Epigenetic modulations in triple-negative breast cancer: Therapeutic implications for tumor microenvironment.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptors, progesterone receptors and lacks HER2 overexpression. This absence of critical molecular targets poses significant challenges for conventional therapies. Immunotherapy, remarkably immune checkpoint blockade, offers promise for TNBC treatment, but its efficacy remains limited. Epigenetic dysregulation, including altered DNA methylation, histone modifications, and imbalances in regulators such as BET proteins, plays a crucial role in TNBC development and resistance to treatment. Hypermethylation of tumor suppressor gene promoters and the imbalance of histone methyltransferases such as EZH2 and histone deacetylases (HDACs) profoundly influence tumor cell proliferation, survival, and metastasis. In addition, epigenetic alterations critically shape the tumor microenvironment (TME), including immune cell composition, cytokine signaling, and immune checkpoint expression, ultimately contributing to immune evasion. Targeting these epigenetic mechanisms with specific inhibitors such as EZH2 and HDAC inhibitors in combination with immunotherapy represents a compelling strategy to remodel the TME, potentially overcoming immune evasion and enhancing therapeutic outcomes in TNBC. This review aims to comprehensively elucidate the current understanding of epigenetic modulation in TNBC, its influence on the TME, and the potential of combining epigenetic therapies with immunotherapy to overcome the challenges posed by this aggressive breast cancer subtype.

Effects of yak rumen anaerobic fungus Orpinomyces sp. YF3 fermented on in vitro wheat straw fermentation and microbial communities in dairy goat rumen fluid, with and without fungal flora.

Rumen fungi play an essential role in the breakdown of dietary fibrous components, facilitating the provision of nutrients and energy to the host animals. This study investigated the fermentation characteristics and effects on rumen microbiota of yak rumen anaerobic fungus Orpinomyces sp. YF3 in goat rumen fluid, both with and without fungal flora, utilizing anaerobic fermentation bottles. Crushed and air-dried wheat straw served as the fermentation substrate, and cycloheximide was used to eradicate microorganisms from the rumen fluid of dairy goats. The experiment compromised four treatment groups (2×2 factorial design): control (C); yak fungus group (CF, Orpinomyces sp. YF3); goat fungi eliminated group (CA, antibiotic: 0.25 mg/mL cycloheximide); goat fungi eliminated+yak fungus group (CAF). Each treatment had six replicates. Fermentation characteristics and microbial composition of the fermentation media were analyzed using one-way analysis of variance and high-throughput sequencing technology. The findings revealed that in the Orpinomyces sp. YF3 addition group (CF and CAF groups), there were significant increases in ammonia nitrogen concentration by 70%, total volatile fatty acids (VFA) by 53%, as well as acetate, isobutyrate, and valerate concentrations, and the ratio of acetate to propionate (p < 0.05), while the propionate proportion declined by 13%, alongside a reduction of butyrate concentration (p < 0.05). Similarly, in the CF and CAF groups, there were a notable increase in the relative abundance of Bacteroidota, Synergistota, Desulfobacterota, Actinobacteria, and Fusobacteriota, alongside a decrease in the relative abundance of Fibrobacterota and Proteobacteria (p < 0.05). Bacteria exhibiting increased relative abundance were positively correlated with the activity of carboxymethyl cellulase and avicelase, total VFA concentration, and acetate proportion, while showing a negatively correlation with propionate proportion. In conclusion, supplementing rumen fermentation media with yak rumen anaerobic fungus Orpinomyces sp. YF3 led to an increase in bacteria associated with fibre degradation and acetic acid production, a decrease in propionate-producing bacteria, enhanced the activity of plant cell wall degrading enzymes, and promoted cellulose degradation, ultimately elevating total VAF concentration and acetate proportion. This presents a novel approach to enhance roughage utilization in ruminants.

Correlative relationship between body mass index and heart rate variability in psychiatric disorders.

OBJECTIVE: Indicators of heart rate variability (HRV) have been used to assess the autonomic activity. However, the influence of obesity on HRV in these patients remains to be determined. This study aimed to examine how obesity (measured with the body mass index [BMI]) affects HRV and determine whether the effect varies among different psychiatric disorders. We recruited 3159 consecutive patients, including 1744 with schizophrenia, 966 with mood disorders, and 449 with anxiety disorders. Patients were divided into four groups based on BMI: underweight (< 18.5), normal weight (18.5-23.9), overweight (24-27.9), and obese (≥ 28). The cardiovascular status was assessed using several time- and frequency-based HRV indicators, measured via electrocardiogram signals recorded for 5 min. The mean BMI of the participants was 23.6 ± 4.0. The patients in the overweight and obese groups were 29.4% and 13.6% of the total, respectively. The HRV indicators were higher in underweight and normal-weight patients than in the overweight and obese ones. After stratification based on the psychiatric diagnosis, the patients with mood disorders showed lower HRV than those with schizophrenia or anxiety disorder in the normal-weight group. In contrast, in the overweight and obese groups the patients with mood disorders showed higher HRV than those with the other disorders. The HRV variables were significantly associated with BMI, and higher BMI was associated with higher heart rates and lower HRV. These results indicate that weight gain in psychiatric disorders is associated with an imbalance in autonomic nerve activity. However, the relationship between autonomic activity, weight gain, and psychiatric disorders warrants further investigation.

B7-H1 agonists suppress the PI3K/AKT/mtor pathway by degrading p110γ and independently induce cell death.

The biological role of B7-H1 intrinsic signal is reportedly diverse and controversial, its signal pathway remains unclear. Although B7-H1 blocking antibodies were found to have agonist capacity, their binding features and agonist mechanisms need further investigation. Here, by constructing cell strains with full-length or truncated B7-H1, we found that B7-H1 functioned as a receptor to transmit cell death signal from PD-1 protein or anti-B7-H1s through its cytoplasmic domain. Specific binding to the IgV-like domain of B7-H1 was required for the downstream signal. Upon agonists interaction, B7-H1 regulated the degradation of phosphoinositide 3-kinases (PI3Ks) subunit p110γ, subsequently inhibited the PI3K/AKT/mTOR pathway, and significantly increased autophagy. Moreover, B7-H1 agonists also suppressed ubiquitylation in B7-H1+cells by reducing ubiquitin-activating enzyme (E1), eventually leading to cell death. Finally, we validated the receptor role of B7-H1 in multiple tumor cells and demonstrated that B7-H1 agonists could suppress tumor progression independent of T cells in vivo. Our findings revealed that B7-H1 agonists functions as a PI3K inhibitor and may offer new strategies for PI3K targeting therapy.

Reliability and validity of the Chinese version of the COMPI Fertility Problem Stress Scale-Short Form for infertile women.

OBJECTIVE: To translate and culturally adapt the COMPI Fertility Problem Stress Scale-Short form (COMPI-FPSS-SF) and to test its reliability and validity in China. METHODS: The cross-sectional study adopted Brislin's translation model to translate, synthesize, back-translate, and cross-culturally adapt the COMPI-FPSS-SF for the Chinese setting. A total of 279 infertile women were invited to participate in the study to test the reliability and validity of the scale between March and June 2021. RESULTS: It was verified that the Chinese version of the COMPI-FPSS-SF has three domains with nine items. The Cronbach's α coefficient of the total scale was 0.907, and the coefficient for each dimension ranged from 0.760 to 0.855. The test-retest validity was 0.891. The exploratory factor analysis extracted three common factors with eigenvalues of 4.499, 1.124, and 1.011 and a cumulative variance contribution of 73.706. The validity factor analysis showed good results for the three-factor structure fit. The criterion-related validity with the Fertility Inventory Short-Form Scale was 0.649. The above analysis revealed statistically significant differences (P < 0.001). CONCLUSIONS: The Chinese version of the COMPI-FPSS-SF can be used for the assessment of fertility-related stress in infertility patients in China with good reliability and validity.

NDP52 SUMOylation contributes to low-dose X-rays-induced cardiac hypertrophy through PINK1/Parkin-mediated mitophagy via MUL1/SUMO2 signalling.

Radiation-induced heart damage caused by low-dose X-rays has a significant impact on tumour patients' prognosis, with cardiac hypertrophy being the most severe noncarcinogenic adverse effect. Our previous study demonstrated that mitophagy activation promoted cardiac hypertrophy, but the underlying mechanisms remained unclear. In the present study, PARL-IN-1 enhanced excessive hypertrophy of cardiomyocytes and exacerbated mitochondrial damage. Isobaric tags for relative and absolute quantification-based quantitative proteomics identified NDP52 as a crucial target mediating cardiac hypertrophy induced by low-dose X-rays. SUMOylation proteomics revealed that the SUMO E3 ligase MUL1 facilitated NDP52 SUMOylation through SUMO2. Co-IP coupled with LC-MS/MS identified a critical lysine residue at position 262 of NDP52 as the key site for SUMO2-mediated SUMOylation of NDP52. The point mutation plasmid NDP52K262R inhibited mitophagy under MUL1 overexpression, as evidenced by inhibition of LC3 interaction with NDP52, PINK1 and LAMP2A. A mitochondrial dissociation study revealed that NDP52K262R inhibited PINK1 targeting to endosomes early endosomal marker (EEA1), late/lysosome endosomal marker (LAMP2A) and recycling endosomal marker (RAB11), and laser confocal microscopy confirmed that NDP52K262R impaired the recruitment of mitochondria to the autophagic pathway through EEA1/RAB11 and ATG3, ATG5, ATG16L1 and STX17, but did not affect mitochondrial delivery to lysosomes via LAMP2A for degradation. In conclusion, our findings suggest that MUL1-mediated SUMOylation of NDP52 plays a crucial role in regulating mitophagy in the context of low-dose X-ray-induced cardiac hypertrophy. Two hundred sixty-second lysine of NDP52 is identified as a key SUMOylation site for low-dose X-ray promoting mitophagy activation and cardiac hypertrophy. Collectively, this study provides novel implications for the development of therapeutic strategies aimed at preventing the progression of cardiac hypertrophy induced by low-dose X-rays.

[Enzyme production mechanism of anaerobic fungus Orpinomyces sp. YF3 in yak rumen induced by different carbon source].

In order to investigate the enzyme production mechanism of yak rumen-derived anaerobic fungus Orpinomyces sp. YF3 under the induction of different carbon sources, anaerobic culture tubes were used for in vitro fermentation. 8 g/L of glucose (Glu), filter paper (Flp) and avicel (Avi) were respectively added to 10 mL of basic culture medium as the sole carbon source. The activity of fiber-degrading enzyme and the concentration of volatile fatty acid in the fermentation liquid were detected, and the enzyme producing mechanism of Orpinomyces sp. YF3 was explored by transcriptomics. It was found that, in glucose-induced fermentation solution, the activities of carboxymethyl cellulase, microcrystalline cellulase, filter paper enzyme, xylanase and the proportion of acetate were significantly increased (P < 0.05), the proportion of propionate, butyrate, isobutyrate were significantly decreased (P < 0.05). The results of transcriptome analysis showed that there were 5 949 differentially expressed genes (DEGs) between the Glu group and the Flp group, 10 970 DEGs between the Glu group and the Avi group, and 6 057 DEGs between the Flp group and the Avi group. It was found that the DEGs associated with fiber degrading enzymes were significantly up-regulated in the Glu group. Gene ontology (GO) function enrichment analysis identified that DEGs were mainly associated with the xylan catabolic process, hemicellulose metabolic process, ß-glucan metabolic process, cellulase activity, endo-1,4-ß-xylanase activity, cell wall polysaccharide metabolic process, carbohydrate catabolic process, glucan catabolic process and carbohydrate metabolic process. Moreover, the differentially expressed pathways associated with fiber degrading enzymes enriched by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were mainly starch and sucrose metabolic pathways and other glycan degradation pathways. In conclusion, Orpinomyces sp. YF3 with glucose as carbon source substrate significantly increased the activity of cellulose degrading enzyme and the proportion of acetate, decreased the proportion of propionate, butyrate and isobutyrate. Furthermore, the degradation ability and energy utilization efficiency of fungus in the presence of glucose were improved by means of regulating the expression of cellulose degrading enzyme gene and participating in starch and sucrose metabolism pathway, and other glycan degradation pathways, which provides a theoretical basis for the application of Orpinomyces sp. YF3 in practical production and facilitates the application of Orpinomyces sp. YF3 in the future.

Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma.

Chemo-activation of mitochondrial ClpP exhibits promising anticancer properties. However, we are currently unaware of any studies using selective and potent ClpP activators in lung squamous cell carcinoma. In this work, we report on such an activator, ZK53, which exhibits therapeutic effects on lung squamous cell carcinoma in vivo. The crystal structure of ZK53/ClpP complex reveals a π-π stacking effect that is essential for ligand binding selectively to the mitochondrial ClpP. ZK53 features on a simple scaffold, which is distinct from the activators with rigid scaffolds, such as acyldepsipeptides and imipridones. ZK53 treatment causes a decrease of the electron transport chain in a ClpP-dependent manner, which results in declined oxidative phosphorylation and ATP production in lung tumor cells. Mechanistically, ZK53 inhibits the adenoviral early region 2 binding factor targets and activates the ataxia-telangiectasia mutated-mediated DNA damage response, eventually triggering cell cycle arrest. Lastly, ZK53 exhibits therapeutic effects on lung squamous cell carcinoma cells in xenograft and autochthonous mouse models.

NEDD4 Regulated Pyroptosis Occurred from Co-infection between Influenza A Virus and Streptococcus pneumoniae.

Co-infection of respiratory tract viruses and bacteria often result in excess mortality, especially pneumonia caused by influenza viruses and Streptococcus pneumoniae. However, the synergistic mechanisms remain poorly understood. Therefore, it is necessary to develop a clearer understanding of the molecular basis of the interaction between influenza virus and Streptococcus pneumonia. Here, we developed the BALB/c mouse model and the A549 cell model to investigate inflammation and pyroptotic cell death during co-infection. Co-infection significantly activated the NLRP3 inflammasome and induced pyroptotic cell death, correlated with excess mortality. The E3 ubiquitin ligase NEDD4 interacted with both NLRP3 and GSDMD, the executor of pyroptosis. NEDD4 negatively regulated NLRP3 while positively regulating GSDMD, thereby modulating inflammation and pyroptotic cell death. Our findings suggest that NEDD4 may play a crucial role in regulating the GSDMD-mediated pyroptosis signaling pathway. Targeting NEDD4 represents a promising approach to mitigate excess mortality during influenza pandemics by suppressing synergistic inflammation during co-infection of influenza A virus and Streptococcus pneumoniae.

The loss of B7-H4 expression in breast cancer cells escaping from T cell cytotoxicity contributes to epithelial-to-mesenchymal transition.

BACKGROUND: B7 homology 4 (B7-H4), a potential target for cancer therapy, has been demonstrated to inhibit T cell cytotoxicity in the early stages of breast cancer. However, B7-H4 manipulating breast tumor immune microenvironment (TIME) in the tumor progression remains unknown. METHODS: We engineered T cells with B7-H4-specific chimeric antigen receptors (CARs) and performed a T cell co-culture assay to characterize B7-H4 expression level in breast cancer cells escaping from T cell cytotoxicity. We generated B7-H4 knockout (KO) and overexpression (OE) breast cancer cells to determine the epithelial-to-mesenchymal transition (EMT) and stemness characteristics in vitro and in vivo, including tumor proliferation, migration, metastasis and chemoresistance. The Cancer Genome Atlas breast cancer database was accessed to investigate the correlation between B7-H4 expression levels and EMT characteristics in patients with breast cancer. RESULTS: Our result found that B7-H4 expression level was significantly reduced in a subset of breast cancer cells that escaped from the cytotoxicity of B7-H4 CAR-T cells. Compared with wild type cells, B7-H4 KO cells prompt EMT and stemness characteristics, including migration, invasion and metastasis, and OE cells vice versa. The increase in H3K27me3 in KO cells confirmed the epigenetic reprogramming of cancer stem cells. The IC50 of doxorubicin or oxaliplatin significantly increased in KO cells, which was in agreement with a decrease in OE cells. Moreover, a trend of downregulated B7-H4 from stage I to stage II breast cancer patients indicates that the low-expressing B7-H4 breast cancer cells escaping from TIME have spread to nearby breast lymph nodes in the cancer progression. CONCLUSIONS: Our study illuminates the novel role of renouncing B7-H4 in breast cancer cells through immune escape, which contributes to EMT processes and provides new insights for breast cancer treatments.

Cardiovascular variations in patients with major depressive disorder versus bipolar disorder.

BACKGROUND: Differentiating depression in major depressive disorder and bipolar disorder is challenging in clinical practice. Therefore, reliable biomarkers are urgently needed to differentiate between these diseases. This study's main objective was to assess whether cardiac autonomic function can distinguish patients with unipolar depression (UD), bipolar depression (BD), and bipolar mania (BM). METHODS: We recruited 791 patients with mood disorders, including 191 with UD, 286 with BD, and 314 with BM, who had been drug free for at least 2 weeks. Cardiovascular status was measured using heart rate variability (HRV) and pulse wave velocity (PWV) indicators via finger photoplethysmography during a 5-min rest period. RESULTS: Patients with BD showed lower HRV but higher heart rates than those with UD and BM. The PWV indicators were lower in the UD group than in the bipolar disorder group. The covariates of age, sex, and body mass index affected the cardiovascular characteristics. After adjusting for covariates, the HRV and PWV variations among the three groups remained significant. Comparisons between the UD and BD groups showed that the variable with the largest effect size was the frequency-domain indices of HRV, very low and high frequency, followed by heart rate. The area under the receiver operating characteristic curve (AUC) for each cardiovascular variable ranged from 0.661 to 0.714. The High-frequency index reached the highest AUC. LIMITATIONS: Cross-sectional design and the magnitude of heterogeneity across participants with mood disorders limited our findings. CONCLUSION: Patients with BD, but not BM, had a greater extent of cardiac imbalance than those with UD. Thus, HRV may serve as a psychophysiological biomarker for the differential diagnosis of UD and BD.

Heart rate variability in patients with psychiatric disorders from adolescence to adulthood.

OBJECTIVE: Age is associated with changes in autonomic nervous system activity. These changes are assessed using heart rate variability(HRV) indicators; however, the effect of age on HRV in patients with psychiatric disorders remains unclear. Our study aimed to explore this effect and determine its variance across different lifespans. METHOD: Consecutive patients(N = 3315), comprising 1833 patients with psychotic disorders, 1040 with mood disorders, and 442 with anxiety disorders, were recruited. The patients were divided into four age groups: adolescence(10-24 years), early adulthood(25-39 years), middle adulthood(40-59 years), and late adulthood(60+ years). HRV indicators were measured during a 5-min rest period. RESULTS: The heart rate and HRV indices were higher in the adolescent and early adulthood groups than they were in the middle and late adulthood groups(increased HRV is beneficial for health, while reduced HRV is detrimental). Age and all the HRV indices were negatively correlated(r-values 0.153-0.350, p < 0.001), with these correlation patterns being more evident in the adolescent and early adulthood groups than in the middle and late adulthood groups. Stratified by sex, the low-frequency/high-frequency ratio was higher in men than in women across most age groups(p < 0.05), except the late adulthood group(p = 0.085). Stratified by diagnosis, most HRV variables(except very low-frequency) were lower in the psychotic disorder group than they were in the mood and anxiety disorder groups, especially in middle and late adulthood patients. After adjusting for confounders, the HRV variables were significantly associated with age, while older age was associated with lower HRV. CONCLUSIONS: These results indicate that the substantial reduction in HRV with age in patients with psychiatric disorders. The association remains significant after correction for sex, heart rate, and diagnoses; this may prove useful to clinical practice and further research.

Association of Attenuated Niacin Response With Inflammatory Imbalance and Prediction of Conversion to Psychosis From Clinical High-risk Stage.

Objective: Attenuated niacin responses and changes in cytokine levels have been reported in schizophrenia. However, prior studies have typically focused on schizophrenia, and little is known about the association between niacin response and inflammatory imbalance in clinically high-risk psychosis (CHR). This study aimed to assess the niacin response to inflammatory imbalance for association with conversion to psychosis within 2 years.Methods: A prospective case-control study was performed to assess the niacin response and interleukin (IL)-1ß, IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-α levels in 60 CHR individuals and 60 age- and sex-matched healthy controls (HC) from May 2019 to December 2021. Participants with CHR were identified using the Structured Interview for Prodromal Syndromes. The niacin-induced responses were measured using laser Doppler flowmetry. From the dose-response curves, the log-transferred concentration of methylnicotinate required to elicit a half-maximal blood flow response (LogEC50) and maximal minus minimal blood flow response (Span) values were calculated for each subject. Serum cytokine levels were measured using enzyme-linked immunosorbent assay. Individuals with CHR were then divided into converters (CHR-C, n = 15) and non-converters (CHR-NC, n = 45) to psychosis based on their 2-year follow-up clinical status.Results: The CHR group exhibited significantly higher LogEC50 (t = 3.650, P < .001) and Span (t = 2.657, P = .009) values than the HC group. The CHR-C group exhibited a significantly shorter Span (t = 4.027, P < .001) than the CHR-NC group. The LogEC50 showed a trend toward significance (t = 1.875, P = .066). None of the cytokine levels were significant. The conversion outcome can therefore be predicted by applying LogEC50 (P = .049) and Span (P < .001). The regression model with variables of LogEC50, Span, family history, and scores of positive symptoms showed good discrimination of subsequent conversion to psychosis and achieved a classification accuracy of 91.7%. The decreased LogEC50 in the CHR-C group was significantly correlated with the increased IL-1ß/IL-10 ratio (Spearman ρ = -0.600, P = .018), but this correlation was nonsignificant in the CHR-NC group.Conclusions: Our findings indicate a significant association between niacin response and psychosis conversion outcomes in individuals with CHR. Compared with peripheral inflammatory cytokines, the niacin response can better predict conversion, although there may be an intersection between the two in biological mechanisms.

Minichromosome maintenance protein family member 6 mediates hepatocellular carcinoma progression by recruiting UBE3A to induce P53 ubiquitination.

With limited therapeutic options for hepatocellular carcinoma (HCC), it is of great significance to investigate the underlying mechanisms and identifying tumor drivers. MCM6, a member of minichromosome maintenance proteins (MCMs), was significantly elevated in HCC progression and associated with poor prognosis. Knockdown of MCM6 significantly inhibited the proliferation and migration of HCC cells with the increased apoptosis ratio and cell cycle arrest, whereas overexpression of MCM6 induced adverse effects. Mechanistically, MCM6 could decrease the P53 activity by inducing the degradation of P53 protein. In addition, MCM6 enhanced the ubiquitination of P53 by recruiting UBE3A to form a triple complex. Furthermore, overexpression of UBE3A significantly rescued the P53 activation and suppression of malignant behaviors mediated by MCM6 inhibition. In conclusion, MCM6 facilitated aggressive phenotypes of HCC cells by UBE3A/P53 signaling, providing potential biomarkers and targets for HCC.

Increased anxiety and stress-related visits to the Shanghai psychiatric emergency department during the COVID-19 pandemic in 2020 compared to 2018-2019.

Background: The coronavirus disease 2019 (COVID-19) pandemic has had a significant and far-reaching impact on mental health. The psychiatric emergency department (PED) is pivotal in the management of acute and severe mental illnesses, especially anxiety-and stress-related disorders. Aims: This study aimed to evaluate whether changes in the frequency or patients' demographics of visiting the PED occurred during the COVID-19 pandemic among individuals with anxiety and stress-related disorders. Methods: This cross-sectional study used data on PED visit counts from the largest psychiatric hospital in China between 2018 and 2020 (before and during the COVID-19 pandemic). Data from 2020, representing the COVID-19 pandemic period, were extracted from electronic medical records and compared using descriptive statistics for the same periods in 2018 and 2019. Results: The number of PED visits related to anxiety and stress disorders per year increased from 83 in 2018 to 136 (63.9% increase) in 2019 and 239 (188.0% increase) in 2020. Compared to that in 2018 and 2019, the proportion of PED visits in 2020 among patients with anxiety and stress disorders increased significantly. Patients with anxiety-and stress-related disorders during PED visits in 2020 were younger than those in 2018 and 2019 (three-year groups: F = 9.124, df = 2, p < 0.001). Conclusion: Despite the epidemic-policy barriers against PED visits, PED care seeking has increased, thereby underscoring the need for crisis prevention services for patients with stress and anxiety disorders.

Adaptive laboratory evolution boosts Yarrowia lipolytica tolerance to vanillic acid.

Microbial tolerance to lignocellulose-derived inhibitors, such as aromatic acids, is critical for the economical production of biofuels and biochemicals. Here, adaptive laboratory evolution was applied to improve the tolerance of Yarrowia lipolytica to a representative aromatic acid inhibitor vanillic acid. The transcriptome profiling of evolved strain suggested that the tolerance could be related to the up-regulation of RNA processing and multidrug transporting pathways. Further analysis by reverse engineering confirmed that the amplification of YALI0_F13475g coding for transcriptional coactivator and YALI0_E25201g coding for multidrug transporter conferred tolerance not only to vanillic acid but also towards ferulic acid, p-coumaric acid, p-hydroxybenzoic acid and syringic acid. These findings suggested that regulation of RNA processing and multidrug transporting pathways may be important for enhanced aromatic acid tolerance in Y. lipolytica. This study provides valuable genetic information for robust strain construction for lignocellulosic biorefinery.

Structural insights into the evolutionary simplification of human ClpP activators.

In this issue of Structure, Mabanglo et al. characterize five ClpP agonists termed TRs. The co-crystal structures reveal more robust shape and charge complementarities than the anti-cancer agent ONC201. These novel compounds are of potential therapeutic interest because they enhance ClpP proteolytic activity and have an inhibitory effect on tumor cell growth.

Changes in Mobile Health Apps Usage Before and After the COVID-19 Outbreak in China: Semilongitudinal Survey.

BACKGROUND: Mobile health (mHealth) apps are rapidly emerging technologies in China due to strictly controlled medical needs during the COVID-19 pandemic while continuing essential services for chronic diseases. However, there have been no large-scale, systematic efforts to evaluate relevant apps. OBJECTIVE: We aim to provide a landscape of mHealth apps in China by describing and comparing digital health concerns before and after the COVID-19 outbreak, including mHealth app data flow and user experience, and analyze the impact of COVID-19 on mHealth apps. METHODS: We conducted a semilongitudinal survey of 1593 mHealth apps to study the app data flow and clarify usage changes and influencing factors. We selected mHealth apps in app markets, web pages from the Baidu search engine, the 2018 top 100 hospitals with internet hospitals, and online shopping sites with apps that connect to smart devices. For user experience, we recruited residents from a community in southeastern China from October 2019 to November 2019 (before the outbreak) and from June 2020 to August 2020 (after the outbreak) comparing the attention of the population to apps. We also examined associations between app characteristics, functions, and outcomes at specific quantiles of distribution in download changes using quantile regression models. RESULTS: Rehabilitation medical support was the top-ranked functionality, with a median 1.44 million downloads per app prepandemic and a median 2.74 million downloads per app postpandemic. Among the top 10 functions postpandemic, 4 were related to maternal and child health: pregnancy preparation (ranked second; fold change 4.13), women's health (ranked fifth; fold change 5.16), pregnancy (ranked sixth; fold change 5.78), and parenting (ranked tenth; fold change 4.03). Quantile regression models showed that rehabilitation (P75, P90), pregnancy preparation (P90), bodybuilding (P50, P90), and vaccination (P75) were positively associated with an increase in downloads after the outbreak. In the user experience survey, the attention given to health information (prepandemic: 249/375, 66.4%; postpandemic: 146/178, 82.0%; P=.006) steadily increased after the outbreak. CONCLUSIONS: mHealth apps are an effective health care approach gaining in popularity among the Chinese population following the COVID-19 outbreak. This research provides direction for subsequent mHealth app development and promotion in the postepidemic era, supporting medical model reformation in China as a reference, which may provide new avenues for designing and evaluating indirect public health interventions such as health education and health promotion.

Uterine torsion complicated by severe placental abruption in the second trimester: a case report and literature review.

BACKGROUND: Uterine torsion is a rare obstetric event that can occur during pregnancy and is difficult to diagnose. Its occurrence may lead to serious adverse pregnancy outcomes. CASE INTRODUCTION: The patient was a 33-year-old woman at 30+ 5 weeks' gestation with a singleton pregnancy. The pregnancy course, including fetal growth, and prenatal examinations were regular. Except for a small amount of vaginal bleeding in early pregnancy and treatment with progesterone, there were no prenatal abnormalities, and the patient denied any trauma or sexual history. The patient was admitted to the emergency department with persistent severe pain in the lower abdomen and slight vaginal bleeding during night sleep. Abdominal pain started two hours prior to admission and was accompanied by nausea, vomiting, and dizziness. Examination revealed positive abdominal tenderness, high uterine tone, and no significant intermittent period of uterine contractions, and measurement of the fetal heart rate by means of the nonstress test revealed a rate of 60 beats per minute. Therefore, placental abruption was highly suspected. Subsequently, an emergency cesarean section was performed under general anesthesia. The newborn boy, with Apgar scores of 0-3-4 after birth and weighing 1880 g, was transferred to the neonatal intensive care unit (NICU) and died two days later due to ineffective rescue. After the uterine incision was sutured, the examination revealed that the uterine incision was located on the posterior wall of the uterus, and the uterus was twisted 180° to the right. The diagnosis after cesarean section was 180° uterine torsion to the right, severe placental abruption, and severe neonatal asphyxia. On the fifth day after surgery, the patient recovered and was discharged from the hospital. CONCLUSIONS: Posterior uterine incision cesarean section may be performed in unexpected circumstances and is also feasible as a safe option for resetting if torsion is not complete. Abdominal pain during pregnancy is less likely to be diagnosed as uterine torsion, which often leads to premature birth, fetal asphyxia, placental abruption, and even perinatal death. Therefore, for abdominal pain during pregnancy, obstetricians should consider the possibility of uterine torsion.