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Abstract This study aimed to manage Helicobacter pylori (H. pylori) infection through a family-centered approach. It conducted a two-year follow-up on infected individuals’ family members in Yichun, Jiangxi, China, to gain comprehensive insights into the transmission dynamics, treatment adherence, and associated risk factors of H. pylori within households. A retrospective analysis was performed on the data obtained from households in Yichun City that participated in the nationwide multicenter H. pylori prevalence study in 2021, along with the corresponding subsequent follow-up data. The collected information encompassed fundamental demographic details of the families, their lifestyle patterns, and the status of H. pylori infection. Among 514 households, 222 comprised two individuals, whereas 68 constituted larger families with five or more members. All member was infected in 9.34% of households. Larger family sizes (≥ 5 individuals) and higher generational counts were closely associated with H. pylori infection (e.g., family size > 6: OR 4.46, 95%CI 1.29 to 15.46). Adult age, marital status, and household members’ infections were identified as primary risk factors (e.g., married individuals: OR 2.03, 95%CI 1.56 to 2.65). Students and previously uninfected individuals exhibited lower infection risks (e.g., tested as negative: OR 0.48, 95%CI 0.31 to 0.73). Maternal, paternal, or sibling infections were linked to increased risks of child infections (e.g., mother infected: OR 2.58 95%CI 1.37 to 4.87). Successful eradication in ≥ 2 individuals reduced the infection risk for other members (OR 0.25, 95%CI (0.07 to 0.89). H. pylori displayed noticeable clustering infection characteristics within families. This study lends support to family-based management strategies, but given suboptimal adherence to household management, there is a need to enhance education on the hazards of H. pylori before implementing screening programs.

Abstract Objective Expand genetic screening for atypical Type I sialidosis (ST‐1) could address its underdiagnosed in both progressive myoclonic ataxia (PMA) and ataxia patients. To evaluate the potential founder effect of mutation in the population. Methods We enrolled 231 patients with PMA or ataxia from the First Affiliated Hospital of Fujian Medical University. Through Whole Exome Sequencing and Sanger sequencing, we identified the causative gene in patients. Haplotype analysis was employed to explore a potential founder effect of the NEU1 c.544A>G mutation. Results A total of 31 patients from 23 unrelated families were genetically diagnosed with ST‐1. A significant 80.6% of these patients were homozygous for the c.544A>G mutation. We discovered six different NEU1 variants, including two novel mutations: c.951_968del and c.517T>G. The mean age of onset was 18.0 ± 7.1 years. The clinical spectrum of ST‐1 featured ataxia and myoclonus as the most common initial symptoms. Over 40% suffered from controlled generalized tonic–clonic seizures. Mobility and independence varied greatly across the cohort. Cherry‐red spots were rare, occurring in just 9.5% (2/21) of patients. Brain MRIs were typically unremarkable, except for two patients with unusual findings. EEGs showed diffuse paroxysmal activity in 17 patients. The c.544A>G mutation in NEU1 is a founder variant in Fujian, with a unique haplotype prevalent in East Asians. Interpretation ST‐1 should be suspected in patients with PMA or ataxia in Southeast China, even without macular cherry‐red spots and seizures, and the premier test could be a variant screening of the founder variant NEU1 c.544A>G.

Abstract Swine acute diarrhoea syndrome coronavirus (SADS-CoV) causes vomiting, severe diarrhoea and death in newborn piglets. The spike (S) protein plays a crucial role in promoting virus invasion and inducing neutralizing antibody production. In this study, the extracellular region of the S protein was used as an immunogen to immunize BALB/c mice. After immunization, B cells were collected, fused with SP2/0 myeloma cells, cultured and subcloned, and a cell line capable of secreting neutralizing antibodies was obtained and named as 5D6. Additionally, it was determined that the 5D6 mAb could be used as the primary antibody for western blotting and indirect immunofluorescence assay (IFA) to detect SADS-CoV. Further studies indicated that the 5D6 mAb binds to the 136STSHAAD142 motif, which located in the N-terminal domain (NTD) of the spike protein. This result suggested that the NTD of the S protein can induce the production of neutralizing antibodies. Amino acid sequence alignment revealed that the epitope of the 5D6 mAb was conserved among SADS-CoV strains. This study helps elucidate the S protein function of SADS-CoV, and the 5D6 mAb may be used to develop diagnostic and treatment tools for detecting SADS-CoV infection.

Abstract A prolific multi‐product sesterterpene synthase CbTPS1 is characterized from the medicinal Brassicaceae plant Capsella bursa‐pastoris. Twenty different sesterterpenes including 16 undescribed compounds, possessing 10 different mono‐/di‐/tri‐/tetra‐/penta‐carbocyclic skeletons, including the unique 15‐membered macrocyclic and 24(15→14)‐abeo‐capbuane scaffolds, are isolated and structurally elucidated from engineered Escherichia coli strains expressing CbTPS1. Site‐directed mutagenesis assisted by molecular dynamics simulations resulted in the variant L354M with up to 13.2‐fold increased sesterterpene production. These structurally diverse products suggest a comprehensive cyclization mechanism for plant sesterterpenes and provide compelling evidence for the initial cyclization of geranylfarnesyl diphosphate via a crucial 15‐membered monocyclic carbocation. The activities of these sesterterpenes against liver fibrosis is inferred from the inhibition of the transforming growth factor‐β/Smad signaling pathway and collagen synthesis. These findings greatly expand the chemical space and biological functions of sesterterpenes and provide new insights into the catalytic mechanism of terpene synthases.

BackgroundThe association of the p53 rs1042522 and rs17878362 polymorphisms with cervical cancer risk has been reported in several published original studies and meta-analyses. However, the conclusions of these studies were contradictory. Consequently, we conducted an updated meta-analysis to further validate these debates.ObjectiveTo evaluate the association between the p53 rs1042522 and rs17878362 polymorphisms and cervical cancer risk.Materials and MethodsPubMed, Medline, Ovid, Embase, CNKI, and China Wanfang databases were searched. Association was assessed using odds ratio (OR) with 95% confidence interval (CI). Moreover, the false-positive reporting probability (FPRP), Bayesian false-finding probability (BFDP), and Venice criteria were used to assess the credibility of statistically significant association.ResultsA significantly decreased cervical cancer risk was revealed for the p53 rs1042522 polymorphism (Pro/Pro +Arg/Pro vs. Arg/Arg: OR = 0.79, 95% CI = 0.71-0.87; Pro/Pro vs. Arg/Arg: OR = 0.80, 95% CI = 0.70-0.91; Arg/Pro vs. Arg/Arg: OR = 0.78, 95% CI = 0.71-0.86; Pro vs. Arg: OR = 0.87, 95% CI = 0.81-0.93) in overall analysis and several subgroup analyses, such as in Caucasians, Asians, Indians, and so on. However, no significant association was found between the p53 rs17878362 polymorphism and cervical cancer risk. Despite these statistically significant results, reliability analysis using FPRP, BFDP, and Venice criteria deemed all associations “unreliable”.ConclusionsAfter considering the reliability of the results, this study indicates that the p53 rs1042522 polymorphism is not associated with the cervical cancer risk.

ABSTRACT The APETALA2/ethylene‐responsive factor (AP2/ERF) superfamily represents a class of transcription factors involved in plant growth, development, and stress responses. Carthamus tinctorius L., also known as safflower, is an important plant whose flowers contain carthamin, an expensive aromatic pigment with various medicinal and flavoring properties. This study aimed to elucidate the roles of these transcription factors in plant growth, metabolic regulation, and environmental adaptation in safflower, providing foundational information and theoretical support for genetic improvement and stress resilience research in this crop. In this study, we identified and characterized the AP2/ERF family genes in safflower through a comprehensive genomic analysis. A total of 127 AP2/ERF genes were identified and clustered into seven groups and 14 subgroups based on phylogenetic analysis. Multiple sequence alignment revealed that the basic region and two helical structures were highly conserved in most AP2/ERF proteins. Cis‐acting elements in the promoters of the AP2/ERF genes were analyzed, and a degree of safflower specificity was observed among different safflower species. Tissue‐specific expression analysis showed that 23, 21, 15, and 9 genes were most abundantly expressed in the roots, leaves, flowers, and buds, respectively, while only eight genes were highly expressed in all tissues examined. These results indicate that the AP2/ERF family genes in safflower are diverse and complex, with distinct expression patterns for different genes in different safflower species. The findings provide important fundamental data for in‐depth studies of the growth, development, and stress response mechanisms in safflower.

IntroductionTraditional risk factors do not fully explain the increased risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA). The Haptoglobin (Hp) 2-2 genotype confers a lower anti-oxidant and higher inflammatory effect on the vasculature compared to the non-Hp 2-2 genotype. This study investigates the association of the Hp genotype with CVD in patients with RA.MethodsData from 69 RA patients with CVD and 207 sex- and ethnicity-matched RA patients without CVD, collected from 1 January 2000 to 31 December 2020, were retrieved from the Tan Tock Seng Hospital RA Registry. CVD was examined against demographics, clinical and laboratory variables in univariate models. Associations between the Hp genotypes and CVD were analyzed using conditional logistic regression.ResultsWe studied 276 patients (65.2% female, 82.6% Chinese, median age 60.9 years). Most participants were in low disease activity or remission (79.3%). The Hp 2-2 genotype was present in 49.6% (137/276). In the group with CVD, the prevalence of the Hp 2-2 genotype was 50.9% (29/57) in the Chinese, 100% (5/5) in the Indians, and 28.6% (2/7) in the Malays. In the non-CVD group, the respective prevalence was 46.8% (80/171), 66.7% (10/15), and 52.4% (11/21). In univariate analysis, the matched odds ratio (OR) of the Hp 2-2 genotype for CVD in RA was 1.34 [95% confidence interval (CI): 1.22–1.47; p

To evaluate four novel SARS-CoV-2 neutralizing antibody assay kits' application in neutralizing antibodies of population. Questionnaires from the voluntary participating researchers and selected the qualified questionnaires to analyse. For negative and positive coincidence rate, four novel SARS-Cov-2 neutralization antibody assay kits were tested. For within-run and between-run Precision verification study, four serum samples with two high and two low titer neutralizing antibodies were used to analyse. Based on the questionnaires, 175 qualified samples were divided into two groups. (1) negative neutralizing antibodies group: 31 samples had not been infected with the novel SARS-Cov-2 nor received the vaccine within the past one year; (2) positive neutralizing antibodies group: 144 samples were infected by COVID-19. There was 28 negative and 3 positive neutralizing antibodies of the individuals among the 31 negative samples which based on the questionnaires. The negative rates of 28 negative individules tested by GenScript, Vazyme and Hygeianey were 82.14 %, 60.71 % and 17.85 %, while the positive rates of the 147 positive samples were 93.87 %, 95.23 % and 100 %. The within-run coefficient of variations (C·V) of PBNAs, GenScript, Vazyme and Hygeianey were 11.49 %, 9.12 %, 7.97 % and 7.48 %, while the between-run coefficient of variations (C·V) were 21.37 %, 14.21 %, 12.29 % and 11.78 %. Due to the large within-run and between-run coefficient of variations, PBNAs was not suitable for large-scale promotion, while ELISAs could be leveraged for routine monitoring the titer of neutralizing antibodies against SARS-CoV-2.

Recently, global science has shown an increasing open trend, however, the characteristics of research integrity of open access (OA) publications have rarely been studied. The aim of this study is to compare the characteristics of retracted articles across different OA levels and discover whether OA level influences the characteristics of retracted articles.

ABSTRACT: Objectives: The objective of this randomised controlled trial was to compare the periodontal healing at the distal of the adjacent second molar after coronectomy or surgical removal and the surgical morbidities of the 2 techniques. Methods: This is a pilot study of a split-mouth randomised clinical trial comparing the periodontal healing of the adjacent second molar after coronectomy or total removal of lower third molars, which was registered with the University of Hong Kong Clinical Trial Centre as HKUCTR-2948 on 21 February 2020. Cone beam computed tomography (CBCT) scans were taken preoperatively and at 6 months postoperatively. Changes in the bone level from the cemento-enamel junction, periodontal probing depth (PPD), and clinical attachment level (CAL) at the distal of the adjacent second molar were compared. Surgical morbidities in terms of pain, infection, neurologic deficit, root exposure, and need for second surgery for removal were assessed. Results: Forty patients (22 male, 18 female) with mean age of 26.7 years were evaluated at 6 months postoperatively. Both coronectomy and total removal groups demonstrated statistically significant reduction in PPD and CAL. There was an alveolar bone gain of 1.28 ± 0.88 mm in the coronectomy group and 1.13 ± 0.73mm in the control group, which was statistically significant (P < .001 for both groups). Conclusions: Early findings show the periodontal healing at the adjacent second molar of coronectomy was as good as that of total removal of lower third molar. There were no differences in terms of surgical morbidities between both groups.

Purpose: To report the use of anterior segment optical coherence tomography (AS-OCT) for superficial keratectomy (SK) in anterior corneal opacity. Methods: The characteristics of 43 eyes (39 patients) with various lesions responsible for anterior corneal opacity were included in this retrospective non-comparative study. AS-OCT was performed on all eyes before surgery. The thickness of corneal opacity and the underlying healthy stroma were measured. SK was performed on each individual. Results: Four types of anterior corneal opacity were evaluated, including corneal degeneration (26/43), Reis-Bücklers corneal dystrophy (8/43), alkali burn (1/43) and corneal tumors (8/43). Based on AS-OCT images, all eyes showed abnormal hyper-reflective signals in the superficial cornea to less than one-third of the normal corneal thickness in the deepest corneal opacity. All 43 eyes underwent an SK procedure. In addition, 1 eye with alkali burns and 7 eyes with corneal tumors were combined with amniotic membrane transplantation. All eyes restored transparency without significant complications. Conclusion: AS-OCT is a valuable method for objective preoperative and noninvasive assessments of anterior corneal opacities and is useful for guiding SK.

Abstract Endocrine receptors play an essential role in tumor metabolic reprogramming and represent a promising therapeutic avenue in pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by a nutrient-deprived microenvironment. To meet their ascendant energy demands, cancer cells can internalize extracellular proteins via macropinocytosis. However, the roles of endocrine receptors in macropinocytosis are not clear. In this study, we found that progesterone receptor (PGR), a steroid-responsive nuclear receptor, is highly expressed in PDAC tissues obtained from both patients and transgenic LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; PDX1-cre (KPC) mice. Moreover, PGR knockdown restrained PDAC cell survival and tumor growth both in vitro and in vivo. Genetic and pharmacological PGR inhibition resulted in a marked attenuation of macropinocytosis in PDAC cells and subcutaneous tumor models, indicating the involvement of this receptor in macropinocytosis regulation. Mechanistically, PGR upregulated CDC42, a critical regulator in macropinocytosis, through PGR-mediated transcriptional activation. These data deepen the understanding of how the endocrine system influences tumor progression via a non-classical pathway and provide a novel therapeutic option for patients with PDAC.

Fever is one of the most common clinical conditions and is characterized by pyrogenic infection, malignancy, inflammation, and tissue damage, among others. Ellagic acid (EA) can inhibit the expression of related proteins on the pathway by blocking the nuclear factor kappa-B(NF-κB) signaling pathway, inhibit the levels of pro-inflammatory factors interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α), increase the level of anti-inflammatory factor IL-10, and effectively alleviate inflammatory symptoms. In addition, EA can also reduce the levels of malondialdehyde(MDA) and nitric oxide(NO) in the body, increase the activities of superoxide dismutase (SOD), glutathione (GSH), and catalase(CAT), scavenge oxidative free radicals, inhibit lipid oxidation, and achieve antipyretic and anti-inflammatory effects. The purpose of this study was to establish the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, prostaglandin E2(PGE2), and cyclic adenosine monophosphate(cAMP), and clarify the mechanism of the cyclooxidase-2(COX-2)/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism. Compared to lipopolysaccharide (LPS)- treated animals, subsequent administration of EA significantly lowered the LPS-induced rectal temperature increase (p < 0.05 or p < 0.01), significantly increased serum SOD and GSH levels (p < 0.05 or p < 0.01), and significantly decreased serum MDA, IL-1β, IL-6, and TNF-α levels (p < 0.05 or p < 0.01). In addition, compared to LPS-treated animals, subsequent administration of EA significantly decreased cerebrospinal fluid cAMP and PGE2 levels (p < 0.05 or p < 0.01), significantly decreased cAMP, significantly increased 5-HT levels (p < 0.05 or p < 0.01), and significantly down-regulated p-NF-κB p65 and COX-2 protein levels in the hypothalamus. Subsequent gas chromatography mass spectrometry(GC-MS) metabolite analysis indicated that 12 differential metabolites were detected in serum isolated 4 h after LPS treatment, and 10 differential metabolites were detected in serum collected 7 h after LPS treatment. Next, Pearson correlation analysis was used to systematically characterize the relationship between the identified metabolites and TNF-α, IL-6, MDA, SOD, PGE2, and cAMP. The levels of propionic acid, pyridine, and L-valine were up-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α and increased the activity of GSH. The levels of inositol, urea, and 2-monopalmitin were down-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α, increased the activity of SOD and GSH, reduced the inflammatory response, and alleviated the oxidative stress state. Combined with the results of the metabolic pathway analysis, we suggest that the pathways of the galactose metabolism, synthesis and degradation of ketone bodies, as well as ascorbic acid and aldehyde acid metabolism are closely related to the antipyretic and anti-inflammatory effects of EA. Our study established the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, PGE2, and cAMP, and clarified the mechanism of the COX-2/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism.

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.

Background: Uptake to anastrozole for breast cancer prevention is low, partly due to women’s concerns about side effects including gains in weight and specifically gains in body fat. Previous evidence does not link anastrozole with gains in weight, but there is a lack of data on any effects on body composition i.e. changes in fat and fat free mass. Here we assess association of anastrozole with body composition changes in a prospective sub-study from the second international breast intervention trial (IBIS-II). Methods: Participants had DXA scans at baseline and for five years of anastrozole/placebo and beyond (between March 2004 and September 2017. Primary outcomes were changes in body weight, body fat and fat free mass at 9–18 months. A linear model was used to estimate the size of a differential effect in these outcomes by randomised treatment allocation adjusted for baseline value and time since last scan, age, 10-year breast cancer risk, smoking and HRT status. Results: 203 postmenopausal women were recruited (n = 95 anastrozole, n = 108 placebo), mean age 58 years (SD = 5.4), BMI 28.0 kg/m2 (SD = 5.5). There was no evidence of a strong association between anastrozole or placebo and endpoints at 9–18 months; effect size (95 %CI) for anastrozole minus placebo for body weight (per/kg) −0.11 (−1.29–1.08); body fat 0.11 (−0.75–0.96) and fat free mass −0.30 (−0.79–0.19). Conclusions: There is unlikely to be a clinically significant change to body composition with anastrozole for breast cancer prevention.

Ferroptosis, a nonapoptotic form of cell death, is an emerging potential therapeutic target for various diseases, including cancer. However, the role of ferroptosis in pancreatic cancer remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis and chemotherapy resistance, attributed to its high Kirsten rats arcomaviral oncogene homolog mutation rate and severe nutritional deficits resulting from a dense stroma. Several studies have linked rat sarcoma (RAS) mutations to ferroptosis, suggesting that inducing ferroptosis may be an effective strategy against oncogenic RAS-bearing tumors. We investigated the role of Family With Sequence Similarity 60 Member A (FAM60A) in this study, a protein closely associated with a poor prognosis and highly expressed in PDAC and tumor tissue from KrasG12D/+;Trp53R172H/+; Pdx1-Cre mice, in regulating ferroptosis, tumor growth, and gemcitabine sensitivity in vitro and in vivo. Our results demonstrate that FAM60A regulates 3 essential metabolic enzymes, ACSL1/4 and GPX4, to protect PDAC cells from ferroptosis. Furthermore, we found that YY1 transcriptionally regulates FAM60A expression by promoting its transcription, and the Hippo-YY1 pathway is restricted in the low-amino-acid milieu in the context of nutrient deprivation, leading to downstream suppression of peroxisome proliferator-activated receptor and ACSL1/4 and activation of GPX4 pathways. Importantly, FAM60A knockdown sensitized PDAC cells to gemcitabine treatment. A new understanding of FAM60A transcriptional regulation pattern in PDAC and its dual function in ferroptosis reliever and chemotherapy resistance is provided by our study. Targeting FAM60A may therefore offer a promising therapeutic approach for PDAC by simultaneously addressing 2 major features of the disease (high RAS mutation rate and tumor microenvironment nutrient deficiency) and preventing tumor cell metabolic adaptation.

Objectives: In 2017, the World Health Organization (WHO) medical eligibility criteria (MEC) for contraception category for intramuscular depot medroxyprogesterone acetate (DMPA-IM) was changed from MEC category 1 to 2 for women at high risk of HIV acquisition. We assessed the impact of communicating this category change among women in the Evidence for Contraceptive options and HIV Outcomes (ECHO) trial. Study design: ECHO was conducted in eSwatini, Kenya, South Africa and Zambia. Women were randomized (1:1:1) to DMPA-IM, levonorgestrel (LNG) implant or copper intrauterine device (Cu IUD). We compared the hazards of DMPA-IM discontinuation and assessed sexual behavior and DMPA-IM satisfaction before and after MEC category change. Results: In DMPA-IM users there was a decrease in the hazards of discontinuation after the MEC change (hazard ratio 0.37; 95% CI=0.26–0.52, p

The lysosome protein RAGA interacts with and promotes lysosome localization and degradation of the macrophage-specific immune checkpoint protein CD47, with possible relevance to lung adenocarcinoma

Abstract Ibrutinib is a drug that inhibits the protein Burton’s tyrosine kinase and thereby the nuclear translocation of Nrf2, which played a key role in mediating the activation of antioxidants during stress conditions and ferroptosis resistance. This study aimed to identify the effect of Ibrutinib and ferroptosis inducer on colorectal cancer (CRC) treatment and its underlying mechanism. In our study, we found the upregulation of Nrf2 was correlated with CRC progression and antioxidant proteins. Ibrutinib sensitized CRC to ferroptosis inducers, suggested by further reduced CRC cell viability, proliferation and decreased antioxidant protein levels in CRC cells after combination treatment of Ibrutinib and RSL3 or Ibrutinib and Erastin both in vivo and in vitro. Knockout of Nrf2 diminished the regulatory effect of Ibrutinib on CRC sensitivity to ferroptosis inducers. Altogether, this study demonstrated that Ibrutinib increases the sensitivity of CRC cell to ferroptosis inducers by inhibiting Nrf2.

Background: The establishment of the anterior-posterior (A-P) axis is a crucial step during tissue repair and regeneration. Despite the association reported recently of N6-methyladenosine (m6A) with regeneration, the mechanism underlying the regulation of m6A in A-P axis specification during regeneration remains unknown. Herein, we deciphered the m6A landscape at a single-base resolution at multiple time points during A-P axis regeneration and constructed the de novo transcriptome assembly of the Dugesia japonica planarian. Results: Immunofluorescence staining and comparative analysis revealed that m6A is widespread across the planarian and dynamically regulated during regeneration along the A-P axis, exhibiting a strong spatiotemporal feature. The resulting datasets of m6A-modified genes identified 80 anterior-specific genes and 13 posterior-specific genes, respectively. In addition, we showed that YTHDC1 serves as the primary m6A reader to be involved in the m6A-mediated specification of A-P axis during regeneration in Dugesia japonica planarian. Conclusions: Our study provides an RNA epigenetic explanation for the specification of the A-P axis during tissue regeneration in planarian.

The need to study language use in literary texts arises due to linguistic complexity, writers’ linguistic choices and subjective understanding of the contextual meaning conveyed by writers. By using Halliday’s (1994) transitivity system, this study analysed ‘The Clay Marble’ novel which highlights the Cambodian Civil War and its implications through the representation of events and characters. By looking at the transitivity processes through the clausal structures and word choices, findings showed that all six processes were employed with material process (69 clauses) used most, followed by relational (42 clauses) and mental (31 clauses) process. Material and relational process is dominantly used to represent themes such as the effects of war, community life among refugees as well as the growth and character development of young refugees during the war. Therefore, transitivity analysis on literary texts helps to uncover writer’s language use and the contextual meaning conveyed through the writer’s linguistic choices.

The need to study language use in literary texts arises due to linguistic complexity, writers’ linguistic choices and subjective understanding of the contextual meaning conveyed by writers. By using Halliday’s (1994) transitivity system, this study analysed ‘The Clay Marble’ novel which highlights the Cambodian Civil War and its implications through the representation of events and characters. By looking at the transitivity processes through the clausal structures and word choices, findings showed that all six processes were employed with material process (69 clauses) used most, followed by relational (42 clauses) and mental (31 clauses) process. Material and relational process is dominantly used to represent themes such as the effects of war, community life among refugees as well as the growth and character development of young refugees during the war. Therefore, transitivity analysis on literary texts helps to uncover writer’s language use and the contextual meaning conveyed through the writer’s linguistic choices.

Abstract Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy expenditure in the brain. The neurons in Cmpk2-knockout (KO) mice have fewer mitochondrial DNA copies, down-regulated mitochondrial proteins, reduced ATP production, and elevated intracellular inorganic phosphate (Pi) level, recapitulating the mitochondrial dysfunction observed in the PBMCs isolated from the FBC patients. Morphologically, the cristae architecture of the Cmpk2-KO murine neurons was also impaired. Notably, calcification developed in a progressive manner in the homozygous Cmpk2-KO mice thalamus region as well as in the Cmpk2-knock-in mice bearing the patient mutation, thus phenocopying the calcification pathology observed in the patients. Together, our study identifies biallelic variants of CMPK2 as novel genetic factors for FBC; and demonstrates how CMPK2 deficiency alters mitochondrial structures and functions, thereby highlighting the mitochondria dysregulation as a critical pathogenic mechanism underlying brain calcification.

Summary: Aedes albopictus is a successful disease vector due to its ability to survive in a wide range of habitats. Despite its ubiquity and impact on public health, little is known about its differential gene flow capabilities across different city habitats. We obtained a comprehensive dataset of >27,000 genome-wide DNA markers across 105 wild-caught Ae. albopictus individuals from Singapore, a dengue-endemic tropical city with heterogeneous landscapes from densely populated urban areas to forests. Despite Singapore’s challenging small-scale heterogeneity, our landscape-genomic approach indicated that dense urban areas are characterized by higher Aedes gene flow rates than managed parks and forests. We documented the incidence of Wolbachia infections of Ae. albopictus involving two strains (wAlbA and wAlbB). Our results dispel the misconception that substantial dispersal of Ae. albopictus is limited to urban greenery, with wide implications for vector management and critical insights into urban planning strategies to combat dengue transmission.

Liver injury is a common pathological process characterized by massive degeneration and abnormal death of liver cells. With increase in dead cells and necrosis, liver injury eventually leads to nonalcoholic fatty liver disease (NAFLD), hepatic fibrosis, and even hepatocellular carcinoma (HCC). Consequently, it is necessary to treat liver injury and to prevent its progression. The drug Bicylol is widely employed in China to treat chronic hepatitis B virus (HBV) and has therapeutic potential for liver injury. It is the derivative of dibenzocyclooctadiene lignans extracted from Schisandra chinensis (SC). The Schisandraceae family is a rich source of dibenzocyclooctadiene lignans, which possesses potential liver protective activity. This study aimed to comprehensively summarize the phytochemistry, structure-activity relationship and molecular mechanisms underlying the liver protective activities of dibenzocyclooctadiene lignans from the Schisandraceae family. Here, we had discussed the analysis of absorption or permeation properties of 358 compounds based on Lipinski’s rule of five. So far, 358 dibenzocyclooctadiene lignans have been reported, with 37 of them exhibited hepatoprotective effects. The molecular mechanism of the active compounds mainly involves antioxidative stress, anti-inflammation and autophagy through Kelch-like ECH-associating protein 1/nuclear factor erythroid 2 related factor 2/antioxidant response element (Keap1/Nrf2/ARE), nuclear factor kappa B (NF-кB), and transforming growth factor β (TGF-β)/Smad 2/3 signaling pathways. This review is expected to provide scientific ideas for future research related to developing and utilizing the dibenzocyclooctadiene lignans from Schisandraceae family.

Understanding the relative contributions of historical and anthropogenic factors to declines in genetic diversity is important for informing conservation action. Using genome-wide DNA of fresh and historic specimens, including that of two species widely thought to be extinct, we investigated fluctuations in genetic diversity and present the first complete phylogenomic tree for all nine species of the threatened shorebird genus Numenius, known as whimbrels and curlews. Most species faced sharp declines in effective population size, a proxy for genetic diversity, soon after the Last Glacial Maximum (around 20,000 years ago). These declines occurred prior to the Anthropocene and in spite of an increase in the breeding area predicted by environmental niche modeling, suggesting that they were not caused by climatic or recent anthropogenic factors. Crucially, these genetic diversity declines coincide with mass extinctions of mammalian megafauna in the Northern Hemisphere. Among other factors, the demise of ecosystem-engineering megafauna which maintained open habitats may have been detrimental for grassland and tundra-breeding Numenius shorebirds. Our work suggests that the impact of historical factors such as megafaunal extinction may have had wider repercussions on present-day population dynamics of open habitat biota than previously appreciated.

Cancer survivors have reduced health-related quality of life (HRQOL) and high levels of distress during and after active treatment, due to physical, psychological, and social problems. Understanding the prevalence and associations of HRQOL and distress in a patient population in the community is important when designing rehabilitation programs. This was a cross-sectional observational study conducted at a community-based cancer rehabilitation center, with the aim of investigating the prevalence and associations of HRQOL and distress in cancer patients. There were 304 patients who were recruited. We found low levels of HRQOL and high levels of distress in patients, with a mean FACT-G7 total score of 11.68, and a mean distress thermometer score of 3.51. In the multivariate regression model, significant factors for low HRQOL were metastatic disease (p = 0.025) and Malay ethnicity (p < 0.001). Regression analyses also found that significant distress was associated with family health issues (p = 0.003), depression (p = 0.001), worry (p = 0.005), breathing (p = 0.007), getting around (p = 0.012) and indigestion (p = 0.039). A high prevalence of impaired HRQOL and distress was reported in cancer survivors even in a community rehabilitation setting. The physical and psychosocial well-being of cancer survivors should be monitored and managed as part of community-based cancer rehabilitation.

Introduction: Singapore’s enhanced surveillance programme for COVID-19 identifies and isolates hospitalised patients with acute respiratory symptoms to prevent nosocomial spread. We developed risk prediction models to identify patients with low risk for COVID-19 from this cohort of hospitalised patients with acute respiratory symptoms. Methods: This was a single-centre retrospective observational study. Patients admitted to our institution’s respiratory surveillance wards from 10 February to 30 April 2020 contributed data for analysis. Prediction models for COVID-19 were derived from a training cohort using variables based on demographics, clinical symptoms, exposure risks and blood investigations fitted into logistic regression models. The derived prediction models were subsequently validated on a test cohort. Results: Of the 1,228 patients analysed, 52 (4.2%) were diagnosed with COVID-19. Two prediction models were derived, the first based on age, presence of sore throat, dormitory residence, blood haemoglobin level (Hb), and total white blood cell counts (TW), and the second based on presence of headache, contact with infective patients, Hb and TW. Both models had good diagnostic performance with areas under the receiver operating characteristic curve of 0.934 and 0.866, respectively. Risk score cut-offs of 0.6 for Model 1 and 0.2 for Model 2 had 100% sensitivity, allowing identification of patients with low risk for COVID-19. Limiting COVID-19 screening to only elevated-risk patients reduced the number of isolation days for surveillance patients by up to 41.7% and COVID-19 swab testing by up to 41.0%. Conclusion: Prediction models derived from our study were able to identify patients at low risk for COVID-19 and rationalise resource utilisation.

Abstract Background Liver fibrosis is a wound-healing response to chronic injury, featuring with excess accumulation of extracellular matrix secreted by the activated hepatic stellate cells (HSC). Disulfiram (DSF), also known as Antabuse, has been used for the treatment of alcohol addiction and substance abuse. Recently, overwhelming studies had revealed anti-cancer effects of DSF in multiple cancers, including liver cancer. But the actual effects of DSF on liver fibrosis and liver function remain unknown. Methods In this study, we evaluated the effects of low-dose DSF in CCl4- and Bile Duct Ligation (BDL)—induced hepatic fibrosis rat models. Cell proliferation was detected by using the Cell-Light™ EdU Apollo®567 Cell Tracking Kit. Cell apoptosis was analyzed using a TdT-mediated dUTP nick end labeling (TUNEL) kit, viability was measured with Cell Counting Kit-8(CCK8). Relative mRNA expression of pro-fibrogenic was assessed using quantitative RT-PCR. The degree of liver fibrosis, activated HSCs, were separately evaluated through Sirius Red-staining, immunohistochemistry and immunofluorescence. Serum alanine aminotransferase (ALT) and asparagine aminotransferase (AST) activities were detected with ALT and AST detecting kits using an automated analyzer. Results Liver fibrosis was distinctly attenuated while liver functions were moderately ameliorated in the DSF-treated group. Activation and proliferation of primary rat HSCs isolated from rat livers were significantly suppressed by low-dose DSF. DSF also inhibited the viability of in vitro cultured rat or human HSC cells dose-dependently but had no repressive role on human immortalized hepatocyte THLE-2 cells. Interestingly, upon DSF treatment, the viability of LX-2 cells co-cultured with THLE-2 was significantly inhibited, while that of THLE-2 co-cultured with LX-2 was increased. Further study indicated that HSCs apoptosis was increased in DSF/CCl4-treated liver samples. These data indicated that DSF has potent anti-fibrosis effects and protective effects toward hepatocytes and could possibly be repurposed as an anti-fibrosis drug in the clinic. Conclusions DSF attenuated ECM remodeling through suppressing the transformation of quiet HSCs into proliferative, fibrogenic myofibroblasts in hepatic fibrosis rat models. DSF provides a novel approach for the treatment of liver fibrosis.

Abstract Primary familial brain calcification (PFBC) is a neurogenetic disorder characterized by bilateral calcified deposits in the brain. We previously identified that MYORG as the first pathogenic gene for autosomal recessive PFBC, and established a Myorg-KO mouse model. However, Myorg-KO mice developed brain calcifications until nine months of age, which limits their utility as a facile PFBC model system. Hence, whether there is another typical animal model for mimicking PFBC phenotypes in an early stage still remained unknown. In this study, we profiled the mRNA expression pattern of myorg in zebrafish, and used a morpholino-mediated blocking strategy to knockdown myorg mRNA at splicing and translation initiation levels. We observed multiple calcifications throughout the brain by calcein staining at 2–4 days post-fertilization in myorg-deficient zebrafish, and rescued the calcification phenotype by replenishing myorg cDNA. Overall, we built a novel model for PFBC via knockdown of myorg by antisense oligonucleotides in zebrafish, which could shorten the observation period and replenish the Myorg-KO mouse model phenotype in mechanistic and therapeutic studies.

Abstract Purpose Causative factors of breast cancer include infections, such as Epstein–Barr virus (EBV) infection. The aim of this study was to analyze the clinicopathological features of EBV-positive (IBC) and determine if EBV affects programmed cell death receptor 1 (PD-1)/PD ligand 1 (PD-L1) expression in IBC, similar to other EBV-infected tumors with PD-L1/PD-1 expression. Methods We collected 140 samples of IBC tissues and 25 samples of adjacent tissues. All patients were followed-up by telephone from the day of surgery to December 2020. Chromogenic in-situ hybridization was performed to evaluate EBV-encoded RNA (EBER). Immunohistochemistry was performed to evaluate PD-L1 and PD-1 expressions. The correlation between PD1/PDL1 expression and clinicopathological features was also analyzed. Results EBER was detected in 57 of 140 (40.7%) IBC tissues and not detected in any adjacent tissue (P 0.05). The positive rate of PD-1/PD-L1 expression was higher in the EBV-positive group than in the EBV-negative group (P

Abstract Background In aged people, tendon injuries frequently occur during sporting and daily activities. In clinical practice, typical physiotherapeutic, pharmacotherapeutic, and surgical techniques do not result in the full recovery of injured tendons, which may lead to chronic degenerative disease. Methods We first isolated tendon stem cells (TSCs) from rats and transfected them with the TGFβ1 gene, resulting in TGFβ1-TSCs. The proliferation of TSCs was detected using the Cell Counting Kit 8, and TSCs were identified by immunofluorescence analysis and differentiation capacity analysis. Aggrecan, COL2A1, alpha smooth muscle actin (α-SMA), and p-Smad2 expression levels were detected using western blotting and quantitative reverse transcription polymerase chain reaction. Additionally, a tendon injury model was generated to explore the effect of TGFβ1 on the repair of the tendon by TSCs. Results Compared with fibrinogen treatment, TSC + fibrinogen or TGFβ1-TSC + fibrinogen treatment significantly promoted the fibrosis of injured tendons, as evidenced by histological analyses, with TGFβ1-TSC + fibrinogen having a greater effect than TSC + fibrinogen. In TGFβ1-TSCs, increased expression levels of aggrecan and COL2A1 indicated that TGFβ1 signaling induced chondrogenic differentiation. Meanwhile, the increased collagen and α-SMA protein levels indicated that TGFβ1 promoted fibrogenesis. Additionally, TGFβ1 stimulated the production of phosphorylated Smad2 in TSCs, which suggested that the chondrogenic and fibrogenic differentiation of TSCs, as well as tissue regeneration, may be associated with the TGFβ1/Smad2 pathway. Conclusion TGFβ1-TSC therapy may be a candidate for effective tendon fibrosis.

Action quality assessment refers to evaluate the action quality performed by human in video,such as calculating the quality score,level and evaluating the performance of different people.It is an important direction in video understanding and computer vision research.This paper summarizes the main methods of action quality assessment,including action quality score prediction methods,level classification and ranking methods.The performance of these methods on public datasets is also analyzed.Finally,the challenge problems in future research are discussed.

RNAs play crucial roles in various essential biological functions, including catalysis and gene regulation. Despite the widespread use of coarse-grained (CG) models/simulations to study RNA 3D structures and dynamics, their direct application is challenging due to the lack of atomic detail. Therefore, the reconstruction of full atomic structures is desirable. In this study, we introduced a straightforward method called ABC2A for reconstructing all-atom structures from RNA CG models. ABC2A utilizes diverse nucleotide fragments from known structures to assemble full atomic structures based on the CG atoms. The diversification of assembly fragments beyond standard A-form ones, commonly used in other programs, combined with a highly simplified structure refinement process, ensures that ABC2A achieves both high accuracy and rapid speed. Tests on a recent large dataset of 361 RNA experimental structures (30–692 nt) indicate that ABC2A can reconstruct full atomic structures from three-bead CG models with a mean RMSD of ~0.34 Å from experimental structures and an average runtime of ~0.5 s (maximum runtime < 2.5 s). Compared to the state-of-the-art Arena, ABC2A achieves a ~25% improvement in accuracy and is five times faster in speed.

This study was conducted to evaluate the Al3+ tolerance of sixteen camelina genotypes and to use melatonin or nano-selenium to alleviate Al3+-induced stress. A Petri dish study indicated seedling root length was suitable for describing the dose–response of seedling growth with increased Al3+ concentrations. Based on GR50 (Al3+ concentration causing a 50% reduction in the seedling root length), CamK6 (232.0 mg L−1) and CamK2 (97.0 mg L−1) were the most Al3+-tolerant and -sensitive genotypes, respectively. Under Al3+ stress, CamK6 and CamK2 treated by melatonin (50 μM) or nano-Se (0.4 mg L−1) showed a similar plant height and seed yield plant−1 (CamK6: 123.6 ± 9.8 cm and 0.562 ± 0.62 g; CamK2: 109.2 ± 8.7 cm and 0.49 ± 0.5 g) as the controls (CamK6: 121.1 ± 10.2 cm and 0.554 ± 0.4 g; CamK2: 110.0 ± 9.8 cm and 0.5 ± 0.4 g), and the values were greater than for the Al3+-treated plants (CamK6: 96.4 ± 9.2 cm and 0.48 ± 0.34 g; CamK2: 97.3 ± 8.1 cm and 0.42 ± 0.31 g). The results showed that melatonin or nano-Se through modulating biochemical reactions (e.g., antioxidant enzyme) can alleviate Al3+-induced growth inhibition in camelina. This study suggested melatonin or nano-Se can alleviate Al3+-induced growth inhibition by maintaining seed yield and improving oil quality in camelina.

Abstract Proper embryonic development requires directional axes to pattern cells into embryonic structures. In Drosophila, spatially discrete expression of transcription factors determines the anterior to posterior organization of the early embryo, while the Toll and TGFβ signalling pathways determine the early dorsal to ventral pattern. Embryonic MAPK/ERK signaling contributes to both anterior to posterior patterning in the terminal regions and to dorsal to ventral patterning during oogenesis and embryonic stages. Here we describe a novel loss of function mutation in the Raf kinase gene, which leads to loss of ventral cell fates as seen through the loss of the ventral furrow, the absence of Dorsal/NFκB nuclear localization, the absence of mesoderm determinants Twist and Snail, and the expansion of TGFβ. Gene expression analysis showed cells adopting ectodermal fates much like loss of Toll signaling. Our results combine novel mutants, live imaging, optogenetics and transcriptomics to establish a novel role for Raf, that appears to be independent of the MAPK cascade, in embryonic patterning.

Objectives This network meta-analysis aimed to compare the efficacy and safety of intravenous (IV) hydralazine, oral nifedipine, and IV labetalol with different dosage regimens in the treatment of severe hypertension during pregnancy. Methods A comprehensive literature search was performed on PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) exploring the effects of hydralazine, nifedipine, and labetalol in the treatment of severe hypertension during pregnancy. Results A total of 21 RCTs with 2183 patients comparing 7 regimens (oral nifedipine 50,60,90 mg; hydralazine 15,25 mg; and labetalol 220,300 mg) were identified. Compared with IV labetalol 300 mg, nifedipine 50,60, and 90 mg significantly improved the successful treatment rate of severe hypertension during pregnancy, nifedipine 50 and 90 mg and IV hydralazine 25 mg required significantly fewer doses to achieve target blood pressure (BP), and nifedipine 50 mg took significantly shorter time to achieve target BP. Subgroup analysis showed that only nifedipine 50 mg tablets, not capsules, required a significantly shorter time and fewer doses to achieve target BP than IV labetalol 300 mg. Moreover, nifedipine 60,90 mg showed superior effectiveness than IV hydralazine 15,25 mg in the successful treatment rate of severe hypertension during pregnancy. SUCRA analysis suggested that nifedipine 50,60,90 mg as the better regimens with the lower rates of overall ADR and neonatal complications. Conclusion These findings demonstrated the superiority of oral nifedipine 50,60,90 mg, especially oral nifedipine 50 mg tablets, in the treatment of severe hypertension during pregnancy than IV labetalol 300 mg, while oral nifedipine 60,90 mg also showed superiority in the successful treatment rate of severe hypertension during pregnancy than IV hydralazine 15,25 mg. However, the limitations of the underlying data indicate that future large-scale and rigorous RCTs are needed to confirm such findings.

PurposeThe study aimed to identify potential risk factors for family transmission and to provide precautionary guidelines for the general public during novel Coronavirus disease 2019 (COVID-19) waves.MethodsA retrospective cohort study with numerous COVID-19 patients recruited was conducted in Shanghai. Epidemiological data including transmission details, demographics, vaccination status, symptoms, comorbidities, antigen test, living environment, residential ventilation, disinfection and medical treatment of each participant were collected and risk factors for family transmission were determined. ResultsA total of 2,334 COVID-19 patients participated. Compared with non-cohabitation infected patients, cohabitated ones were younger (p = 0.019), more commonly unvaccinated (p = 0.048) or exposed to infections (p

Abstract Objectives Kashgar prefecture is an important transportation and trade hub with a high incidence of tuberculosis. The following study analyzed the composition and differences in Mycobacterium tuberculosis (M.tb) lineage and specific tags to distinguish the lineage of the M.tb in Kashgar prefecture, thus providing a basis for the classification and diagnosis of tuberculosis in this area. Methods Whole-genome sequencing (WGS) of 161 M.tb clinical strains was performed. The phylogenetic tree was constructed using Maximum Likelihood (ML) based on single nucleotide polymorphisms (SNPs) and verified through principal component analysis (PCA). The composition structure of M.tb in different regions was analyzed by combining geographic information. Results M.tb clinical strains were composed of lineage 2 (73/161, 45.34%), lineage 3 (52/161, 32.30%) and lineage 4 (36/161, 22.36%). Moreover, the 3 lineages were subdivided into 11 sublineages, among which lineage 2 included lineage 2.2.2/Asia Ancestral 1 (9/73, 12.33%), lineage 2.2.1-Asia Ancestral 2 (9/73, 12.33%), lineage 2.2.1-Asia Ancestral 3 (18/73, 24.66%), and lineage 2.2.1-Modern Beijing (39/73, 53.42%). Lineage 3 included lineage 3.2 (14/52, 26.92%) and lineage 3.3 (38/52, 73.08%), while lineage 4 included lineage 4.1 (3/36, 8.33%), lineage 4.2 (2/36, 5.66%), lineage 4.4.2 (1/36, 2.78%), lineage 4.5 (28/36, 77.78%) and lineage 4.8 (2/36, 5.66%), all of which were consistent with the PCA results. One hundred thirty-six markers were proposed for discriminating known circulating strains. Reconstruction of a phylogenetic tree using the 136 SNPs resulted in a tree with the same number of delineated clades. Based on geographical location analysis, the composition of Lineage 2 in Kashgar prefecture (45.34%) was lower compared to other regions in China (54.35%-90.27%), while the composition of Lineage 3 (32.30%) was much higher than in other regions of China (0.92%-2.01%), but lower compared to the bordering Pakistan (70.40%). Conclusion Three lineages were identified in M.tb clinical strains from Kashgar prefecture, with 136 branch-specific SNP. Kashgar borders with countries that have a high incidence of tuberculosis, such as Pakistan and India, which results in a large difference between the M.tb lineage and sublineage distribution in this region and other provinces of China.

In the electrolyte containing Nd2O3 particles with different concentrations, the micro - arc oxidation technology was used to prepare the coatings on the surface of 2A12 aluminum alloy. The effects of Nd2O3 particles with different concentrations on the hardness, thickness and adhesion strength between the micro - arc oxidation coating and the substrate were studied, which provided a theoretical basis for the preparation of the coatings with good performance on the surface of 2A12 aluminum alloy by micro - arc oxidation. In addition, scanning electron microscope (SEM), X - ray diffraction (XRD) and X - ray photoelectron spectroscopy (XPS) were used to analyze the cross section morphology and phase composition of the coatings. TT - 230 eddy current thickness tester, HVS - 1000 digital Vickers hardness tester and MFT - 4000 multi - functional material surface performance tester were used to test the coating thickness, hardness, and adhesion strength, respectively. Results showed that the coatings were mainly composed of α - Al2O3, γ - Al2O3 and SiO2 phases. With the increase of Nd2O3 particle concentration, the hardness, thickness, and adhesion strength between the coating and the substrate performed a trend of first increasing and then decreasing. Moreover, when Nd2O3 particle concentration was 0.3 g/L, the micro hardness, thickness, and adhesion strength between the coating and the substrate reached the maximum value of 576.38 HV, 8.17 μm and 16.7 N. In summary, adding Nd2O3 was an effective method to enhance the properties of 2A12 aluminum alloy micro - arc oxidation coating, and the optimal concentration was 0.3 g/L.

Icariin (ICA) has a significant capacity to protect against depression and hippocampal injury, but it cannot effectively cross the blood-brain barrier and accumulate in the brain. Therefore, the mechanism by which ICA protects against hippocampal injury in depression remains unclear. In this study, we performed proteomics analysis of cerebrospinal fluid to investigate the mechanism by which ICA prevents dysfunctional hippocampal neurogenesis in depression. A rat model of depression was established through exposure to chronic unpredictable mild stress for 6 weeks, after which 120 mg/kg ICA was administered subcutaneously every day. The results showed that ICA alleviated depressive symptoms, learning and memory dysfunction, dysfunctional neurogenesis, and neuronal loss in the dentate gyrus of rats with depression. Neural stem cells from rat embryonic hippocampi were cultured in media containing 20% cerebrospinal fluid from each group of rats and then treated with 100 μM corticosterone. The addition of cerebrospinal fluid from rats treated with ICA largely prevented the corticosterone-mediated inhibition of neuronal proliferation and differentiation. Fifty-two differentially expressed proteins regulated by chronic unpredictable mild stress and ICA were identified through proteomics analysis of cerebrospinal fluid. These proteins were mainly involved in the ribosome, PI3K-Akt signaling, and interleukin-17 signaling pathways. Parallel reaction monitoring mass spectrometry showed that Rps4x, Rps12, Rps14, Rps19, Hsp90b1, and Hsp90aa1 were up-regulated by chronic unpredictable mild stress and down-regulated by ICA. In contrast, HtrA1 was down-regulated by chronic unpredictable mild stress and up-regulated by ICA. These findings suggest that ICA can prevent depression and dysfunctional hippocampal neurogenesis through regulating the expression of certain proteins found in the cerebrospinal fluid. The study was approved by the Experimental Animal Ethics Committee of Guangzhou University of Chinese Medicine of China in March 2017.

Abstract Mutational signatures are characteristic patterns of mutations generated by exogenous mutagens or by endogenous mutational processes. Mutational signatures are important for research into DNA damage and repair, aging, cancer biology, genetic toxicology, and epidemiology. Unsupervised learning can infer mutational signatures from the somatic mutations in large numbers of tumors, and separating correlated signatures is a notable challenge for this task. To investigate which methods can best meet this challenge, we assessed 18 computational methods for inferring mutational signatures on 20 synthetic data sets that incorporated varying degrees of correlated activity of two common mutational signatures. Performance varied widely, and four methods noticeably outperformed the others: hdp (based on hierarchical Dirichlet processes), SigProExtractor (based on multiple non-negative matrix factorizations over resampled data), TCSM (based on an approach used in document topic analysis), and mutSpec.NMF (also based on non-negative matrix factorization). The results underscored the complexities of mutational signature extraction, including the importance and difficulty of determining the correct number of signatures and the importance of hyperparameters. Our findings indicate directions for improvement of the software and show a need for care when interpreting results from any of these methods, including the need for assessing sensitivity of the results to input parameters.

Abstract Resource partitioning may facilitate the coexistence of sympatric species with similar ecological requirements. Here, we study a colony of unusual echolocating birds called swiftlets, which nest underground on an island off the coast of Singapore. The colony comprises two congeneric swiftlet species, black‐nest swiftlets (Aerodramus maximus) and edible‐nest swiftlets (A. fuciphagus), nesting at high densities and in close proximity. Bioacoustic recordings and monitoring of nesting biology at the site across multiple seasons revealed significant differences in echolocation calls as well as survival rates between the species, with the larger black‐nest swiftlet nesting at locations with the highest fledging rates. We also observe an additional off‐season breeding peak by the smaller species, the edible‐nest swiftlet. Unexpectedly, off‐season egg‐hatching rates were significantly higher compared with the rates during the shared breeding season (mean difference = 14%). Our study on the breeding biology of these echolocating cave‐dwelling birds provides an example of spatial and temporal strategies that animals employ to partition resources within a confined habitat.

Abstract Few studies have investigated the relationship between sarcopenia and mild to moderate renal decline. This study aimed to investigate the relationship between chronic kidney disease (CKD) and sarcopenia. In total, 123 patients hospitalized with CKD and 57 healthy volunteers who underwent physical examination during the same period (control group) were analyzed. Body compositions were measured by dual-energy X-ray absorptiometry, and the relative appendicular skeletal muscle index (RASMI) was calculated. Muscular strength was evaluated using hydraulic hand dynamometer. Walking speed within 6 m was measured for muscular function assessment. Single-photon emission computed tomography was performed to measure the glomerular filtration rate of CKD patients, who were then divided into CKD1 (55 patients in CKD stages 1 and 2) and CKD2 (68 patients in CKD stages 3–5). RASMI showed a downward trend with CKD progression (P = 0.001). Multivariate logistic regression analysis showed that age and CKD progression were independent risk factors for sarcopenia. The morbidity of sarcopenia was significantly greater in CKD patients than in healthy volunteers, and the degree of muscle loss was closely related to CKD progression.

Triple-negative breast cancer (TNBC) is a severe threat to women’s health because of its aggressive nature, early age of onset, and high recurrence rate. Therefore, in this study, we aimed to evaluate the anti-tumor effects of Gallic acid (GA) on the TNBC HCC1806 cells in vitro. The cell proliferation was detected by MTT and plate clone formation assays, cell apoptosis, cell cycle, and mitochondrial membrane potential (MMP) were analyzed by flow cytometry and Hoechst 33258 staining assays, and the intracellular reactive oxygen species (ROS) accumulation were also investigated. Real-Time PCR and western blot were examined to explore the mechanism of action. The results indicated that GA suppressed HCC1806 cells proliferation and promoted HCC1806 cells apoptosis. Meanwhile, GA treatment changed the morphology of the HCC1806 cells. In addition, GA blocked the HCC1806 cells cycle in the S phase, and it induced cells apoptosis accompanied by ROS accumulation and MMP depolarization. Real-Time PCR results suggested that GA increased Bax, Caspase-3, Caspase-9, P53, JINK and P38 mRNA expression, and decreased Bcl-2, PI3K, AKT and EGFR mRNA expression. Western blotting results suggested that GA increased Bax, cleaved-Caspase-3, cleaved-Caspase-9, P53, P-ERK1/2, P-JNK, P-P38 proteins expression, and decreased Bcl-2, P-PI3K, P-AKT, P-EGFR proteins expression. Furthermore, molecular docking suggested that GA has the high affinity for PI3K, AKT, EGFR, ERK1/2, JNK, and P38. In conclusion, GA could suppress HCC1806 cells proliferation and promote HCC1806 cells apoptosis through the mitochondrial apoptosis pathway and induces ROS generation which further inhibits PI3K/AKT/EGFR and activates MAPK signaling pathways. Our study will provide some new references for using GA in the treatment of TNBC.

Direct conversion of amides to ketones typically requires the use of transition metal catalysts or reactive organometallic reagents. Here the direct alkylation of benzamides with methyl sulfides using LDA as base provides access to thioalkoxyketones.

Abstract Background Patients who have breast cancer surgery are at risk of axillary web syndrome (AWS), an under-recognized postsurgical complication which can result in shoulder morbidity and functional impairment. Emerging studies have indicated that AWS may persist beyond the first few months after surgery, although few studies have assessed the prevalence and association of AWS beyond a year after diagnosis. Therefore, the aim of this study was to investigate the prevalence and associations for AWS in post-operative breast cancer patients up to 3 years after surgery. Methods This cross sectional observational study was conducted at a community-based cancer rehabilitation center. Patients were evaluated for the presence of AWS via physical examination. Disease-related data was obtained from clinical review and medical records. Descriptive statistics were utilized to illustrate patient demographics and clinical characteristics. Logistic regression analyses were used to determine associations of AWS. Results There were 111 Asian women who were recruited, who had undergone breast surgery and were referred to a national outpatient rehabilitation center. The prevalence of AWS in this population was 28.9%. In the multivariate regression model, significant factors were age

In this paper a novel precision forging process for the manufacture of CPU heat spreaders is presented. The study included numerical and simulation verification and the purpose was to replace the commonly used forging methods used for heat spreader manufacture with sheet-bulk metal forming (SBMF). The process includes roughing, finishing and trimming from a pre-formed shape. The finite element method (FEM) was used to optimize the design of the width and variable flash controllable deformation zones (W-CDZ/VF-CDZ) to ensure the dimensions were within the 0.1 mm critical specifications for flatness and parallelism. Simulation analysis took into account all the related microscopic phenomena: forming, material flow, flow velocity and strain distribution. The simulations and experiments showed that the occurrence of SBMF overlapping defects could be successfully avoided by the proper design of W-CDZ and VF-CDZ. The forming load, material flow, flow velocity and strain related distribution were thoroughly investigated within the controllable and stable deformation zones. It was found that the forming sequence and filling ratio could be improved, and uniform distributed cross-sectional hardness could be attained which augmented uniform heat dissipation.

Disturbances in the excitatory/inhibitory balance of brain neural circuits are the main source of encephalopathy during neurodevelopment. Changes in the function of neural circuits can lead to depolarization or repeat rhythmic firing of neurons in a manner similar to epilepsy. GABAergic neurons are inhibitory neurons found in all the main domains of the CNS. Previous studies suggested that DjCamkII and DjCaln play a crucial role in the regulation of GABAergic neurons during planarian regeneration. However, the mechanisms behind the regeneration of GABAergic neurons have not been fully explained. Herein, we demonstrated that DjCamkII and DjCaln were mutual negative regulation during planarian head regeneration. DjNFAT exerted feedback positive regulation on both DjCaln and DjCamkII. Whole-mount in situ hybridization (WISH) and fluorescence in situ hybridization (FISH) revealed that DjNFAT was predominantly expressed in the pharynx and parenchymal cells in intact planarian. Interestingly, during planarian head regeneration, DjNFAT was predominantly located in the newborn brain. Down-regulation of DjNFAT led to regeneration defects in the brain including regenerative brain became small and the lateral nerves cannot be regenerated completely, and a decreasein the number of GABAergic neurons during planarian head regeneration. These findings suggest that the feedback loop between DjCaln, DjCamkII, and DjNFAT is crucial for the formation of GABAergic neurons during planarian head regeneration.