Cell type-specific attenuation of brassinosteroid signaling precedes stomatal asymmetric cell division.

In Arabidopsis thaliana, brassinosteroid (BR) signaling and stomatal development are connected through the SHAGGY/GSK3-like kinase BR INSENSITIVE2 (BIN2). BIN2 is a key negative regulator of BR signaling but it plays a dual role in stomatal development. BIN2 promotes or restricts stomatal asymmetric cell division (ACD) depending on its subcellular localization, which is regulated by the stomatal lineage-specific scaffold protein POLAR. BRs inactivate BIN2, but how they govern stomatal development remains unclear. Mapping the single-cell transcriptome of stomatal lineages after triggering BR signaling with either exogenous BRs or the specific BIN2 inhibitor, bikinin, revealed that the two modes of BR signaling activation generate spatiotemporally distinct transcriptional responses. We established that BIN2 is always sensitive to the inhibitor but, when in a complex with POLAR and its closest homolog POLAR-LIKE1, it becomes protected from BR-mediated inactivation. Subsequently, BR signaling in ACD precursors is attenuated, while it remains active in epidermal cells devoid of scaffolds and undergoing differentiation. Our study demonstrates how scaffold proteins contribute to cellular signal specificity of hormonal responses in plants.

Measuring dynamic media bias.

Ideological media bias is increasingly central to the study of politics. Yet, past literature often assumes that the ideological bias of any outlet, at least in the short term, is static and exogenous to the political process. We challenge this assumption. We use longitudinal data from the Stanford Cable News Analyzer (2010 to 2021), which reports the screen time of various political actors on cable news, and quantify the partisan leaning of those actors using their past campaign donation behavior. Using one instantiation of media bias-the mean ideology of political actors on a channel, i.e., visibility bias-we examine weekly, within-day, and program-level estimates of media bias. We find that media bias is highly dynamic even in the short term and that the heightened polarization between TV channels over time was mostly driven by the prime-time shows.

Shaping brassinosteroid signaling through scaffold proteins.

Cellular responses to internal and external stimuli are orchestrated by intricate intracellular signaling pathways. To ensure an efficient and specific information flow, cells employ scaffold proteins as critical signaling organizers. With the ability to bind multiple signaling molecules, scaffold proteins can sequester signaling components within specific subcellular domains or modulate the efficiency of signal transduction. Scaffolds can also tune the output of signaling pathways by serving as regulatory targets. This review focuses on scaffold proteins associated with the plant GLYCOGEN SYNTHASE KINASE3-like kinase, BRASSINOSTEROID-INSENSITIVE2 (BIN2) that serve as a key negative regulator of brassinosteroid (BR) signaling. Here we summarize the current understanding of how scaffold proteins actively shape BR signaling outputs and crosstalk in plant cells via interactions with BIN2.

Dynamic Imaging of Lipid Droplets in Cells and Tissues by Using Dioxaborine Barbiturate-Based Fluorogenic Probes.

Lipids are essential for various cellular functions, including energy storage, membrane flexibility, and signaling molecule production. Maintaining proper lipid levels is important to prevent health problems such as cancer, neurodegenerative disorders, cardiovascular diseases, obesity, and diabetes. Monitoring cellular lipid droplets (LDs) in real-time with high resolution can provide insights into LD-related pathways and diseases owing to the dynamic nature of LDs. Fluorescence-based imaging is widely used for tracking LDs in live cells and animal models. However, the current fluorophores have limitations such as poor photostability and high background staining. Herein, we developed a novel fluorogenic probe based on a push-pull interaction combined with aggregation-induced emission enhancement (AIEE) for dynamic imaging of LDs. Probe 1 exhibits favorable membrane permeability and spectroscopic characteristics, allowing specific imaging of cellular LDs and time-lapse imaging of LD accumulation. This probe can also be used to examine LDs in fruit fly tissues in various metabolic states, serving as a highly versatile and specific tool for dynamic LD imaging in cellular and tissue environments.

Effect of Fibroblast Growth Factor (FGF) 19 and 21 on Hip Geometry and Strength in Post-menopausal Osteoporosis (PMO).

Fibroblast Growth Factor (FGF) receptor signalling is important for skeletal development. The FGF19 subfamily which includes FGF19 and FGF21 are involved in bone metabolism, although their effects on bone mineral density (BMD) and bone strength remain unclear. To further characterise the influence of these two factors on the skeleton, we studied the association between circulating concentrations of FGF19 and 21 with BMD and parameters of hip geometry and strength in post-menopausal osteoporosis (PMO). The study cohort consisted of 374 women aged (mean [SD]) 68.7[12.3] years with PMO. FGF19 and FGF21 were measured in serum by ELISA. BMD was measured at the lumbar spine (LS), total hip (TH) and femoral neck (FN) (n = 277) by dual energy X-ray absorptiometry (DXA) and hip structural analysis (HSA) parameters (n = 263) at the narrow neck of the femur (NN), Intertrochanter (IT) and Femoral shaft (FS) were derived from DXA scans. FGF19 and 21 were not associated with prevalent fractures or BMD when corrected for covariates; age, BMI, smoking habits and alcohol intake. Log-transformed FGF 21 was negatively associated with HSA parameters including Outer Diameter (OD) (p = 0.019), Cross-sectional area (CSA) (p = 0.01), cross-sectional moment of inertia (CSMI) (p = 0.011), Section modulus (Z) (p = 0.002) and cortical thickness (Co Th) (p = 0.026) at the IT only. CSA, CSMI, Z and Co Th were significantly lower (p < 0.05) in women with FGF21 concentrations greater than the median (> 103.5 pg/ml). Our data suggest that FGF 21 may have potentially adverse effects on the skeleton. Further characterisation is needed, particularly as FGF 21 analogues or agonists may be used to treat obesity-related metabolic disorders.

Heat wave exposure and increased heat-related hospitalizations in young children in South Korea: A time-series study.

BACKGROUND: Numerous studies have investigated the association between heat wave exposure increased heat-related hospitalizations in the general population. However, little is known about heat-related morbidity in young children who are more vulnerable than the general population. Therefore, we aimed to evaluate the association between hospitalization for heat-related illness in children and heat wave exposure in South Korea. METHODS: We used the National Health Insurance Service (NHIS) database, which provides medical records from 2015 to 2019 in South Korea. We defined daily hospitalizations for heat-related illness of children younger than five years during the summer period (June to August). We considered the definition of heat waves considering the absolute temperature and percentile. A total of 12 different heat waves were used. A time-series analysis was used to investigate the association between heat wave exposure and heat-related hospitalization among children younger than five years. We used a two-stage design involving a meta-analysis after modeling by each region. RESULTS: We included 16,879 daily heat-related hospitalizations among children younger than five years. Overall, heat wave exposure within two days was most related for heat-related hospitalizations in young children. The relative risk (RR) due to heat wave exposure within two days (lag2) (12 definitions: 70th to 90th percentile of maximum temperature) ranged from 1.038 (95% confidence interval (CI): 0.971, 1.110) to 1.083 (95% CI: 1.036, 1.133). We found that boys were more vulnerable to heat exposure than girls. In addition, we found that urban areas were more vulnerable to heat exposure than rural areas. CONCLUSIONS: In our study, heat wave exposure during summer was found to be associated with an increased risk of hospitalization for heat-related illness among children younger than five years. Our findings suggest the need for summer heat wave management and prevention for children.

Perceived familial financial insecurity and obesity among Korean adolescents during the COVID-19 pandemic.

BACKGROUND: In high-income countries, socioeconomically disadvantaged adolescents experience a higher risk of obesity, which may have been further exacerbated during the early phase of the COVID-19 pandemic. This study aimed to investigate the association between obesity and familial financial insecurity, utilizing data on subjective household socioeconomic status (SES) and perceived family-level financial deterioration induced by COVID-19. METHODS: We utilized data from the Korea Youth Risk Behavior Survey, a nationally representative sample of Korean adolescents, in 2020 and 2021. The independent and joint associations of two primary exposures, subjective household SES and perceived family-level financial deterioration, with obesity were assessed using multivariable logistic regression models. RESULTS: Among 106,979 adolescents aged 12-18 years, 16.9% of boys and 9.0% of girls met the criteria for obesity. Notably, 70.5% reported experiencing COVID-19-related financial deterioration. Both subjective household SES and perceived family-level financial deterioration independently and synergistically increased the odds of obesity. A graded association was observed between obesity and lower SES and more severe financial deterioration, particularly among girls. Younger adolescents were more sensitive to household SES, whereas older adolescents were more sensitive to financial deterioration. CONCLUSIONS: While the COVID-19 pandemic presented a unique social context, our findings highlight that financially insecure adolescents were at an increased risk of obesity during the early phase of the pandemic. This underscores the need for obesity-prevention strategies in times of macroeconomic recession to address not only the persistent influence of household SES but also the direct and indirect effects of family-level financial deterioration.

Disparities in the association between ambient temperature and preterm birth according to individual and regional characteristics: a nationwide time-stratified case-crossover study.

BACKGROUND: Several studies have reported that climate change elevates heat exposure in pregnant women and high temperatures during pregnancy are associated with preterm births (PTBs). Although the association might be disproportionate, related evidence remains sparse. We evaluated the disproportionate risk of PTB associated with ambient temperature during pregnancy by individual and regional characteristics in South Korea. METHODS: We collected data on birth certificates and daily mean temperatures during the period from 2011 to 2019. A time-stratified case-crossover design was used to investigate the association between temperature and PTB and stratified analyses were conducted to examine the effect modification of individual and regional characteristics. RESULTS: A total of 160,067 singleton PTBs were recorded in Korea from 2011 to 2019. A 5℃ increase in the mean temperature during the last four weeks before delivery was associated with an increased risk of PTB with an odds ratio (OR) of 1.03 (95% confidence interval [CI]: 1.02, 1.05), and the association was more evident in mothers aged ≥35 years (OR: 1.06 [95% CI: 1.03, 1.10]) and with low education levels (OR: 1.04 [95% CI: 1.02, 1.05]). Additionally, the estimated risk was evident in districts with lower medical resources and more prominent disparities were shown by individual and regional characteristics in rural areas than in urban areas. CONCLUSIONS: This study provides evidence that the risk of PTB related to ambient temperature is disproportionate by individual and regional characteristics and suggests the need for public health policies to alleviate the disparities, especially in rural areas.

Transcutaneous electrical nerve stimulation (TENS) for pain control in women with primary dysmenorrhoea.

BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological treatment that works by delivering electrical currents via electrodes attached to the skin at the site of pain. It can be an alternative to pharmacological treatments. The mechanism of action of TENS for pain relief is related to the inhibition of the transmission of painful stimuli, release of endogenous opioids, and reduced muscle ischaemia of the uterus. Although it has been used for primary dysmenorrhoea ((PD); period pain or menstrual cramps), evidence of the efficacy and safety of high-frequency TENS, low-frequency TENS, or other treatments for PD is limited. OBJECTIVES: To evaluate the effectiveness and safety of transcutaneous electrical nerve stimulation (TENS) in comparison with placebo, no treatment, and other treatments for primary dysmenorrhoea (PD). SEARCH METHODS: We searched the Gynaecology and Fertility Group's Specialized Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, AMED, CINAHL, and the Korean and Chinese language databases up to 9 April 2024. We also searched for ongoing trials in trials registries and the reference lists of relevant studies for additional trials. Language restrictions were not applied. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that included women (aged 12 to 49 years) with PD. Included trials compared low-frequency TENS or high-frequency TENS with other TENS, placebo, or other treatment. DATA COLLECTION AND ANALYSIS: Four review authors screened the trials, extracted the data according to the protocol, assessed the risk of bias using RoB 2, and assessed the certainty of evidence for all review comparisons and primary outcomes (i.e. pain relief and adverse effects) using the GRADE approach. MAIN RESULTS: This review replaces the current review, published in 2009. We included 20 RCTs involving 585 randomized women with high-frequency TENS, low-frequency TENS, placebo or no treatment, or other treatment. We included five comparisons: high-frequency TENS versus placebo or no treatment, low-frequency TENS versus placebo or no treatment, high-frequency TENS versus low-frequency TENS, high-frequency TENS versus other treatments, and low-frequency TENS versus other treatments. High-frequency TENS versus placebo or no treatment High-frequency TENS may reduce pain compared with placebo or no treatment (mean difference (MD) -1.39, 95% confidence interval (CI) -2.51 to -0.28; 10 RCTs, 345 women; low-certainty evidence; I2 = 88%). Two out of three RCTs reported no adverse effects and hence we were unable to estimate the effect of high-frequency TENS on adverse effects. Low-frequency TENS versus placebo or no treatment Low-frequency TENS may reduce pain compared with placebo or no treatment (MD -2.04, 95% CI -2.95 to -1.14; 3 RCTs, 645 women; low-certainty evidence; I2 = 0%). No trials reported adverse effects for this comparison. High-frequency TENS versus low-frequency TENS It is uncertain whether high-frequency TENS had an effect on pain relief compared with low-frequency TENS (MD 0.89, 95% CI -0.19 to 1.96; 3 RCTs, 54 women; low-certainty evidence; I2 = 0%). One trial contributed data on adverse effects but no adverse events occurred. High-frequency TENS versus other treatments It is uncertain whether high-frequency TENS had an effect on pain relief compared to acupressure (MD -0.66, 95% CI -1.72 to 0.40; 1 RCT, 18 women; very low-certainty evidence), acetaminophen (paracetamol) (MD -0.98, 95% CI -3.30 to 1.34; 1 RCT, 20 women; very low-certainty evidence), and interferential current therapy (MD -0.03, 95% CI -1.04 to 0.98; 2 RCTs, 62 women; low-certainty evidence; I2 = 0%). The occurrence of adverse effects may not differ significantly between high-frequency TENS and NSAIDs (OR 12.06, 95% CI 0.26 to 570.62; 2 RCTs, 88 women; low-certainty evidence; I2 = 78%). Low-frequency TENS versus other treatments It is uncertain whether low-frequency TENS had an effect on pain relief compared with acetaminophen (MD -1.48, 95% CI -3.61 to 0.65; 1 RCT, 20 women; very low-certainty evidence). No trials reported adverse effects for this comparison. AUTHORS' CONCLUSIONS: High-frequency TENS and low-frequency TENS may reduce pain compared with placebo or no treatment. We downgraded the certainty of the evidence because of the risk of bias. Future RCTs should focus more on secondary outcomes of this review (e.g. requirement for additional analgesics, limitation of daily activities, or health-related quality of life) and should be designed to ensure a low risk of bias.

Subjective memory complaints and medication adherence among hypertensive Korean older adults with multimorbidity: mediating effect of depression and social support.

BACKGROUND & AIM(S): Medication adherence (MA) is a key factor in maintaining adequate blood pressure and preventing complications. However, some older adults experience difficulties in taking medicine properly due to declines in cognitive function. Although subjective memory complaints (SMC) are recognized as early markers of cognitive impairment, previous studies concerning the relationship between MA and cognitive function have focused only on objective cognitive function. Furthermore, while depression has a high correlation with SMC, low MA, and social support, there is limited evidence on their relationship. This study aims to understand the effect of SMC on MA and the mediating effect of depression and social support. METHOD(S): This study is a descriptive cross-sectional investigation. A sample of 195 community-dwelling hypertensive older adults with multimorbidity from 3 community senior centers in Gwangju, South Korea were recruited through convenience sampling. Data was collected through face-to-face survey from January to March 2018. The PROCESS macro v4.2 program [Model 6] was used to analyze the mediating effect of depression and social support in the relationship between SMC and MA. Data analysis was performed using SPSS/WIN 26.0 and STATA MP 17.0. RESULTS: The average MA was 6.74. There were significant differences in MA according to awareness of prescribed drugs, awareness of side effects, insomnia, and healthcare accessibility. SMC was positively correlated with depression, while social support and MA were negatively correlated. While depression was a significant mediator of the effect of SMC on MA, the mediating effect of social support was not significant. The multiple mediation effect of depression and social support was not significant. CONCLUSION: The results suggest that medication management of older adults in community settings should be accompanied by a comprehensive health assessment of associated factors. Health professionals should explore strategies to improve memory as well as prevent and alleviate depression to increase MA among hypertensive older adults with multimorbidity.

HBV Transmission Knowledge Among Korean-American Chronic Hepatitis B Patients in the United States.

Chronic hepatitis B (CHB) is a condition that disproportionately affects Asian Americans in the United States. Knowledge of transmission is crucial for CHB patients to practice prevention methods to limit the spread of the hepatitis B virus (HBV), but also live their lives free from unwarranted fears or restrictions. Among Asian CHB patients, several misperceptions about HBV transmission have been identified. This analysis aims to assess the current state of HBV knowledge among a cohort of Korean-American CHB patients. This mixed-methods study includes 363 respondents who completed a survey in either Korean (N = 298) or English (N = 65) at two clinical care settings in Philadelphia (N = 161) and Los Angeles (N = 202); 30 participants also completed in-depth interviews. Knowledge was measured on a 10-point scale, asking patients yes or no transmission questions (n = 10, alpha = 0.87). The average knowledge score was 6.3. In multivariate analyses, older age was associated with lower knowledge (ß=-0.25, p < 0.001). More years of formal education (ß = 0.09, p = 0.076) and utilizing more sources for health information (ß = 0.12, p = 0.023) were both independently associated with higher knowledge scores. Qualitative findings show that misperceptions about transmission through shared food still exist and that provider communication is an important part of knowledge acquisition. These results suggest that despite receiving specialized, culturally concordant medical care for their disease, some Korean-American CHB patients have an inadequate understanding of transmission and that opportunities exist to improve education in this population. Identifying additional factors that influence knowledge acquisition and retention is key to developing culturally effective education interventions for this population.

Arenicolide Family Macrolides Provide a New Therapeutic Lead Combating Multidrug-resistant Tuberculosis.

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) poses a significant threat to health globally. During searching for new chemical entities regulating MDR- and XDR-Mtb, chemical investigation of the black oil beetle gut bacterium Micromonospora sp. GR10 led to the discovery of eight new members of arenicolides along with the identification of arenicolide A (Ar-A, 1), which was a previously reported macrolide with incomplete configuration. Genomic analysis of the bacterial strain GR10 revealed their putative biosynthetic pathway. Quantum mechanics-based computation, chemical derivatizations, and bioinformatic analysis established the absolute stereochemistry of Ar-A and arenicolides D-K (Ar-D-K, 2-9) completely for the first time. Biological studies of 1-9 revealed their antimicrobial activity against MDR and XDR strains of Mtb. Ar-A had the most potent in vitro antimicrobial efficacy against MDR- and XDR-Mtb. Mechanistically, Ar-A induced ATP depletion and destabilized Mtb cell wall, thereby inhibiting growth. Notably, Ar-A exerted a significant antimicrobial effect against Mtb in macrophages, was effective in the treatment of Mtb infections, and showed a synergistic effect with amikacin (AMK) in a mouse model of MDR-Mtb lung infection. Collectively, our findings indicate Ar-A to be a promising drug lead for drug-resistant tuberculosis.

Targeted and Logical Discovery of Piperazic Acid-Bearing Natural Products Based on Genomic and Spectroscopic Signatures.

A targeted and logical discovery method was devised for natural products containing piperazic acid (Piz), which is biosynthesized from ornithine by l-ornithine N-hydroxylase (KtzI) and N-N bond formation enzyme (KtzT). Genomic signature-based screening of a bacterial DNA library (2020 strains) using polymerase chain reaction (PCR) primers targeting ktzT identified 62 strains (3.1%). The PCR amplicons of KtzT-encoding genes were phylogenetically analyzed to classify the 23 clades into two monophyletic groups, I and II. Cultivating hit strains in media supplemented with 15NH4Cl and applying 1H-15N heteronuclear multiple bond correlation (HMBC) along with 1H-15N heteronuclear single quantum coherence (HSQC) and 1H-15N HSQC-total correlation spectroscopy (HSQC-TOCSY) NMR experiments detected the spectroscopic signatures of Piz and modified Piz. Chemical investigation of the hit strains prioritized by genomic and spectroscopic signatures led to the identification of a new azinothricin congener, polyoxyperuin B seco acid (1), previously reported chloptosin (2) in group I, depsidomycin D (3) incorporating two dehydropiperazic acids (Dpz), and lenziamides A and B (4 and 5), structurally novel 31-membered cyclic decapeptides in group II. By consolidating the phylogenetic and chemical analyses, clade-structure relationships were elucidated for 19 of the 23 clades. Lenziamide A (4) inhibited STAT3 activation and induced G2/M cell cycle arrest, apoptotic cell death, and tumor growth suppression in human colorectal cancer cells. Moreover, lenziamide A (4) resensitized 5-fluorouracil (5-FU) activity in both in vitro cell cultures and the in vivo 5-FU-resistant tumor xenograft mouse model. This work demonstrates that the genomic and spectroscopic signature-based searches provide an efficient and general strategy for new bioactive natural products containing specific structural motifs.

Genomic and Spectroscopic Signature-Based Discovery of Natural Macrolactams.

The logical and effective discovery of macrolactams, structurally unique natural molecules with diverse biological activities, has been limited by a lack of targeted search methods. Herein, a targeted discovery method for natural macrolactams was devised by coupling genomic signature-based PCR screening of a bacterial DNA library with spectroscopic signature-based early identification of macrolactams. DNA library screening facilitated the efficient selection of 43 potential macrolactam-producing strains (3.6% of 1,188 strains screened). The PCR amplicons of the amine-deprotecting enzyme-coding genes were analyzed to predict the macrolactam type (α-methyl, α-alkyl, or ß-methyl) produced by the hit strains. 1H-15N HSQC-TOCSY NMR analysis of 15N-labeled culture extracts enabled macrolactam detection and structural type assignment without any purification steps. This method identified a high-titer Micromonospora strain producing salinilactam (1), a previously reported α-methyl macrolactam, and two Streptomyces strains producing new α-alkyl and ß-methyl macrolactams. Subsequent purification and spectroscopic analysis led to the structural revision of 1 and the discovery of muanlactam (2), an α-alkyl macrolactam with diene amide and tetraene chromophores, and concolactam (3), a ß-methyl macrolactam with a [16,6,6]-tricyclic skeleton. Detailed genomic analysis of the strains producing 1-3 identified putative biosynthetic gene clusters and pathways. Compound 2 displayed significant cytotoxicity against various cancer cell lines (IC50 = 1.58 µM against HCT116), whereas 3 showed inhibitory activity against Staphylococcus aureus sortase A. This genomic and spectroscopic signature-based method provides an efficient search strategy for new natural macrolactams and will be generally applicable for the discovery of nitrogen-bearing natural products.

Antiphotoaging Effect of AGEs Blocker™ in UVB-Irradiated Cells and Skh:HR-1 Hairless Mice.

Chronic exposure to ultraviolet (UV) radiation is a major cause of photoaging. It involves extrinsic aging, wrinkle formation, and skin dehydration, and leads to excessive production of active oxygen that adversely affects the skin. Here, we investigated the antiphotoaging effect of AGEs BlockerTM (AB), which comprises Korean mint aerial part and fig and goji berry fruits. Compared to its individual components, AB was more potent at increasing the expression of collagen and hyaluronic acid and decreasing MMP-1 expression in UVB-irradiated Hs68 fibroblasts and HaCaT keratinocytes. In Skh:HR-1 hairless mice exposed to 60 mJ/cm2 UVB for 12 weeks, oral administration of 20 or 200 mg/kg/day AB restored skin moisture by improving UVB-induced erythema, skin moisture, and transepidermal water loss, and alleviated photoaging by improving UVB-induced elasticity and wrinkles. Moreover, AB upregulated the mRNA levels of hyaluronic acid synthase and collagen-related Col1a1, Col3a1, and Col4a1 genes, increasing hyaluronic acid and collagen expression, respectively. AB inhibited UVB-induced MAPK and AP-1 (c-fos) activation, resulting in significantly downregulated expression of MMP-1 and -9, which are responsible for collagen degradation. AB also stimulated the expression and activity of antioxidative enzymes and reduced lipid peroxidation. Thus, AB is a potential preventive and therapeutic agent for photoaging.

Hierarchically Interpenetrated and Reentrant Microcellular Frameworks for Stretchable Lithium Metal Batteries.

With the rapid development of human-friendly wearable devices, energy storage components are required to have skin-like stretchability or free-form to fit closer and more comfortably to the human body. This study introduces a hierarchically interpenetrated reentrant microcellular structure combined with 2D cellular graphene/MXene/carbon nanotubes (CNTs) and 3D cellular melamine foam. This composite structure works as a stretchable framework of lithium metal composite electrodes to provide stretchability for lithium metal electrodes, which are promising as next-generation energy storage systems. The interpenetrated but independent cellular structures successfully obtain stable structural deformability from the nonconductive and deformable melamine foam, while at the same time, high electrical conductivity, lithiophilicity, and mechanical stability of the graphene/CNT/MXene network serve as a lithium deposition support during the electrodeposition of lithium. The reentrant structure is fabricated by radial compressing the hierarchical cellular structures to take advantage of the structural stretchability of the accordion-like reentrant frameworks. The lithium-deposited composite electrodes exhibit much lower overpotential during Li stripping and plating than lithium metal foil anodes and show stable electrochemical performances under 30% of mechanical strain. The reentrant microcellular electrodes offer great potential for advanced designs of lithium metal electrodes for stretchable batteries with high energy density.

Whole-Genome Sequencing Reveals Mutational Signatures Related to Radiation-Induced Sarcomas and DNA-Damage-Repair Pathways.

Radiation-induced sarcoma (RIS) is a rare but serious late complication arising from radiotherapy. Despite unfavorable clinical outcomes, the genomic footprints of ionizing radiation in RIS development remain largely unknown. Hence, this study aimed to characterize RIS genomes and the genomic alterations in them. We analyzed whole-genome sequencing in 11 RIS genomes matched with normal genomes to identify somatic alterations potentially associated with RIS development. Furthermore, the abundance of mutations, mutation signatures, and structural variants in RIS were compared with those in radiation-naïve spontaneous sarcomas. The mutation abundance in RIS genomes, including one hypermutated genome, was variable. Cancer-related genes might show different types of genomic alterations. For instance, NF1, NF2, NOTCH1, NOTCH2, PIK3CA, RB1, and TP53 showed singleton somatic mutations; MYC, CDKN2A, RB1, and NF1 showed recurrent copy number alterations; and NF2, ARID1B, and RAD51B showed recurrent structural variations. The genomic footprints of nonhomologous end joining are prevalent at indels of RIS genomes compared with those in spontaneous sarcoma genomes, representing the genomic hallmark of RIS genomes. In addition, frequent chromothripsis was identified along with predisposing germline variants in the DNA-damage-repair pathways in RIS genomes. The characterization of RIS genomes on a whole-genome sequencing scale highlighted that the nonhomologous end joining pathway was associated with tumorigenesis, and it might pave the way for the development of advanced diagnostic and therapeutic strategies for RIS.

Downregulation of the RNA-binding protein PUM2 facilitates MSC-driven bone regeneration and prevents OVX-induced bone loss.

BACKGROUND: Although mRNA dysregulation can induce changes in mesenchymal stem cell (MSC) homeostasis, the mechanisms by which post-transcriptional regulation influences MSC differentiation potential remain understudied. PUMILIO2 (PUM2) represses translation by binding target mRNAs in a sequence-specific manner. METHODS: In vitro osteogenic differentiation assays were conducted using human bone marrow-derived MSCs. Alkaline phosphatase and alizarin red S staining were used to evaluate the osteogenic potential of MSCs. A rat xenograft model featuring a calvarial defect to examine effects of MSC-driven bone regeneration. RNA-immunoprecipitation (RNA-IP) assay was used to determine the interaction between PUM2 protein and Distal-Less Homeobox 5 (DLX5) mRNA. Ovariectomized (OVX) mice were employed to evaluate the effect of gene therapy for postmenopausal osteoporosis. RESULTS: Here, we elucidated the molecular mechanism of PUM2 in MSC osteogenesis and evaluated the applicability of PUM2 knockdown (KD) as a potential cell-based or gene therapy. PUM2 level was downregulated during MSC osteogenic differentiation, and PUM2 KD enhanced MSC osteogenic potential. Following PUM2 KD, MSCs were transplanted onto calvarial defects in 12-week-old rats; after 8 weeks, transplanted MSCs promoted bone regeneration. PUM2 KD upregulated the expression of DLX5 mRNA and protein and the reporter activity of its 3'-untranslated region. RNA-IP revealed direct binding of PUM2 to DLX5 mRNA. We then evaluated the potential of adeno-associated virus serotype 9 (AAV9)-siPum2 as a gene therapy for osteoporosis in OVX mice. CONCLUSION: Our findings suggest a novel role for PUM2 in MSC osteogenesis and highlight the potential of PUM2 KD-MSCs in bone regeneration. Additionally, we showed that AAV9-siPum2 is a potential gene therapy for osteoporosis.

Reduced forced expiratory flow between 25% and 75% of vital capacity in children with allergic rhinitis without asthmatic symptoms.

INTRODUCTION: Allergic rhinitis (AR) and asthma are closely associated in children. Reduced FEF25%-75% which reflects small airway airflow limitation is frequently observed in asthma. This study aimed to examine the proportion of small airway dysfunction in children with AR and to determine its associated factors.Methods: The medical records of 144 aged 6-18-year children with AR without overt asthmatic symptoms were retrospectively reviewed. Subjects were divided into 2 groups according to the FEF25%-75% values; normal FEF25%-75% group (n = 129) and reduced FEF25%-75% group (n = 15). Clinical data, allergen sensitization profile, exhaled nitric oxide, spirometry, and methacholine provocation test results were compared between the two groups.Results: The mean FEV1 and FEF25%-75% values in the reduced FEF25%-75% group (73.5 ± 9.4%pred and 56.0 ± 7.7%pred, respectively) were significantly lower than in the normal FEF25%-75% group (87.0 ± 12.5%pred and 99.1 ± 21.4%pred, respectively). The mean disease duration was significantly longer in the reduced FEF25%-75% group than in the normal FEF25%-75% group (5.39 ± 1.85 y vs 3.14 ± 1.80 y, p < 0.001). Subjects with positive bronchial hyperresponsiveness (MChPC20<16 mg/mL) were more frequently detected in the reduced FEF25%-75% group than in the normal FEF25%-75% group (26.7% vs 8.52%, p = 0.013). Long disease duration and severity of AR were significantly associated with impaired FEF25%-75% values.Conclusions: Subjects with AR alone may have impaired FEF25%-75% values which is considered as a marker of early bronchial involvement. Longer disease duration and severity of AR are important risk factors for progressive declines in small airway function. Physicians should be aware of need for the measurement of FEF25%-75% values for early detection of small airway dysfunction, particularly in children with severe long-lasting allergic rhinitis.

Use of gastrointestinal prokinetics and the risk of parkinsonism: A population-based case-crossover study.

BACKGROUND: The disease burden of parkinsonism is extremely costly in the United States. Unlike Parkinson's disease, drug-induced parkinsonism (DIP) is acute and reversible; exploring the causative drug is important to prevent DIP in patients at high-risk of parkinsonism. OBJECTIVE: To examine whether the use of gastrointestinal (GI) prokinetics is associated with an increased risk of parkinsonism. METHODS: We conducted a case-crossover study using nationally representative data. We included patients who were newly diagnosed with parkinsonism (ICD-10 G20, G21.1, G25.1) between January 1, 2007 and December 1, 2015. The first prescription date of G20, G21.1, or G25.1 diagnoses was defined as the index date (0 day). Patients with prior extrapyramidal and movement disorders or brain tumors were excluded. We assessed the exposure within the risk (0-29 days) and control periods (60-89 days), before or on the index date. Conditional logistic regression estimated the adjusted odds ratio (aOR) for parkinsonism. RESULTS: Overall, 2268 and 1674 patients were exposed to GI prokinetics during the risk and control periods, respectively. The use of GI prokinetics significantly increased the occurrence of parkinsonism (aOR = 2.31; 95% Confidence Interval [CI], 2.06-2.59). The use of GI prokinetics was associated with a higher occurrence of parkinsonism in elderly patients (≥65 years old; aOR = 2.69; 95% CI, 2.30-3.14) than in younger patients (aOR = 1.90; 95% CI, 1.59-2.27). CONCLUSIONS: The use of GI prokinetics was significantly associated with higher occurrences of parkinsonism, necessitating close consideration when using GI prokinetics.