While epidermal growth factor receptor (EGFR) is prominently expressed in TNBC and recognized as a therapeutic target, anti-EGFR therapies have yet to gain approval for breast cancer treatment due to their associated side effects and limited efficacy. Here, we discovered that intercellular adhesion molecule-1 (ICAM-1) exhibits elevated expression levels in metastatic breast cancer and serves as a pivotal binding adaptor for EGFR activation, playing a crucial role in malignant progression. The activation of EGFR by tumor-expressed ICAM-1 initiates biased signaling within the JAK1/STAT3 pathway, consequently driving epithelial-to-mesenchymal transition and facilitating heightened metastasis without influencing tumor growth. Remarkably, ICAM-1-neutralizing antibody treatment significantly suppressed cancer metastasis in a breast cancer orthotopic xenograft mouse model. In conclusion, our identification of ICAM-1 as a novel tumor intrinsic regulator of EGFR activation offers valuable insights for the development of TNBC-specific anti-EGFR therapies.

ACVR1/ALK2-p21 signaling axis modulates proliferation of the venous endothelium in the retinal vasculature.

The proliferation of the endothelium is a highly coordinated process to ensure the emergence, expansion, and homeostasis of the vasculature. While Bone Morphogenetic Protein (BMP) signaling fine-tunes the behaviors of endothelium in health and disease, how BMP signaling influences the proliferation of endothelium and therefore, modulates angiogenesis remains largely unknown. Here, we evaluated the role of Activin A Type I Receptor (ACVR1/ALK2), a key BMP receptor in the endothelium, in modulating the proliferation of endothelial cells. We show that ACVR1/ALK2 is a key modulator for the proliferation of endothelium in the retinal vessels. Loss of endothelial ALK2 leads to a significant reduction in endothelial proliferation and results in fewer branches/endothelial cells in the retinal vessels. Interestingly, venous endothelium appears to be more susceptible to ALK2 deletion. Mechanistically, ACVR1/ALK2 inhibits the expression of CDKN1A/p21, a critical negative regulator of cell cycle progression, in a SMAD1/5-dependent manner, thereby enabling the venous endothelium to undergo active proliferation by suppressing CDKN1A/p21. Taken together, our findings show that BMP signaling mediated by ACVR1/ALK2 provides a critical yet previously underappreciated input to modulate the proliferation of venous endothelium, thereby fine-tuning the context of angiogenesis in health and disease.

The mediating effect of attentional impulsivity between mindfulness and problematic smartphone use.

OBJECTIVE: Problematic smartphone use has been linked to lower levels of mindfulness, impaired attentional function, and higher impulsivity. This study aimed to identify the psychological mechanisms of problematic smartphone use by exploring the relationship between addictive smartphone use, mindfulness, attentional function and impulsivity. METHODS: Ninety participants were evaluated with the smartphone addiction proneness scale and classified into the problematic smartphone use group (n = 42; 24 women; mean age: 27.6 ± 7.2 years) or normal use group (n = 48; 22 women; mean age: 30.1 ± 5.7 years). All participants completed self-report questionnaires evaluating their trait impulsivity and mindfulness and attention tests that assessed selective, sustained and divided attention. We compared the variables between the groups and explored the relationship between mindfulness, attentional function, impulsivity and addictive smartphone use through mediation analysis. RESULTS: The problematic smartphone use group showed higher trait impulsivity and lower mindfulness than the normal use group. There were no significant group differences in performance on attention tests. Levels of addictive smartphone use were significantly correlated with higher levels of trait impulsivity and lower levels of mindfulness, but not with performance on attention tests. Mediation analysis showed that acting with awareness, an aspect of mindfulness, reduces the degree of addictive smartphone use through attentional impulsivity, one of the trait impulsivity. CONCLUSION: Acting without sufficient awareness could influence addictive smartphone use by mediating attentional impulsivity. This supports that executive control deficits, reflected in high attentional impulsivity, contribute to problematic smartphone use. Our findings imply that mindfulness-based interventions can enhance executive control over smartphone use by promoting awareness.

Smartphone-Based Speech Therapy for Poststroke Dysarthria: Pilot Randomized Controlled Trial Evaluating Efficacy and Feasibility.

BACKGROUND: Dysarthria is a common poststroke speech disorder affecting communication and psychological well-being. Traditional speech therapy is effective but often poses challenges in terms of accessibility and patient adherence. Emerging smartphone-based therapies may offer promising alternatives for the treatment of poststroke dysarthria. OBJECTIVE: This study aimed to assess the efficacy and feasibility of smartphone-based speech therapy for improving speech intelligibility in patients with acute and early subacute poststroke dysarthria. This study also explored the impact of the intervention on psychological well-being, user experience, and overall feasibility in a clinical setting. METHODS: Participants were divided into 2 groups for this randomized, evaluator-blinded trial. The intervention group used a smartphone-based speech therapy app for 1 hour per day, 5 days per week, for 4 weeks, with guideline-based standard stroke care. The control group received standard guideline-based stroke care and rehabilitation. Speech intelligibility, psychological well-being, quality of life, and user acceptance were assessed using repeated measures ANOVA. RESULTS: In this study, 40 patients with poststroke dysarthria were enrolled, 32 of whom completed the trial (16 in each group). The intervention group showed significant improvements in speech intelligibility compared with the control group. This was evidenced by improvements from baseline (F1,30=34.35; P<.001), between-group differences (F1,30=6.18; P=.02), and notable time-by-group interactions (F1,30=6.91; P=.01). Regarding secondary outcomes, the intervention led to improvements in the percentage of correct consonants over time (F1,30=5.57; P=.03). In addition, significant reductions were noted in the severity of dysarthria in the intervention group over time (F1,30=21.18; P<.001), with a pronounced group effect (F1,30=5.52; P=.03) and time-by-group interaction (F1,30=5.29; P=.03). Regarding quality of life, significant improvements were observed as measured by the EQ-5D-3L questionnaire (F1,30=13.25; P<.001) and EQ-VAS (F1,30=7.74; P=.009) over time. The adherence rate to the smartphone-based app was 64%, with over half of the participants completing all the sessions. The usability of the app was rated high (system usability score 80.78). In addition, the intervention group reported increased self-efficacy in using the app compared with the control group (F1,30=10.81; P=.003). CONCLUSIONS: The smartphone-based speech therapy app significantly improved speech intelligibility, articulation, and quality of life in patients with poststroke dysarthria. These findings indicate that smartphone-based speech therapy can be a useful assistant device in the management of poststroke dysarthria, particularly in the acute and early subacute stroke stages. TRIAL REGISTRATION: ClinicalTrials.gov NCT05146765; https://clinicaltrials.gov/ct2/show/NCT05146765.

Multi-Granularity Aggregation with Spatiotemporal Consistency for Video-Based Person Re-Identification.

Video-based person re-identification (ReID) aims to exploit relevant features from spatial and temporal knowledge. Widely used methods include the part- and attention-based approaches for suppressing irrelevant spatial-temporal features. However, it is still challenging to overcome inconsistencies across video frames due to occlusion and imperfect detection. These mismatches make temporal processing ineffective and create an imbalance of crucial spatial information. To address these problems, we propose the Spatiotemporal Multi-Granularity Aggregation (ST-MGA) method, which is specifically designed to accumulate relevant features with spatiotemporally consistent cues. The proposed framework consists of three main stages: extraction, which extracts spatiotemporally consistent partial information; augmentation, which augments the partial information with different granularity levels; and aggregation, which effectively aggregates the augmented spatiotemporal information. We first introduce the consistent part-attention (CPA) module, which extracts spatiotemporally consistent and well-aligned attentive parts. Sub-parts derived from CPA provide temporally consistent semantic information, solving misalignment problems in videos due to occlusion or inaccurate detection, and maximize the efficiency of aggregation through uniform partial information. To enhance the diversity of spatial and temporal cues, we introduce the Multi-Attention Part Augmentation (MA-PA) block, which incorporates fine parts at various granular levels, and the Long-/Short-term Temporal Augmentation (LS-TA) block, designed to capture both long- and short-term temporal relations. Using densely separated part cues, ST-MGA fully exploits and aggregates the spatiotemporal multi-granular patterns by comparing relations between parts and scales. In the experiments, the proposed ST-MGA renders state-of-the-art performance on several video-based ReID benchmarks (i.e., MARS, DukeMTMC-VideoReID, and LS-VID).

The Effect of the Mixed Extract of Kalopanax pictus Nakai and Achyranthes japonica Nakai on the Improvement of Degenerative Osteoarthritis through Inflammation Inhibition in the Monosodium Iodoacetate-Induced Mouse Model.

Osteoarthritis is a chronic inflammatory disease, and, due to the lack of fundamental treatment, the main objective is to alleviate pain and prevent cartilage damage. Kalopanax pictus Nakai and Achyranthes japonica Nakai are herbal plants known for their excellent anti-inflammatory properties. The objective of this study is to confirm the potential of a mixture extract of Kalopanax pictus Nakai and Achyranthes japonica Nakai as a functional raw material for improving osteoarthritis through anti-inflammatory effects in macrophages and MIA-induced arthritis experimental animals. In macrophages inflamed by lipopolysaccharide (LPS), treatment of Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture inhibits NF-κB and mitogen-activated protein kinase (MAPK) activities, thereby inhibiting inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), inflammatory factors PGE2, MMP-2, and MMP-9, and nitric oxide (NO) was reduced. In addition, in an animal model of arthritis induced by MIA (monosodium iodoacetate), administration of Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture reduced blood levels of inflammatory cytokines TNF-α and IL-6, inflammatory factors prostaglandin E2(PGE2), matrix metalloproteinase-2(MMP-2), and NO. Through these anti-inflammatory effects, MIA-induced pain reduction (recovery of clinical index, increase in weight bearing, and increase in area and width of the foot), recovery of meniscus damage, loss of cartilage tissue or inflammatory cells in tissue infiltration reduction, and recovery of the proteglycan layer were confirmed. Therefore, it is considered that Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture has the potential as a functional raw material that promotes joint health.

The PAX-SIX-EYA-DACH network modulates GATA-FOG function in fly hematopoiesis and human erythropoiesis.

The GATA and PAX-SIX-EYA-DACH transcriptional networks (PSEDNs) are essential for proper development across taxa. Here, we demonstrate novel PSEDN roles in vivo in Drosophila hematopoiesis and in human erythropoiesis in vitro Using Drosophila genetics, we show that PSEDN members function with GATA to block lamellocyte differentiation and maintain the prohemocyte pool. Overexpression of human SIX1 stimulated erythroid differentiation of human erythroleukemia TF1 cells and primary hematopoietic stem-progenitor cells. Conversely, SIX1 knockout impaired erythropoiesis in both cell types. SIX1 stimulation of erythropoiesis required GATA1, as SIX1 overexpression failed to drive erythroid phenotypes and gene expression patterns in GATA1 knockout cells. SIX1 can associate with GATA1 and stimulate GATA1-mediated gene transcription, suggesting that SIX1-GATA1 physical interactions contribute to the observed functional interactions. In addition, both fly and human SIX proteins regulated GATA protein levels. Collectively, our findings demonstrate that SIX proteins enhance GATA function at multiple levels, and reveal evolutionarily conserved cooperation between the GATA and PSEDN networks that may regulate developmental processes beyond hematopoiesis.

Dysbiotic microbiome variation in colorectal cancer patients is linked to lifestyles and metabolic diseases.

BACKGROUND: Differences in the composition and diversity of the gut microbial communities among individuals are influenced by environmental factors. However, there is limited research on factors affecting microbiome variation in colorectal cancer patients, who display lower inter-individual variations than that of healthy individuals. In this study, we examined the association between modifiable factors and the microbiome variation in colorectal cancer patients. METHODS: A total of 331 colorectal cancer patients who underwent resection surgery at the Department of Surgery, Seoul National University Hospital between October 2017 and August 2019 were included. Fecal samples from colorectal cancer patients were collected prior to the surgery. Variations in the gut microbiome among patients with different lifestyles and metabolic diseases were examined through the network analysis of inter-connected microbial abundance, the assessment of the Anna Karenina principle effect for microbial stochasticity, and the identification of the enriched bacteria using linear discrimination analysis effect size. Associations of dietary diversity with microbiome variation were investigated using the Procrustes analysis. RESULTS: We found stronger network connectivity of microbial communities in non-smokers, non-drinkers, obese individuals, hypertensive subjects, and individuals without diabetes than in their counterparts. The Anna Karenina principle effect was found for history of smoking, alcohol consumption, and diabetes (with significantly greater intra-sample similarity index), whereas obesity and hypertension showed the anti-Anna Karenina principle effect (with significantly lower intra-sample similarity index). We found certain bacterial taxa to be significantly enriched in patients of different categories of lifestyles and metabolic diseases using linear discrimination analysis. Diversity of food and nutrient intake did not shape the microbial diversity between individuals (pProcrustes>0.05). CONCLUSIONS: Our findings suggested an immune dysregulation and a reduced ability of the host and its microbiome in regulating the community composition. History of smoking, alcohol consumption, and diabetes were shown to affect partial individuals in shifting new microbial communities, whereas obesity and history of hypertension appeared to affect majority of individuals and shifted to drastic reductions in microbial compositions. Understanding the contribution of modifiable factors to microbial stochasticity may provide insights into how the microbiome regulates effects of these factors on the health outcomes of colorectal cancer patients.

Thrombopoietin receptor agonist antibody for treating chemotherapy-induced thrombocytopenia.

BACKGROUND: Thrombocytopenia is a common complication in cancer patients undergoing chemotherapy. Chemotherapy-induced thrombocytopenia (CIT) leads to dose reduction and treatment delays, lowering chemotherapy efficacy and survival rate. Thus, rapid recovery and continuous maintenance of platelet count during chemotherapy cycles are crucial in patients with CIT. Thrombopoietin (TPO) and its receptor, myeloid proliferative leukemia (MPL) protein, play a major role in platelet production. Although several MPL agonists have been developed to regulate thrombopoiesis, none have been approved for the management of CIT due to concerns regarding efficacy or safety. Therefore, the development of effective MPL agonists for treating CIT needs to be further expanded. METHODS: Anti-MPL antibodies were selected from the human combinatorial antibody phage libraries using phage display. We identified 2R13 as the most active clone among the binding antibodies via cell proliferation assay using BaF3/MPL cells. The effect of 2R13 on megakaryocyte differentiation was evaluated in peripheral blood CD34+ cells by analyzing megakaryocyte-specific differentiation markers (CD41a+ and CD42b+) and DNA ploidy using flow cytometry. The 2R13-induced platelet production was examined in 8- to 10-week-old wild-type BALB/c female mice and a thrombocytopenia mouse model established by intraperitoneal injection of 5-fluorouracil (150 mg/kg). The platelet counts were monitored twice a week over 14 days post-initiation of treatment with a single injection of 2R13, or recombinant human TPO (rhTPO) for seven consecutive days. RESULTS: We found that 2R13 specifically interacted with MPL and activated its signaling pathways. 2R13 stimulated megakaryocyte differentiation, evidenced by increasing the proportion of high-ploidy (≥ 8N) megakaryocytes in peripheral blood-CD34+ cells. The platelet count was increased by a single injection of 2R13 for up to 14 days. Injection of 5-fluorouracil considerably reduced the platelet count by day 4, which was recovered by 2R13. The platelets produced by 2R13 sustained a higher count than that achieved using seven consecutive injections of rhTPO. CONCLUSIONS: Our findings suggest that 2R13 is a promising therapeutic agent for CIT treatment.

Carbohydrate antigen 19-9 plus carcinoembryonic antigen for prognosis in colorectal cancer: An observational study.

AIM: Carcinoembryonic antigen (CEA) is a primary prognostic marker and can detect colorectal cancer (CRC) recurrence; however, it has low sensitivity. Carbohydrate antigen 19-9 (CA 19-9) can be used as a supplemental tumour marker along with CEA. The purpose of this study was to determine whether preoperative CA 19-9 added to CEA helped predict long-term prognosis and whether follow-up CA 19-9 added to CEA had additional benefits in diagnosing the recurrence of CRC. METHOD: We retrospectively assessed patients who underwent surgery for primary CRC between January 2004 and December 2015 at Seoul National University Hospital. Data on demographics, preoperative and follow-up CEA and CA 19-9 levels, recurrence and survival were obtained and analysed with respect to tumour marker levels to ascertain their prognostic and diagnostic values. RESULTS: A total of 4972 and 1530 patients were included to analyse preoperative and follow-up tumour marker levels, respectively. The 5-year relapse-free survival rates were 72.2% ± 0.8%, 52.5% ± 2.2%, 55.5% ± 3.2% and 32.1% ± 2.3% in the normal CEA and CA 19-9, high CEA, high CA 19-9, and high CEA and high CA 19-9 groups, respectively (all P < 0.001). Patients whose elevated CEA or CA 19-9 levels reduced to normal levels had better survival outcomes than those with postoperatively elevated levels. Elevated follow-up CA 19-9 and CEA levels were related to higher incidences of distant metastasis (CA 19-9, 14.0% vs. 23.1%, P = 0.004; CEA, 12.6% vs. 30.1%, P < 0.001) but not to local recurrence. Combined follow-up CEA and CA 19-9 increased the sensitivity for recurrence to 31.4%, with a 5% difference from the sensitivity of CEA alone. In the subgroup with high preoperative CA 19-9 levels, sensitivity increased by 18.2% overall. CONCLUSION: CA 19-9 is a valuable prognostic and diagnostic marker for CRC when used adjunctively with CEA and can be a supplementary marker with CEA to improve sensitivity, especially with elevated preoperative CA 19-9.

Patterns of coparenting and young children's social-emotional adjustment in low-income families.

This study identified coparenting patterns using data collected across 2007-2010 from low-income couples (N = 2915; 26.90% non-Hispanic White; 9.41% non-Hispanic Black; 34.24% Hispanic, 29.27% other or mixed race) with young children (M = 3.65 years; SD = 1.31 years; 48% girls) and examined relations with children's social-emotional adjustment. Latent profile analysis revealed four coparenting patterns: mutual high-quality (43.4%), moderate-quality, mothers less positive (31.8%), moderate-quality, fathers less positive (15.9%), and low-quality, mothers less positive (8.9%). When parents' perspectives on coparenting were positive and congruent, children fared best. Children also fared well when coparenting quality was moderate, and mothers were less positive than fathers. When coparenting quality was moderate and fathers were less positive than mothers, children showed the poorest adjustment.

A comparison of the methods for detecting dyadic patterns in the actor-partner interdependence model.

In the actor-partner interdependence model (APIM), various dyadic patterns between an actor and partner can be examined. One widely used approach is the parameter k method, which tests whether the ratio of the partner effect to the actor effect (p/a) is significantly different from pattern values such as -1 (contrast), 0 (actor-only or partner-only), and 1 (couple). Although using a phantom variable was a useful method for estimating the k ratio, it is no longer necessary due to the availability of statistical packages that allow for a direct estimation of the k ratio without the inclusion of the phantom variable. Moreover, it is possible to examine the patterns by testing new variables defined in different forms from the k or using the χ2 difference test. To date, no previous studies have evaluated and compared the various approaches for detecting the dyadic patterns in APIM. This study aims to assess and compare the performance of four different methods for detecting dyadic patterns: (1) phantom variable approach, (2) direct estimation of the parameter k, (3) new-variable approach, and (4) χ2 difference test. The first two methods frequently included multiple pattern values in there confidence interval. Furthermore, the phantom variable approach was prone to convergence issues. The other two alternatives performed better in detecting the dyadic patterns without convergence problems. Given the findings of the study, we suggest a novel procedure for examining dyadic patterns in APIM.

Usefulness of the perfusion index for monitoring the response to intravenous ketamine infusion therapy in patients with complex regional pain syndrome.

BACKGROUND: This study was performed to compare the perfusion index (PI) between affected and unaffected limbs in patients with complex regional pain syndrome (CRPS); it also evaluated the usefulness of the PI for monitoring the response to intravenous ketamine infusion therapy in such patients. METHODS: In total, 46 patients with CRPS in one arm or leg were enrolled in this study. The PIs of the unaffected (PIControl ) and affected (PICRPS ) limbs were simultaneously evaluated before and after treatment. RESULTS: PICRPS was significantly lower than PIControl at all time points. The change in PI from immediately before to 30 min after intravenous ketamine infusion therapy (TBefore and T30 min , respectively) in the affected limb was significantly correlated with the change in visual analog pain scale (VAS) between the two time points (r = 0.646, p < 0.001). The area under the curve for the changes in VAS and PICRPS between TBefore and T30 min was 0.928. The optimal threshold value for the change in PICRPS between TBefore and T30 min , to distinguish responders with a ≥ 50-point reduction in VAS score from nonresponders, was 22.60% with a sensitivity of 0.811 (95% CI: 0.774-0.848) and a specificity of 0.889 (95% CI: 0.848-0.930). Thirty-one patients showed a ≥ 50-point reduction in VAS score [67% (95% CI: 54%-80%)] and 15 patients showed a < 50-point reduction in VAS score [33% (95% CI: 20%-46%)]. Thirty patients showed an increased PI ≥ 22.60% [65% (95% CI: 50%-78%)] and 16 patients showed an increased PI < 22.60% [35% (95% CI: 22%-50%)]. Twenty-seven patients had a ≥ 50-point reduction in VAS score and an increased PI ≥ 22.60% [59% (95% CI: 44%-74%)]. Eleven patients had shown a < 50-point pain reduction in VAS score and increased PI < 22.60% [24% (95% CI: 13%-37%)]. CONCLUSION: The PI significantly differed between affected and unaffected limbs in patients with CRPS. The PI may be useful for monitoring the response to intravenous ketamine therapy in patients with CRPS.

Ceramide kinase regulates acute wound healing by suppressing 5-oxo-ETE biosynthesis and signaling via its receptor OXER1.

The sphingolipid, ceramide-1-phosphate (C1P), has been shown to promote the inflammatory phase and inhibit the proliferation and remodeling stages of wound repair via direct interaction with group IVA cytosolic phospholipase A2, a regulator of eicosanoid biosynthesis that fine-tunes the behaviors of various cell types during wound healing. However, the anabolic enzyme responsible for the production of C1P that suppresses wound healing as well as bioactive eicosanoids and target receptors that drive enhanced wound remodeling have not been characterized. Herein, we determined that decreasing C1P activity via inhibitors or genetic ablation of the anabolic enzyme ceramide kinase (CERK) significantly enhanced wound healing phenotypes. Importantly, postwounding inhibition of CERK enhanced the closure rate of acute wounds, improved the quality of healing, and increased fibroblast migration via a "class switch" in the eicosanoid profile. This switch reduced pro-inflammatory prostaglandins (e.g., prostaglandin E2) and increased levels of 5-hydroxyeicosatetraenoic acid and the downstream metabolite 5-oxo-eicosatetraenoic acid (5-oxo-ETE). Moreover, dermal fibroblasts from mice with genetically ablated CERK showed enhanced wound healing markers, while blockage of the murine 5-oxo-ETE receptor (oxoeicosanoid receptor 1) inhibited the enhanced migration phenotype of these cell models. Together, these studies reinforce the vital roles eicosanoids play in the wound healing process and demonstrate a novel role for CERK-derived C1P as a negative regulator of 5-oxo-ETE biosynthesis and the activation of oxoeicosanoid receptor 1 in wound healing. These findings provide foundational preclinical results for the use of CERK inhibitors to shift the balance from inflammation to resolution and increase the wound healing rate.

Characterization of Clofazimine Metabolism in Human Liver Microsomal Incubation In Vitro.

Clofazimine [N,5-bis(4-chlorophenyl)-3-[(propane-2-yl)rimino]-3,5-dihydrophenazin-2-amine] is an antimycobacterial agent used as a second-line antituberculosis (anti-TB) drug. Nonetheless, little information is known about the metabolic routes of clofazimine, and the enzymes involved in metabolism. This study aimed to characterize the metabolic pathways and enzymes responsible for the metabolism of clofazimine in human liver microsomes. Eight metabolites, including four oxidative metabolites, three glucuronide conjugates, and one sulfate conjugate were identified, and their structures were deduced based on tandem mass spectrometry (MS/MS) spectra. Hydroxylated clofazimine and hydrated clofazimine was generated even in the absence of the NADPH generating system presumably via a nonenzymatic pathway. Hydrolytic-dehalogenated clofazimine was catalyzed mainly by CYP1A2 whereas hydrolytic-deaminated clofazimine was formed by CYP3A4/A5. In case of glucuronide conjugates, UGT1A1, UGT1A3, and UGT1A9 showed catalytic activity toward hydroxylated and hydrated clofazimine glucuronide whereas hydrolytic-deaminated clofazimine glucuronide was catalyzed by UGT1A4, UGT1A9, UGT1A3, and UGT2B4. Our results suggested that CYP1A2 and CYP3A are involved in the formation of oxidative metabolites while UGT1A1, 1A3, 1A4, 1A9, and 2B4 are involved in the formation of glucuronide conjugates of oxidative metabolites of clofazimine.

Dual-Colored Janus Microspheres with Photonic and Plasmonic Faces.

Photonic and plasmonic colors, stemming from nanostructures of dielectric materials and metals, are promising for pigment-free coloration. In particular, nanostructures with structural colors have been employed in stimuli-responsive Janus microparticles to provide active color pixels. Here, the authors report a simple strategy to produce electro-responsive Janus microspheres composed of photonic and plasmonic faces for active color change. The photonic microspheres are first prepared by self-assembly of silica particles in emulsion droplets of photocurable resin. The silica particles form 3D crystalline arrays in the interior and 2D hexagonal arrays on the interface. The emulsion droplets are photocured and the silica particles are selectively removed to make porous photonic microspheres with hexagonal arrays of dimples on the surface. Directional deposition of gold or aluminum on the photonic microsphere develops plasmonic color on the top hemisphere while maintaining photonic color on the bottom hemisphere. Moreover, the metal deposited on one side renders the Janus microspheres electro-responsive. Therefore, the photonic and plasmonic colors are switchable by the orientation control of the Janus microspheres with an external electric field. The photonic and plasmonic colors are independently adjustable by employing two different sizes of silica particles in core-shell emulsion drops.

Transcriptomic analysis identifies novel targets for individual bone morphogenetic protein type 1 receptors in endothelial cells.

Bone Morphogenetic Protein (BMP) signaling regulates diverse biological processes. Upon ligand binding, BMP receptors (BMPRs) phosphorylate SMAD1/5 and other noncanonical downstream effectors to induce transcription of downstream targets. However, the precise role of individual BMP receptors in this process remains largely unknown due to the complexity of downstream signaling and the innate promiscuity of ligand-receptor interaction. To delineate unique downstream effectors of individual BMPR1s, we analyzed the transcriptome of human umbilical endothelial cells (HUVECs) expressing three distinct constitutively active BMPR1s of which expression was detected in endothelial cells (ECs). From our analyses, we identified a number of novel downstream targets of BMPR1s in ECs. More importantly, we found that each BMPR1 possesses a distinctive set of downstream effectors, suggesting that each BMPR1 is likely to retain unique function in ECs. Taken together, our analyses suggest that each BMPR1 regulates downstream targets non-redundantly in ECs to create context-dependent outcomes of the BMP signaling.

Central obesity is associated with lower prevalence of sarcopenia in older women, but not in men: a cross-sectional study.

BACKGROUND: Obesity is a chronic disease that causes various medical health problems, increases morbidity, and reduces the quality of life. Obesity (especially central obesity) in older adults is expected to act with the development of sarcopenia. However, the relationship between obesity, central obesity, and sarcopenia remains controversial. This study aimed to investigate the impact of obesity on sarcopenia. METHODS: In this cross-sectional study, we used data from the Korean Frailty and Aging Cohort Study; 1,827 community-dwelling older adults (883 men and 944 women) aged 70-84 years were recruited. The Asian Working Group for Sarcopenia (AWGS) criteria were used to evaluate sarcopenia. Subjects with a low appendicular skeletal muscle mass index (ASMI; men: < 7.0 kg/m2, women: < 5.4 kg/m2) and either low handgrip strength (HGS; men: < 28 kg, women: < 18 kg) or low Short Physical Performance Battery (SPPB; ≤ 9) were diagnosed with sarcopenia. Obesity was defined as a body mass index (BMI) of ≥ 25 kg/m2, while central obesity was defined as WC measurements of ≥ 90 cm in men and ≥ 85 cm in women. Logistic regression analyses were performed to evaluate the impact of obesity and central obesity on sarcopenia and the parameters of sacropenia. RESULTS: In both sexes, the obese group, defined based on the BMI, had a significantly low prevalence of low ASMI (odds ratio [OR] = 0.14, 95% confidence interval CI = 0.10-0.20 in men, OR = 0.17, 95% CI = 0.12-0.25 in women) and sarcopenia (OR = 0.28, 95% CI = 0.16-0.50 in men, OR = 0.17, 95% CI = 0.08-0.35 in women) in the multivariable logistic regression analysis. In women, the central obese group had a low prevalence of sarcopenia (OR = 0.46, 95% CI = 0.27-0.77) in the multivariable logistic regression analysis. Meanwhile, the obese group had a significantly higher prevalence of low SPPB in women (OR = 1.75, 95% CI = 1.18-2.59). CONCLUSIONS: Obesity may have a protective effect on low ASMI and sarcopenia, as defined by the AWGS criteria. Central obesity was associated with a low prevalence of sarcopenia in women only. However, obesity did not have a positive impact on functional parameters of sarcopenia including muscle strength and physical performance.