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C/EBP homologous protein (CHOP) triggers the death of multiple cancers via endoplasmic reticulum (ER) stress. However, the function and regulatory mechanism of CHOP in liver cancer remain elusive. We have reported that late endosomal/lysosomal adapter, mitogen-activated protein kinase and mTOR activator 5 (LAMTOR5) suppresses apoptosis in various cancers. Here, we show that the transcriptional and posttranscriptional inactivation of CHOP mediated by LAMTOR5 accelerates liver cancer growth. Clinical bioinformatic analysis revealed that the expression of CHOP was low in liver cancer tissues and that its increased expression predicted a good prognosis. Elevated CHOP contributed to destruction of LAMTOR5-induced apoptotic suppression and proliferation. Mechanistically, LAMTOR5-recruited DNA methyltransferase 1 (DNMT1) to the CpG3 region (-559/-429) of the CHOP promoter and potentiated its hypermethylation to block its interaction with general transcription factor IIi (TFII-I), resulting in its inactivation. Moreover, LAMTOR5-enhanced miR-182/miR-769 reduced CHOP expression by targeting its 3'UTR. Notably, lenvatinib, a first-line targeted therapy for liver cancer, could target the LAMTOR5/CHOP axis to prevent liver cancer progression. Accordingly, LAMTOR5-mediated silencing of CHOP via the regulation of ER stress-related apoptosis promotes liver cancer growth, providing a theoretical basis for the use of lenvatinib for the treatment of liver cancer., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

An effective orthodontic treatment should not only aim for satisfactory occlusal outcomes but also consider its impact on facial esthetics. The study aims to evaluate and compare the perception of profile esthetics of skeletal Class II patients treated with two orthodontic modalities: (1) Two-phase approach involving functional appliances followed by fixed appliances with premolar extractions, or (2) One-phase approach using fixed appliances with premolar extractions. Additionally, the study aims to evaluate the correlation between the perceived esthetics and the corresponding cephalometric measurements. The study included 40 skeletal Class II adolescents who underwent either two-phase (n = 20, mean age = 12.38 ± 1.18) or one-phase (n = 20, mean age = 12.53 ± 0.79) orthodontic treatments. Eighty profile silhouettes (pre- and post-treatment) were assessed by 64 raters, including 23 orthodontists, 21 general dental practitioners, and 20 laypersons. The raters used a visual analog scale (VAS) to access profiles, upper and lower lips, and chin esthetics. At pre-treatment, all three groups of raters gave significantly lower scores to the profile silhouettes of the two-phase group compared to the one-phase group (P < 0.01); however, after treatment, they rated the two-phase group significantly higher (P ≤ 0.001). The two-phase group exhibited greater improvements in profile and upper and lower lip esthetics as perceived by all raters (P ≤ 0.001). Furthermore, cephalometric results revealed greater reductions in SNA, ANB, Wits appraisal, and G'-Sn-Pog' in the two-phase group compared to the one-phase group (P < 0.05). Five cephalometric parameters (SNB, SNPog, overjet, overbite, and UL-SnPog') demonstrated significant correlations with VAS scores given by orthodontists (P < 0.05). In conclusion, the two-phase group showed greater subjective and objective improvements in facial esthetics than the one-phase group. Additionally, the anteroposterior mandibular position and upper lip protrusion may be the primary cephalometric parameters correlated with subjective facial profile perceptions., (© 2024. The Author(s).)

Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA-binding protein that is involved in various biological functions, including DNA damage repair and transcription regulation. It plays a crucial role in cisplatin resistance. Nevertheless, the exact regulatory pathways governing PARP1 have not yet been fully elucidated. In this study, we present evidence suggesting that the hepatitis B X-interacting protein (HBXIP) may exert regulatory control over PARP1. HBXIP functions as a transcriptional coactivator and is positively associated with PARP1 expression in tissues obtained from hepatoma patients in clinical settings, and its high expression promotes cisplatin resistance in hepatoma. We discovered that the oncogene HBXIP increases the level of PARP1 m 6 A modification by upregulating the RNA methyltransferase WTAP, leading to the accumulation of the PARP1 protein. In this process, on the one hand, HBXIP jointly activates the transcription factor ETV5, promoting the activation of the WTAP promoter and further facilitating the promotion of the m 6 A modification of PARP1 by WTAP methyltransferase, enhancing the RNA stability of PARP1. On the other hand, HBXIP can also jointly activate the transcription factor CEBPA, enhance the activity of the PARP1 promoter, and promote the upregulation of PARP1 expression, ultimately leading to enhanced DNA damage repair capability and promoting cisplatin resistance in hepatoma. Notably, aspirin inhibits HBXIP, thereby reducing the expression of PARP1. Overall, our research revealed a novel mechanism for increasing PARP1 abundance, and aspirin therapy could overcome cisplatin resistance in hepatoma., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Psychological interventions delivered by non-specialist providers have shown mixed results for treating maternal depression. mHealth solutions hold the possibility for unobtrusive behavioural data collection to identify challenges and reinforce change in psychological interventions. We conducted a proof-of-concept study using passive sensing integrated into a depression intervention delivered by non-specialists to twenty-four adolescents and young mothers (30% 15-17 years old; 70% 18-25 years old) with infants (< 12 months old) in rural Nepal. All mothers showed a reduction in depression symptoms as measured with the Beck Depression Inventory. There were trends toward increased movement away from the house (greater distance measured through GPS data) and more time spent away from the infant (less time in proximity measured with the Bluetooth beacon) as the depression symptoms improved. There was considerable heterogeneity in these changes and other passively collected data (speech, physical activity) throughout the intervention. This proof-of-concept demonstrated that passive sensing can be feasibly used in low-resource settings and can personalize psychological interventions. Care must be taken when implementing such an approach to ensure confidentiality, data protection, and meaningful interpretation of data to enhance psychological interventions., (© 2024. The Author(s).)

Lumbar sympathetic ganglion neurolysis (LSGN) has been used for long-term pain relief in patients with complex regional pain syndrome (CRPS). However, the actual effect duration of LSGN has not been accurately measured. This prospective observational study measured the effect duration of LSGN in CRPS patients and investigated the relationship between temperature change and pain relief. After performing LSGN, the skin temperatures of both the maximum pain site and the plantar area in the affected and unaffected limbs were measured by infrared thermography, and pain intensity was assessed before and at 2 weeks, 1 month, and 3 months. The median time to return to baseline temperature was calculated using survival analysis. The skin temperature increased significantly at all-time points relative to baseline in both regions (maximum pain site: 1.4 °C ± 1.0 °C, plantar region: 1.28 °C ± 0.8 °C, all P < 0.001). The median time to return to baseline temperature was 12 weeks (95% confidence interval [CI] 7.7-16.3) at the maximum pain site and 12 weeks (95% CI 9.4-14.6) at the plantar area. Pain intensity decreased significantly relative to baseline, at all-time points after LSGN. In conclusion, the median duration of the LSGN is estimated to be 12 weeks., (© 2024. The Author(s).)

Diabetes-related distress (DRD) refers to the psychological distress specific to living with diabetes. DRD can lead to negative clinical consequences such as poor self-management. By knowing the local prevalence and severity of DRD, primary care teams can improve the DRD evaluation in our daily practice. This was a cross-sectional study conducted in 3 General Out-patient Clinics (GOPCs) from 1 December 2021 to 31 May 2022. A random sample of adult Chinese subjects with T2DM, who regularly followed up in the selected clinic in the past 12 months, were included. DRD was measured by the validated 15-item Chinese version of the Diabetes Distress Scale (CDDS-15). An overall mean score ≥ 2.0 was considered clinically significant. The association of DRD with selected clinical and personal factors was investigated. The study recruited 362 subjects (mean age 64.2 years old, S.D. 9.5) with a variable duration of living with T2DM (median duration 7.0 years, IQR 10.0). The response rate was 90.6%. The median HbA1c was 6.9% (IQR 0.9). More than half (59.4%) of the subjects reported a clinically significant DRD. Younger subjects were more likely to have DRD (odds ratio of 0.965, 95% CI 0.937-0.994, p = 0.017). Patients with T2DM in GOPCs commonly experience clinically significant DRD, particularly in the younger age group. The primary care clinicians could consider integrating the evaluation of DRD as a part of comprehensive diabetes care., (© 2024. The Author(s).)

Deregulation of lipid composition in adipose tissue adjacent to breast tumour is observed in ex vivo and animal models. Novel non-invasive magnetic resonance imaging (MRI) allows rapid lipid mapping of the human whole breast. We set out to elucidate the spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive (ER +) breast cancer. Thirteen participants (mean age, 62 ± [SD] 6 years) with ER + breast cancer and 13 age-matched postmenopausal healthy controls were scanned on MRI. The number of double bonds in triglycerides was computed from MRI images to derive lipid composition maps of monounsaturated, polyunsaturated, and saturated fatty acids (MUFA, PUFA, SFA). The spatial heterogeneity measures (mean, median, skewness, entropy and kurtosis) of lipid composition in the peri-tumoural region and the whole breast of participants and in the whole breast of controls were computed. The Ki-67 proliferative activity marker and CD163 antibody on tumour-associated macrophages were assessed histologically. Mann Whitney U or Wilcoxon tests and Spearman's coefficients were used to assess group differences and correlations, respectively. For comparison against the whole breast in participants, peri-tumoural MUFA had a lower mean (median (IQR), 0.40 (0.02), p < .001), lower median (0.42 (0.02), p < .001), a negative skewness with lower magnitude (- 1.65 (0.77), p = .001), higher entropy (4.35 (0.64), p = .007) and lower kurtosis (5.13 (3.99), p = .001). Peri-tumoural PUFA had a lower mean (p < .001), lower median (p < .001), a positive skewness with higher magnitude (p = .005) and lower entropy (p = .002). Peri-tumoural SFA had a higher mean (p < .001), higher median (p < .001), a positive skewness with lower magnitude (p < .001) and lower entropy (p = .012). For comparison against the whole breast in controls, peri-tumoural MUFA had a negative skewness with lower magnitude (p = .01) and lower kurtosis (p = .009), however there was no difference in PUFA or SFA. CD163 moderately correlated with peri-tumoural MUFA skewness (r s  = - .64), PUFA entropy (r s  = .63) and SFA skewness (r s  = .59). There was a lower MUFA and PUFA while a higher SFA, and a higher heterogeneity of MUFA while a lower heterogeneity of PUFA and SFA, in the peri-tumoural region in comparison with the whole breast tissue. The degree of lipid deregulation was associated with inflammation as indicated by CD163 antibody on macrophages, serving as potential marker for early diagnosis and response to therapy., (© 2024. The Author(s).)

The association of bipolar disorder (BD) with the risk of cardiometabolic diseases and premature death in Asians needs to be further determined. Relatively less attention has been paid to heart failure (HF) among cardiometabolic outcomes. We analyzed the Korean National Health Insurance Service database (2002-2018) for this population-based, matched cohort study. The hazards of ischemic stroke, ischemic heart disease (IHD), hospitalization for HF (hHF), composite cardiometabolic diseases, and all-cause mortality during follow-up were compared between individuals with BD (n = 11,329) and 1:1-matched controls without psychiatric disorders among adults without cardiometabolic disease before or within 3 months of baseline. Hazards of outcomes were higher in individuals with BD than in matched controls (adjusted hazard ratios [95% confidence intervals]: 1.971 [1.414-2.746] for ischemic stroke, 1.553 [1.401-1.721] for IHD, 2.526 [1.788-3.567] for hHF, 1.939 [1.860-2.022] for composite cardiometabolic diseases, and 2.175 [1.875-2.523] for all-cause mortality) during follow-up. Associations between BD and outcome hazards were more prominent in younger individuals (p for interaction < 0.02, except for ischemic stroke) and women (p for interaction < 0.04, except for hHF). Screening and preventive measures for cardiometabolic deterioration and early mortality may need to be intensified in individuals with BD, even in young adults, especially women., (© 2024. The Author(s).)

We aimed to determine the association between cholesterol values and the risk of all-cause mortality in newly diagnosed patients with cancer in a large-scale longitudinal cohort. Newly diagnosed patients with cancer were reviewed retrospectively. Cox proportional hazards regression models determined the association between baseline levels of total cholesterol (TC), triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and the risk of all-cause mortality. A restricted cubic spline curve was used to identify the association between total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol with the risk of death on a continuous scale and to present the lowest values of lipid measurements associated with death. The median follow-up duration of the study was 5.77 years. Of the 59,217 patients with cancer, 12,624 patients were expired. The multivariable adjusted hazard ratio (aHR) for all-cause mortality in patients with cancer with 1st-5th (≤ 97 mg/dL) and 96th-100th (> 233 mg/dL) in TC levels was 1.54 (95% CI 1.43-1.66) and 1.28 (95% CI 1.16-1.41), respectively, compared to 61st-80th (172-196 mg/dL). The TC level associated with the lowest mortality risk in the multivariable model was 181 mg/dL. In comparison with LDL-C levels in the 61st-80th (115-136 mg/dL), the multivariable aHR for all-cause mortality in cancer patients with LDL-C levels in the 1st-5th (≤ 57 mg/dL) and 96th-100th (> 167 mg/dL) was 1.38 (95% CI 1.14-1.68) and 0.94 (95% CI 0.69-1.28), respectively. The 142 mg/dL of LDL cholesterol showed the lowest mortality risk. We demonstrated a U-shaped relationship between TC levels at baseline and risk of mortality in newly diagnosed patients with cancer. Low LDL levels corresponded to an increased risk of all-cause death., (© 2024. The Author(s).)

Chromosomal instability (CIN) is a hallmark of cancer, caused by persistent errors in chromosome segregation during mitosis. Aggressive cancers like high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) have a high frequency of CIN and TP53 mutations. Here, we show that inhibitors of the KIF18A motor protein activate the mitotic checkpoint and selectively kill chromosomally unstable cancer cells. Sensitivity to KIF18A inhibition is enriched in TP53-mutant HGSOC and TNBC cell lines with CIN features, including in a subset of CCNE1-amplified, CDK4-CDK6-inhibitor-resistant and BRCA1-altered cell line models. Our KIF18A inhibitors have minimal detrimental effects on human bone marrow cells in culture, distinct from other anti-mitotic agents. In mice, inhibition of KIF18A leads to robust anti-cancer effects with tumor regression observed in human HGSOC and TNBC models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via KIF18A inhibition., (© 2023. The Author(s).)

Dengue virus (DENV) infection remains a challenging health threat worldwide. Ubiquitin-specific protease 18 (USP18), which preserves the anti-interferon (IFN) effect, is an ideal target through which DENV mediates its own immune evasion. However, much of the function and mechanism of USP18 in regulating DENV replication remains incompletely understood. In addition, whether USP18 regulates DENV replication merely by causing IFN hyporesponsiveness is not clear. In the present study, by using several different approaches to block IFN signaling, including IFN neutralizing antibodies (Abs), anti-IFN receptor Abs, Janus kinase inhibitors and IFN alpha and beta receptor subunit 1 (IFNAR1)knockout cells, we showed that USP18 may regulate DENV replication in IFN-associated and IFN-unassociated manners. Localized in mitochondria, USP18 regulated the release of mitochondrial DNA (mtDNA) to the cytosol to affect viral replication, and mechanisms such as mitochondrial reactive oxygen species (mtROS) production, changes in mitochondrial membrane potential, mobilization of calcium into mitochondria, 8-oxoguanine DNA glycosylase 1 (OGG1) expression, oxidation and fragmentation of mtDNA, and opening of the mitochondrial permeability transition pore (mPTP) were involved in USP18-regulated mtDNA release to the cytosol. We therefore identify mitochondrial machineries that are regulated by USP18 to affect DENV replication and its association with IFN effects., (© 2023. The Author(s).)

Optic disc pit maculopathy (ODP-M) is a rare complication of optic disc pit which can cause irreversible visual impairment. The aim of this study is to evaluate the anatomical and functional outcomes and pattern of resolution of ODP-M following vitrectomy with posterior vitreous detachment (PVD) induction and scleral tissue plug for treatment of ODP-M without ILM peeling, laser or use of long term gas/tamponade or head positioning. This retrospective study included 7 patients with ODP-M, meeting the inclusion criteria. Patients were followed up for 6 months. Complete anatomical success was defined as "Total resolution of all the fluid in retinal compartments". All of the patients had complete resolution of the optic pit maculopathy following surgery. The mean duration for complete resolution was 18.3 weeks. Pattern of resolution of ODP-M was found to be resolution of the subretinal fluid (SRF) followed by disappearance of the retinoschitic lesions (RL) and finally disappearance of macular edema (ME). The proposed minimally invasive procedure (MIP) can produce comparably good and equally reliable results for the treatment of ODP-M., (© 2023. Springer Nature Limited.)

We aimed to compare the risk of incident diabetes according to fatty liver disease (FLD) definition, focusing on the comparison between those who met criteria for either metabolic dysfunction-associated fatty liver disease (MAFLD) or nonalcoholic fatty liver disease (NAFLD) but not the other. This was a 5.0-year (interquartile range, 2.4-8.2) retrospective longitudinal cohort study of 21,178 adults who underwent at least two serial health checkup examinations. The presence of hepatic steatosis was determined by abdominal ultrasonography at the first health examination. Cox proportional hazard analyses were used to compare the risk of incident diabetes among five groups. Incident diabetes cases occurred in 1296 participants (6.1%). When non-FLD without metabolic dysfunction (MD) group was set as a reference, the risk of incident diabetes increased in the order of NAFLD-only, non-FLD with MD, both FLD, and MAFLD-only groups. The presence of excessive alcohol consumption and/or hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, FLD, and MD synergistically increased the risk of incident diabetes. MAFLD-only group showed a greater increase in incidence of diabetes than non-FLD with MD and NAFLD-only groups. The interaction among excessive alcohol consumption, HBV/HCV infection, MD, and hepatic steatosis on the development of diabetes should not be overlooked., (© 2023. The Author(s).)

Mass spectrometry (MS) based proteomics is widely used for biomarker discovery. However, often, most biomarker candidates from discovery are discarded during the validation processes. Such discrepancies between biomarker discovery and validation are caused by several factors, mainly due to the differences in analytical methodology and experimental conditions. Here, we generated a peptide library which allows discovery of biomarkers in the equal settings as the validation process, thereby making the transition from discovery to validation more robust and efficient. The peptide library initiated with a list of 3393 proteins detectable in the blood from public databases. For each protein, surrogate peptides favorable for detection in mass spectrometry was selected and synthesized. A total of 4683 synthesized peptides were spiked into neat serum and plasma samples to check their quantifiability in a 10 min liquid chromatography-MS/MS run time. This led to the PepQuant library, which is composed of 852 quantifiable peptides that cover 452 human blood proteins. Using the PepQuant library, we discovered 30 candidate biomarkers for breast cancer. Among the 30 candidates, nine biomarkers, FN1, VWF, PRG4, MMP9, CLU, PRDX6, PPBP, APOC1, and CHL1 were validated. By combining the quantification values of these markers, we generated a machine learning model predicting breast cancer, showing an average area under the curve of 0.9105 for the receiver operating characteristic curve., (© 2023. The Author(s).)

Sorafenib, which inhibits multiple kinases, is an effective frontline therapy for hepatocellular carcinoma (HCC). Ferroptosis is a form of iron-dependent programmed cell death regulated by lipid peroxidation, which can be induced by sorafenib treatment. Oncoprotein hepatitis B X-interacting protein (HBXIP) participates in multiple biological pro-tumor processes, including growth, metastasis, drug resistance, and metabolic reprogramming. However, the role of HBXIP in sorafenib-induced ferroptotic cell death remains unclear. In this study, we demonstrated that HBXIP prevents sorafenib-induced ferroptosis in HCC cells. Sorafenib decreased HBXIP expression, and overexpression of HBXIP blocked sorafenib-induced HCC cell death. Interestingly, suppression of HBXIP increased malondialdehyde (MDA) production and glutathione (GSH) depletion to promote sorafenib-mediated ferroptosis and cell death. Ferrostatin-1, a ferroptosis inhibitor, reversed the enhanced anticancer effect of sorafenib caused by HBXIP silencing in HCC cells. Regarding the molecular mechanism, HBXIP transcriptionally induced the expression of stearoyl-CoA desaturase (SCD) via coactivating the transcriptional factor ZNF263, resulting in the accumulation of free fatty acids and suppression of ferroptosis. Functionally, activation of the HBXIP/SCD axis reduced the anticancer activity of sorafenib and suppressed ferroptotic cell death in vivo and in vitro. HBXIP/SCD axis-mediated ferroptosis can serve as a novel downstream effector of sorafenib. Our results provide new evidence for clinical decisions in HCC therapy., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Whether metabolic dysfunction-associated fatty liver disease (MAFLD) can replace nonalcoholic fatty liver disease (NAFLD) is under debate. This study evaluated which definition better predicted incident chronic kidney disease (CKD). This was a 5.3-year (range, 2.8-8.3) retrospective cohort study of 21,713 adults who underwent at least two serial health examinations. Cox analyses were used to compare the risk of incident CKD among non-fatty liver disease (FLD) without metabolic dysregulation (MD; reference), non-FLD with MD, MAFLD-only, NAFLD-only, or both-FLD groups. Non-FLD with MD group (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.00-1.53), both-FLD group (HR 1.50, 95% CI 1.19-1.89), and MAFLD-only group (HR 1.97, 95% CI 1.49-2.60), but not NAFLD-only group (HR 1.06, 95% CI 0.63-1.79) demonstrated an increased risk of CKD. The increased risk of CKD was significant in MAFLD subgroups with overweight/obesity (HR 2.94, 95% CI 1.91-4.55), diabetes (HR 2.20, 95% CI 1.67-2.90), MD only (HR 1.50, 95% CI 1.19-1.89), excessive alcohol consumption (HR 2.71, 95% CI 2.11-3.47), and viral hepatitis (HR 2.38, 95% CI 1.48-3.84). The switch from NAFLD to MAFLD criteria may identify a greater number of individuals at CKD risk. The association was also significant in MAFLD patients with excessive alcohol consumption or viral hepatitis., (© 2023. The Author(s).)

The high effectiveness of the third dose of BNT162b2 in healthy adolescents against Omicron BA.1 has been reported in some studies, but immune responses conferring this protection are not yet elucidated. In this analysis, our study (NCT04800133) aims to evaluate the humoral and cellular responses against wild-type and Omicron (BA.1, BA.2 and/or BA.5) SARS-CoV-2 before and after a third dose of BNT162b2 in healthy adolescents. At 5 months after 2 doses, S IgG, S IgG Fc receptor-binding, and neutralising antibody responses waned significantly, yet neutralising antibodies remained detectable in all tested adolescents and S IgG avidity increased from 1 month after 2 doses. The antibody responses and S-specific IFN-γ + and IL-2 + CD8 + T cell responses were significantly boosted in healthy adolescents after a homologous third dose of BNT162b2. Compared to adults, humoral responses for the third dose were non-inferior or superior in adolescents. The S-specific IFN-γ + and IL-2 + CD4 + and CD8 + T cell responses in adolescents and adults were comparable or non-inferior. Interestingly, after 3 doses, adolescents had preserved S IgG, S IgG avidity, S IgG FcγRIIIa-binding, against Omicron BA.2, as well as preserved cellular responses against BA.1 S and moderate neutralisation levels against BA.1, BA.2 and BA.5. Sera from 100 and 96% of adolescents tested at 1 and 5 months after two doses could also neutralise BA.1. Our study found high antibody and T cell responses, including potent cross-variant reactivity, after three doses of BNT162b2 vaccine in adolescents in its current formulation, suggesting that current vaccines can be protective against symptomatic Omicron disease., (© 2022. The Author(s).)

We explored the association between cholesterol levels and dementia risk according to the presence of diabetes and statin use. In this population-based longitudinal cohort study, the Korean National Health Insurance Service datasets (2002-2017) were used. Among individuals aged ≥ 40 years who underwent health examinations in 2009 (N = 6,883,494), the hazard of dementia was evaluated according to cholesterol levels. During a median 8.33 years, 263,185 dementia cases were detected. In statin non-users with or without diabetes, the hazards of all-cause dementia were highest for those in the lowest quartile or quintile of low-density lipoprotein-cholesterol (LDL-C) level, showing an inverted J-shaped relationship. Among statin users with or without diabetes, an advance in LDL-C group was associated with an increase in hazards of all-cause dementia. In statin users with diabetes, even very low LDL-C level was not associated with an increased risk of all-cause dementia. Although there was a seemingly paradoxical association between low LDL-C level and dementia risk in statin non-users, the trend was not observed in statin users and is not likely to be clinically relevant. Rather, an advance in LDL-C levels was associated with an increase in the hazard of all-cause dementia in statin users, regardless of the presence of diabetes., (© 2022. The Author(s).)

This study aimed to investigate the association between socio-demographic factors and designated healthy lifestyle behaviours in a nationally-representative sample of Malaysian adults aged 18 years and above. Secondary data involving 7388 participants aged 18-96 years from the National Health and Morbidity Survey 2019, a national cross-sectional survey, was used in this study. A healthy lifestyle score (0-5 points) was calculated based on five modifiable lifestyle factors: non-smoker, body mass index < 25 kg/m 2 , physically active, moderate (or less) alcohol intake, and daily consumption of ≥ 5 servings of fruits and vegetables. Associations between socio-demographic factors and healthy lifestyle behaviours were examined using multinomial logistic regression adjusted for sampling design. About 30.6% of the participants met at least four out of the five healthy lifestyle factors. In multinomial model, subjects who were female (aOR = 3.26, 95%CI = 2.58, 4.12), of Chinese (aOR = 2.31, 95%CI = 1.62, 3.30 or other ethnicity (aOR = 1.44, 95%CI = 1.05, 1.98), and aged 18-30 years (aOR = 1.74, 95% CI = 1.12, 2.71) showed significant association with achieving healthy lifestyle compared to male, Malay and ≥ 61 years old as reference categories. Our results indicated that gender, age and ethnicity associated with healthy lifestyle behaviours. Information on the influence of socio-demographic factors on the prevalence of healthy lifestyles will facilitate the development of effective intervention strategies to improve the adaptation of healthy lifestyle practices., (© 2022. The Author(s).)

The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and red cell distribution width (RDW) are emerging biomarkers to predict outcomes in general ward patients. However, their role in the prognostication of critically ill patients with pneumonia is unclear. A total of 216 adult patients were enrolled over 2 years. They were classified into viral and bacterial pneumonia groups, as represented by influenza A virus and Streptococcus pneumoniae, respectively. Demographics, outcomes, and laboratory parameters were analysed. The prognostic power of blood parameters was determined by the respective area under the receiver operating characteristic curve (AUROC). Performance was compared using the APACHE IV score. Discriminant ability in differentiating viral and bacterial aetiologies was examined. Viral and bacterial pneumonia were identified in 111 and 105 patients, respectively. In predicting hospital mortality, the APACHE IV score was the best prognostic score compared with all blood parameters studied (AUC 0.769, 95% CI 0.705-0.833). In classification tree analysis, the most significant predictor of hospital mortality was the APACHE IV score (adjusted P = 0.000, χ 2 = 35.591). Mechanical ventilation was associated with higher hospital mortality in patients with low APACHE IV scores ≤ 70 (adjusted P = 0.014, χ 2 = 5.999). In patients with high APACHE IV scores > 90, age > 78 (adjusted P = 0.007, χ 2 = 11.221) and thrombocytopaenia (platelet count ≤ 128, adjusted P = 0.004, χ 2 = 12.316) were predictive of higher hospital mortality. The APACHE IV score is superior to all blood parameters studied in predicting hospital mortality. The single inflammatory marker with comparable prognostic performance to the APACHE IV score is platelet count at 48 h. However, there is no ideal biomarker for differentiating between viral and bacterial pneumonia., (© 2022. The Author(s).)

The big-data use is becoming a standard practice in the neuroimaging field through data-sharing initiatives. It is important for the community to realize that such open science effort must protect personal, especially facial information when raw neuroimaging data are shared. An ideal tool for the face anonymization should not disturb subsequent brain tissue extraction and further morphological measurements. Using the high-resolution head images from magnetic resonance imaging (MRI) of 215 healthy Chinese, we discovered and validated a template effect on the face anonymization. Improved facial anonymization was achieved when the Chinese head templates but not the Western templates were applied to obscure the faces of Chinese brain images. This finding has critical implications for international brain imaging data-sharing. To facilitate the further investigation of potential culture-related impacts on and increase diversity of data-sharing for the human brain mapping, we released the 215 Chinese multi-modal MRI data into a database for imaging Chinese young brains, namely'I See your Brains (ISYB)', to the public via the Science Data Bank ( https://doi.org/10.11922/sciencedb.00740 )., (© 2022. The Author(s).)

The COVID-19 pandemic struck the world unguarded, some places outperformed others in COVID-19 containment. This longitudinal study considered a comparative evaluation of COVID-19 containment across 50 distinctly governed regions between March 2020 and November 2021. Our analysis distinguishes between a pre-vaccine phase (March-November 2020) and a vaccinating phase (December 2020-November 2021). In the first phase, we develop an indicator, termed lockdown efficiency (LE), to estimate the efficacy of measures against monthly case numbers. Nine other indicators were considered, including vaccine-related indicators in the second phase. Linear mixed models are used to explore the relationship between each government policy & hygiene education (GP&HE) indicator and each vital health & socioeconomic (VH&SE) measure. Our ranking shows that surveyed countries in Oceania and Asian outperformed countries in other regions for pandemic containment prior to vaccine development. Their success appears to be associated with non-pharmaceutical interventions, acting early, and adjusting policies as needed. After vaccines have been distributed, maintaining non-pharmacological intervention is the best way to achieve protection from variant viral strains, breakthrough infections, waning vaccine efficacy, and vaccine hesitancy limiting of herd immunity. The findings of the study provide insights into the effectiveness of emerging infectious disease containment policies worldwide., (© 2022. The Author(s).)

Selection of appropriate biomarker to identify inflammatory skin diseases is complicated by the involvement of thousands of differentially expressed genes (DEGs) across multiple cell types and organs. This study aimed to identify combinatorial biomarkers in inflammatory skin diseases. From one gene expression microarray profiling dataset, we performed bioinformatic analyses on dataset from lesional skin biopsies of patients with inflammatory skin diseases (atopic dermatitis [AD], contact eczema [KE], lichen planus [Li], psoriasis vulgaris [Pso]) and healthy controls to identify the involved pathways, predict upstream regulators, and potential measurable extracellular biomarkers. Overall, 434, 629, 581, and 738 DEGs were mapped in AD, KE, Li, and Pso, respectively; 238 identified DEGs were shared among four different inflammatory skin diseases. Bioinformatic analysis on four inflammatory skin diseases showed significant activation of pathways with known pathogenic relevance. Common upstream regulators, with upregulated predicted activity, identified were CNR1 and BMP4. We found the following common serum biomarkers: ACR, APOE, ASIP, CRISP1, DKK1, IL12B, IL9, MANF, MDK, NRTN, PCSK5, and VEGFC. Considerable differences of gene expression changes, involved pathways, upstream regulators, and biomarkers were found in different inflammatory skin diseases. Integrated bioinformatic analysis identified 12 potential common biomarkers of inflammatory skin diseases requiring further evaluation., (© 2022. The Author(s).)

Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF). Intrathecal administration of edema toxin (ET (PA + EF)) targeted DRG neurons and induced analgesia in mice. ET inhibited mechanical and thermal sensation, and pain caused by formalin, carrageenan or nerve injury. Analgesia depended on ANTXR2 expressed by Na v 1.8 + or Advillin + neurons. ET modulated protein kinase A signaling in mouse sensory and human induced pluripotent stem cell-derived sensory neurons, and attenuated spinal cord neurotransmission. We further engineered anthrax toxins to introduce exogenous protein cargoes, including botulinum toxin, into DRG neurons to silence pain. Our study highlights interactions between a bacterial toxin and nociceptors, which may lead to the development of new pain therapeutics., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Mitochondria are essential organelles that provide energy for mammalian cells and participate in multiple functions, such as signal transduction, cellular differentiation, and regulation of apoptosis. Compared with the mitochondria in somatic cells, oocyte mitochondria have an additional level of importance since they are required for germ cell maturation, dysfunction in which can lead to severe inherited disorders. Thus, a systematic proteomic profile of oocyte mitochondria is urgently needed to support the basic and clinical research, but the acquisition of such a profile has been hindered by the rarity of oocyte samples and technical challenges associated with capturing mitochondrial proteins from live oocytes. Here, in this work, using proximity labeling proteomics, we established a mitochondria-specific ascorbate peroxidase (APEX2) reaction in live GV-stage mouse oocytes and identified a total of 158 proteins in oocyte mitochondria. This proteome includes intrinsic mitochondrial structural and functional components involved in processes associated with "cellular respiration", "ATP metabolism", "mitochondrial transport", etc. In addition, mitochondrial proteome capture after oocyte exposure to the antitumor chemotherapeutic cisplatin revealed differential changes in the abundance of several oocyte-specific mitochondrial proteins. Our study provides the first description of a mammalian oocyte mitochondrial proteome of which we are aware, and further illustrates the dynamic shifts in protein abundance associated with chemotherapeutic agents., (© 2021. The Author(s).)

We aimed to determine whether hospital admissions during an extended holiday period (Chinese New Year) and weekends were associated with increased mortality risk from pulmonary embolism (PE), compared to admissions on weekdays. We conducted a nationwide retrospective cohort study using Taiwan's National Health Insurance Research Database. Data of newly diagnosed PEs during the months of January and February from 2001 to 2017 were obtained from patient records and classified into three admission groups: Chinese New Year (≥ 4 consecutive holiday days), weekends, and weekdays. The adjusted odds ratios (aORs) (95% confidence intervals [CIs]) for 7-day and in-hospital mortality were calculated using multivariable logistic regression models. The 7-day and in-hospital mortality risks were higher for patients admitted during the Chinese New Year holiday (10.6% and 18.7%) compared to those admitted on weekends (8.4% and 16.1%) and weekdays (6.6% and 13.8%). These higher mortality risks for holiday admissions compared to weekday admissions were confirmed by multivariable analysis (7-day mortality: aOR = 1.68, 95% CI 1.15-2.44, P = 0.007; in-hospital mortality: aOR = 1.41, 95% CI 1.05-1.90, P = 0.022), with no subgroup effects by sex or age. Hospital admission for PE over an extended holiday period, namely Chinese New Year, was associated with an increased risk of mortality., (© 2021. The Author(s).)

Multilocus variable-number tandem repeat analysis (MLVA) is widely used for genotyping of Bordetella pertussis, the causative bacteria for pertussis. However, MLVA genotyping is losing its discriminate power because prevalence of the epidemic MT27 strain (MLVA-27) is increasing worldwide. To address this, we developed a single nucleotide polymorphism (SNP) genotyping method for MT27 based on multiplexed single-base extension (SBE) assay. A total of 237 MT27 isolates collected in Japan during 1999-2018 were genotyped and classified into ten SNP genotypes (SG1 to SG10) with a Simpson's diversity index (DI) of 0.79 (95% CI 0.76-0.82). Temporal trends showed a marked increase in the genotypic diversity in the 2010s: Simpson's DI was zero in 1999-2004, 0.16 in 2005-2009, 0.83 in 2010-2014, and 0.76 in 2015-2018. This indicates that the SNP genotyping is applicable to the recently circulating MT27 strain. Additionally, almost all outbreak-associated MT27 isolates were classified into the same SNP genotypes for each outbreak. Multiplexed SBE assay allows for rapid and simple genotyping, indicating that the SNP genotyping can potentially be a useful tool for subtyping the B. pertussis MT27 strain in routine surveillance and outbreak investigations.

Many pathogenic fungi depend on the development of specialized infection structures called appressoria to invade their hosts and cause disease. Impairing the function of fungal infection structures therefore provides a potential means by which diseases could be prevented. In spite of this extraordinary potential, however, relatively few anti-penetrant drugs have been developed to control fungal diseases, of either plants or animals. In the present study, we report the identification of compounds that act specifically to prevent fungal infection. We found that the organization of septin GTPases, which are essential for appressorium-mediated infection in the rice blast fungus Magnaporthe oryzae, requires very-long-chain fatty acids (VLCFAs), which act as mediators of septin organization at membrane interfaces. VLCFAs promote septin recruitment to curved plasma membranes and depletion of VLCFAs prevents septin assembly and host penetration by M. oryzae. We observed that VLCFA biosynthesis inhibitors not only prevent rice blast disease, but also show effective, broad-spectrum fungicidal activity against a wide range of fungal pathogens of maize, wheat and locusts, without affecting their respective hosts. Our findings reveal a mechanism underlying septin-mediated infection structure formation in fungi and provide a class of fungicides to control diverse diseases of plants and animals.

Lipid composition in breast cancer, a central marker of disease progression, can be non-invasively quantified using 2D MRS method of double quantum filtered correlation spectroscopy (DQF-COSY). The low signal to noise ratio (SNR), arising from signal retention of only 25% and depleted lipids within tumour, demands improvement approaches beyond signal averaging for clinically viable applications. We therefore adapted and examined combination algorithms, designed for 1D MRS, for 2D MRS with both internal and external references. Lipid composition spectra were acquired from 17 breast tumour specimens, 15 healthy female volunteers and 25 patients with breast cancer on a clinical 3 T MRI scanner. Whitened singular value decomposition (WSVD) with internal reference yielded maximal SNR with an improvement of 53.3% (40.3-106.9%) in specimens, 84.4 ± 40.6% in volunteers, 96.9 ± 54.2% in peritumoural adipose tissue and 52.4% (25.1-108.0%) in tumours in vivo. Non-uniformity, as variance of improvement across peaks, was low at 21.1% (13.7-28.1%) in specimens, 5.5% (4.2-7.2%) in volunteers, 6.1% (5.0-9.0%) in peritumoural tissue, and 20.7% (17.4-31.7%) in tumours in vivo. The bias (slope) in improvement ranged from - 1.08 to 0.21%/ppm along the diagonal directions. WSVD is therefore the optimal algorithm for lipid composition spectra with highest SNR uniformly across peaks, reducing acquisition time by up to 70% in patients, enabling clinical applications.

Internet addiction (IA) is common among adolescents and significantly determined by sociocultural and economic factors. The aim of this study was to compare the prevalence of IA among adolescents between Macau and mainland China and also examine its association with quality of life. A total of 2892 secondary school students were included. Standardized instruments were used to measure IA, depressive symptoms and quality of life. The overall prevalence of IA was 23.7%, with 32.5% in Macau and 19.8% in mainland China. Students in Macau were more likely to suffer from IA than those in mainland China (OR = 2.15, p < 0.001). Correlates of IA included being in higher school grades, poor academic performance, and more severe depressive symptoms. Students with IA reported lower quality of life in physical, psychological, social, and environmental domains. IA is common among Chinese adolescents, particularly in Macau. Considering the negative impact of IA on health and quality of life, regular screening and effective interventions should be undertaken for young Internet users.

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

To investigate the value of modified calcaneal axial radiograph-the horizontal calcaneal axial radiograph in diagnosing calcaneal fractures, patients who had acute calcaneal fractures or internal fixation were enrolled, and three groups were established, including the acute fracture group (n = 20), the internal fixation group (n = 20), and the healthy control group (n = 20). All the subjects had regular and modified calcaneal axial radiograph for comparison. In analysis of the results, all volunteers could have ankle dorsiflexion at different degrees. When the ankle was at 30º dorsiflexion for regular axial radiograph, the subtalar joint and the sustentaculum tali could not be clearly displayed. The calcaneus was elongated if the tube tilted in a larger angle but shortened if the tube titled in a smaller angle. When the ankle was at neutral (0º dorsiflexion) location with the tube tilting 45° cephalad or when the ankle was at 20° plantarflexion with the tube tilting 35° cephalad, the subtalar joint, sustentaculum tali, calcaneal body and internal and external calcaneal processes could all be clearly demonstrated. No significant difference (P = 0.79) existed in displaying the bony anatomical structures in regular compared with modified calcaneal axial radiography. For patients with acute calcaneal factures or with internal fixation, the modified calcaneal axial radiography could display more significantly clearly (P = 0.001) bony anatomical structures than the regular one. In conclusion, the modified calcaneal axial radiograph can be performed easily and can clearly show the bony structure of the calcaneus and surrounding bones without adding pain to the patients with calcaneal fractures.

Cataract is the primary cause of visual impairment and can be corrected by cataract surgery. We investigated the impact of cataract on the risk of depression along with the benefits of cataract surgery. Patients newly diagnosed with cataract by ophthalmologists between 2001 and 2015 were identified from the National Health Insurance Research Database (NHIRD) in Taiwan. Non-cataract individuals were recruited by 1:1 matching for age, sex and index year. After propensity score matching, 233,258 patients in total were included in our study: 116,629 in each of the cataract and non-cataract cohorts. The primary outcome was the new diagnosis of depression by psychiatrists. In a mean follow-up period of 7.8 years, cataract was significantly associated with increased risk of developing depression (adjusted hazard ratio [aHR] = 1.78, 95% confidence interval [CI] 1.70-1.87, p < 0.001). We further divided the cataract cohort into surgery and non-surgery groups. Notably, cataract surgery group was associated with a decreased risk of depression compared with non-surgery patients (aHR = 0.75, 95% CI 0.71-0.79, p < 0.001). Our results emphasise the importance of regular screening for depression among cataract patients and the beneficial effect of cataract surgery in reducing the risk of depression.

This study was to analyze ankle fractures for determining the epidemiology, types, distribution, possible mechanisms and diagnosis precision. Between January 2013 and December 2017, all Chinese patients older than 16 years of age with ankle fractures excluding old ankle fractures and pathological fractures in a tertiary care hospital were analyzed by using the Danis-Weber and Lauge-Hansen classification systems. Among 3952 patients with ankle fractures, 1225 fractures (31%) were Danis-Weber type A, 1640 (42%) were type B, 751 (19%) were type C, and 336 (9%) were perpendicular compression fracture. There were 1949 fractures on the left side and 2003 on the right with no significant difference (P > 0.05). Male patients between 16 and 50 years of age and women over 50 years had a higher incidence of ankle fractures accounting for 38.4% (1517/3952) and 22.2% (800/3952), respectively. Posterior malleolar fractures, fibular fractures above the inferior tibiofibular joint and Tillaux fractures were easily missed in the diagnosis, with 38 fractures (0.96%) being missed in the diagnosis. In conclusion, young and middle-aged men and older women have a higher incidence of ankle fractures, and use of the Lauge-Hansen and Danis-Weber classification systems can better help assessing the varied and complex ankle fractures, predicting the injuries, increasing diagnostic precision and decreasing misdiagnosis rate.

We aimed to identify the association between low skeletal muscle, sarcopenic obesity, and the incidence of albuminuria in the general population using a longitudinal study. Data from 29,942 subjects who underwent two or more routine health examinations from 2006 to 2013 were retrospectively reviewed. Relative skeletal muscle mass was presented using the skeletal muscle mass index (SMI), a measure of body weight-adjusted appendicular skeletal muscle mass estimated by bioelectrical impedance analysis. The cumulative incidence of albuminuria was 981 (3.3%) during the 7-year follow-up period. The hazard ratio of incident albuminuria was 1.44 (95% CI: 1.22-1.71, p for trend <0.001) in the lowest SMI tertile relative to the highest SMI tertile after multivariable adjustment. After additionally adjusting for general and central obesity, the hazard ratio was 1.35 (95% CI: 1.13-1.61, p for trend = 0.001) and 1.30 (95% CI: 1.08-1.56, p for trend = 0.003), respectively. Furthermore, the risk of developing albuminuria was much higher in the sarcopenic obesity group (HR: 1.49, 95% CI: 1.21-1.81, p for trend <0.001) compared to the other groups. Sarcopenic obesity, as well as low skeletal muscle, may lead to albuminuria in general populations.

To investigate the characteristics of imaging changes with time of facial fractures, patients with facial fractures who had computed tomographic scan were enrolled including 500 patients who were divided into six groups based on the time of scanning: super early (<3 d), early (4-7 d), early-to-medium (8-14 d), medium (15-21d), medium-to-late (22d-2 months) and late stage (>2 months). The data were compared and analyzed. Forty two patients with frontal bone fractures had high-energy impact as the reason of fractures. The fracture line was clear and sharp within one week but blunt and sclerotic due to bone absorption at 2-3 weeks, and might exist for a long time. All patients had soft tissue swelling and paranasal sinus effusion at 1-2 weeks after injury. Air might gather in the adjacent soft tissues and/or intracranially within 3 days of injury if the fracture involved the frontal or other sinuses. Twelve of the 42 patients (28.6%) had intracranial hematoma, and five (11.9%) had epidural effusion. Subarachnoid hemorrhage was mostly absorbed within one week while epidural hematoma was completely absorbed over 3 weeks. Significant changes (P < 0.05) in the fracture lines, effusion of paranasal sinuses, soft tissue swelling and pneumocephalus were observed during the study period. For patients with medial orbital wall fractures, the fracture line was sharp and clear at early stages with concurrent sphenoid sinus effusion, and the fracture line became depressed 3 weeks later with disappearance of sphenoid sinus effusion. Significant changes (P < 0.05) were observed in the sharp fracture line, soft tissue swelling, sphenoid sinus effusion and smooth depression at fracture sites. For nasal fractures, the fracture line was sharp and clear at early stages with concurrent soft tissue swelling which disappeared one week later. The fracture line became smooth three weeks later. A significant (P < 0.05) difference was demonstrated in the changes of fracture line and soft tissue swelling with time. In conclusion, facial fractures have some dynamic alterations with time and identification of these characteristics may help reaching a correct clinical diagnosis with regard to fracture severity and time.

Activation of the inflammasome is involved in the progression of retinal degenerative diseases, in particular, in the pathogenesis of Age-Related Macular Degeneration (AMD), with NLRP3 activation the focus of many investigations. In this study, we used genetic and pharmacological approaches to explore the role of the inflammasome in a mouse model of retinal degeneration. We identify that Casp1/11 -/- mice have better-preserved retinal function, reduced inflammation and increased photoreceptor survivability. While Nlrp3 -/- mice display some level of preservation of retinal function compared to controls, pharmacological inhibition of NLRP3 did not protect against photoreceptor cell death. Further, Aim2 -/- , Nlrc4 -/- , Asc -/- , and Casp11 -/- mice show no substantial retinal protection. We propose that CASP-1-associated photoreceptor cell death occurs largely independently of NLRP3 and other established inflammasome sensor proteins, or that inhibition of a single sensor is not sufficient to repress the inflammatory cascade. Therapeutic targeting of CASP-1 may offer a more promising avenue to delay the progression of retinal degenerations.

Transcription factor PAX8 expression is upregulated in several types of cancers. However, little is known about the function of PAX8 in the progression of hepatoma and its regulatory mechanisms. Here, we show that PAX8 silencing inhibits the proliferation and clonogenicity of hepatoma cells and its growth in vivo. The HBV X protein (HBx) does not directly interacts, but stabilizes PAX8 by inhibiting proteasome-dependent ubiquitination and degradation. Furthermore, the E3 ubiquitin ligase complex component Skp2 through its LRR domain directly interacts with the Prd domain of PAX8 and targets PAX8 by recognizing its lysine 275 for ubiquitination and degradation in hepatoma cells. In addition, HBx directly interacts and is colocalized with Skp2 to inhibit its recognition and subsequent ubiquitination and degradation of PAX8 in hepatoma cells. Moreover, HBx upregulates the expression and phosphorylation of Aurora A, a serine-threonine kinase, which interacts with and phosphorylates PAX8 at S209 and T277, compromising the Skp2-recognized PAX8 ubiquitination and destabilization. Thus, HBx stabilizes PAX8 protein by inhibiting the Skp2 targeted PAX8 ubiquitination and enhancing the Aurora A-mediated its phosphorylation, contributing to the progression of hepatoma. Our findings suggest that PAX8 may a new target for design of therapies and uncover new insights into the pathogenesis of hepatoma.

A global priority for the behavioural sciences is to develop cost-effective, scalable interventions that could improve the academic outcomes of adolescents at a population level, but no such interventions have so far been evaluated in a population-generalizable sample. Here we show that a short (less than one hour), online growth mindset intervention-which teaches that intellectual abilities can be developed-improved grades among lower-achieving students and increased overall enrolment to advanced mathematics courses in a nationally representative sample of students in secondary education in the United States. Notably, the study identified school contexts that sustained the effects of the growth mindset intervention: the intervention changed grades when peer norms aligned with the messages of the intervention. Confidence in the conclusions of this study comes from independent data collection and processing, pre-registration of analyses, and corroboration of results by a blinded Bayesian analysis.

Polyunsaturated fatty acid (PUFA), a key marker in breast cancer, is non-invasively quantifiable using multiple quantum coherence (MQC) magnetic resonance spectroscopy (MRS) at the expense of losing half of the signal. Signal combination for phased array coils provides potential pathways to enhance the signal to noise ratio (SNR), with current algorithms developed for conventional brain MRS. Since PUFA spectra and the biochemical environment in the breast deviate significantly from those in the brain, we set out to identify the optimal algorithm for PUFA in breast cancer. Combination algorithms were compared using PUFA spectra from 17 human breast tumour specimens, 15 healthy female volunteers, and 5 patients with breast cancer on a clinical 3 T MRI scanner. Adaptively Optimised Combination (AOC) yielded the maximum SNR improvement in specimens (median, 39.5%; interquartile range: 35.5-53.2%, p < 0.05), volunteers (82.4 ± 37.4%, p < 0.001), and patients (median, 61%; range: 34-105%, p < 0.05), while independent from voxel volume (rho = 0.125, p = 0.632), PUFA content (rho = 0.256, p = 0.320) or water/fat ratio (rho = 0.353, p = 0.165). Using AOC, acquisition in patients is 1.5 times faster compared to non-noise decorrelated algorithms. Therefore, AOC is the most suitable current algorithm to improve SNR or accelerate the acquisition of PUFA MRS from breast in a clinical setting.

The NLRP3 inflammasome promotes the pathogenesis of metabolic, neurodegenerative and infectious diseases. Increasing evidences show that the NLRP3 inflammasome is a promising therapeutic target in inflammatory diseases. Glucosamine is widely used as a dietary supplement to promote the health of cartilage tissue and is expected to exert anti-inflammatory activity in joint inflammation, which is a nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome-associated complication. Here, we investigated whether GlcN inhibits the NLRP3 inflammasome and dissected the underlying molecular mechanisms. We found that GlcN suppressed the NLRP3 inflammasome in mouse and human macrophages. A mechanistic study revealed that GlcN inhibited the expression of NLRP3 and IL-1β precursor by reducing reactive oxygen species generation and NF-κB activation in lipopolysaccharide-activated macrophages. GlcN also suppressed mitochondrial reactive oxygen species generation and mitochondrial integrity loss in NLRP3-activated macrophages. Additionally, GlcN disrupted NLRP3 inflammasome assembly by inhibiting NLRP3 binding to PKR, NEK7 and ASC. Furthermore, oral administration of GlcN reduced peritoneal neutrophils influx and lavage fluids concentrations of IL-1β, IL-6 MCP-1 and TNF-α in uric acid crystal-injected mice. These results indicated that GlcN might be a novel dietary supplement for the amelioration of NLRP3 inflammasome-associated complications.