Biosynthesis of Atypical Angucyclines Unveils New Ring Rearrangement Reactions Catalyzed by Flavoprotein Monooxygenases.

Six new angucycline structures, including spirocyclione A (1), which contains an unusual oxaspiro[5.5]undecane architecture, and its ring-A-cleaved product spirocyclione B (2), were discovered by heterologous expression of a type II polyketide biosynthetic gene cluster captured from a marine actinomycete strain Streptomyces sp. HDN155000. Three flavoprotein monooxygenases are confirmed to be responsible for the oxidative carbon skeleton rearrangements in the biosynthesis of compounds 1 and 2. The obtained compounds showed promising cytotoxicity against different types of cancer cells.

Bioorthogonal Delivery of Carbon Disulfide in Living Cells.

Carbon disulfide (CS2) is an environmental contaminant, which is deadly hazardous to the workers under chronic or acute exposure. However, the toxicity mechanisms of CS2 are still unclear due to the scarcity of biocompatible donors, which can release CS2 in cells. Here we developed the first bioorthogonal CS2 delivery system based on the "click-and-release" reactions between mesoionic 1,3-thiazolium-5-thiolates (TATs) and strained cyclooctyne exo-BCN-OH. We successfully realized intracellular CS2 release and investigated the causes of CS2-induced hepatotoxicity, including oxidative stress, proteotoxic stress and copper-dependent cell death. It is found that CS2 can be copper vehicles bypassing copper transporters after reacting with nucleophiles in cytoplasm, and extra copper supplementation will exacerbate the loss of homeostasis of cells and ultimately cell death. These findings inspired us to explore the anticancer activity of CS2 in combination with copper by introducing a copper chelating group in our CS2 delivery system.

Breast Cancer Knowledge and Mammography Use Among Asian American Women Aged 40 and Older: Using the Transtheoretical Model Approach.

Mammography screening rates remain low among Asian American women (AAW). The aims of our study were to: (a) assess breast cancer knowledge and mammography screening behaviors, and (b) identify the factors related to the transtheoretical model (TTM) stages of change in relation to mammography utilization among AAW aged 40 and older. Using a cross-sectional design, a convenience sample of 714 AAW completed a structured questionnaire in 2021. Participants demonstrated a moderate level of knowledge regarding breast cancer and mammography. Only 34.2% of the participants reported obtaining regular mammograms. The ordinal logistic regression indicated that age, birthplace, health perception, breast biopsy history, breast cancer knowledge, self-efficacy, and perceived barriers were correlated with TTM stages of change. Our results highlight the need for implementing effective interventions aimed at increasing knowledge and screening rates for breast cancer among AAW. Additional TTM studies with AAW are needed to determine the relationships among TTM constructs and develop theory-based programs to improve adherence to screening guidelines. Future research using a mixed-method design may provide opportunities to explore complex phenomena associated with breast cancer screening behaviors. Finally, further assessments of the Breast Cancer Knowledge Scale's psychometric properties are necessary to improve this instrument.

Human papillomavirus vaccination: a quantitative cross-sectional study of perceived barriers, influential advisors, and acculturation among Chinese college students aged 18-26 in the USA.

HPV vaccines are highly effective in preventing HPV-associated cancers; however, HPV vaccination uptake is low among Chinese students studying at U.S. colleges. The purposes of this study were to evaluate (a) perceived barriers and influential others trusted for advice regarding HPV vaccination and (b) factors (i.e. HPV vaccination, acculturation) related to barriers and influential advisors among 18- to 26-year-old Chinese students attending U.S. colleges. We used a cross-sectional design to obtain self-reported data in 2019 from a chain-referral sample of 213 Chinese students. Among 125 respondents who were unvaccinated or partially vaccinated, the reported barriers to receiving the HPV vaccine included: (a) lack of recommendations from a healthcare provider, (b) lack of risk perception for HPV infection, and (c) limited knowledge about HPV vaccination locations. The influential advisors for receiving HPV vaccination were doctors, parents, self, nurses, and same-sex friends. Multivariate analysis revealed that unvaccinated respondents were more likely to report the following barriers to HPV vaccination: (a) lack of recommendations from a healthcare provider, (b) lack of risk perception for HPV infection, (c) limited knowledge about vaccination locations, and (d) uncertainty about effectiveness. High Asian identified respondents were more likely to perceive barriers related to limited knowledge about vaccination locations and uncertainty about effectiveness, while they were less likely to state nurses as influential advisors. Individuals who received one or more HPV vaccine doses were more inclined to view same-sex friends and nurses as influential advisors for HPV vaccination. The influence of culture on preferences for information sources, such as specific providers and provider gender, needs to be addressed. Programs designed to decrease barriers and improve HPV vaccination among Chinese students should also focus on acculturation status.

Composite Dietary Antioxidant Index Is Negatively Associated with Hyperuricemia in US Adults: An Analysis of NHANES 2007-2018.

Hyperuricemia and its complications are severe risks to human health. Dietary intervention is considered an essential part of the management of hyperuricemia. Studies have reported that the intake of antioxidants has a positive effect on hyperuricemia. Here, we collected data from 8761 participants of the National Health and Nutrition Examination Survey for this analysis. Daily intakes of vitamins A, C, and E; manganese; selenium; and zinc were calculated as the composite dietary antioxidant index (CDAI). The participants were divided into four groups (Q1, Q2, Q3, and Q4) according to the CDAI. Univariate analysis was used to assess the association of covariates with hyperuricemia. The association between the CDAI and hyperuricemia was evaluated using multinomial logistic regression, and its stability was determined by stratified analysis. Our results revealed that the CDAI has a significant negative association with hyperuricemia (Q2: 0.81 (0.69, 0.95); Q3: 0.75 (0.62, 0.90); Q4: 0.65 (0.51, 0.82); P < 0.01). The results of stratified analysis emphasize that this association between CDAI and hyperuricemia is stable. In conclusion, this study suggested a negative association between the CDAI and hyperuricemia.

Site-Selective Arylation of Carboxamides from Unprotected Peptides.

The amidated peptides are an important class of biologically active compounds due to their unique biological properties and wide applications as potential peptide drugs and biomarkers. Despite the abundance of free amide motifs (Asn, Gln, and C-terminal amide) in native peptides, late-stage modification of the amide unit in naturally occurring peptides remains very rare because of the intrinsically weak nucleophilicity of amides and the interference of multiple competing nucleophilic residues, which generally lead to undesired side reactions. Herein, chemoselective arylation of amides in unprotected polypeptides has been developed under an air atmosphere to afford the N-aryl amide peptides bearing various functional motifs. Its success relies on the combination of gold catalysis and silver salt to differentiate the relative inert amide among a collection of reactive nucleophilic amino acid residues (e.g., -NH2, -OH, and -COOH), favoring the C-N bond coupling toward amides over other more nucleophilic groups. Experimental and DFT studies reveal a crucial role of the silver cation, which serves as a transient coordination mask of the more reactive reaction sites, overcoming the inherently low reactivity of amides. The excellent biocompatibility of this strategy has been applied to functionalize a wide range of peptide drugs and complex peptides. The application could be further extended to peptide labeling and peptide stapling.

Rewilding of laboratory mice enhances granulopoiesis and immunity through intestinal fungal colonization.

The paucity of blood granulocyte populations such as neutrophils in laboratory mice is a notable difference between this model organism and humans, but the cause of this species-specific difference is unclear. We previously demonstrated that laboratory mice released into a seminatural environment, referred to as rewilding, display an increase in blood granulocytes that is associated with expansion of fungi in the gut microbiota. Here, we find that tonic signals from fungal colonization induce sustained granulopoiesis through a mechanism distinct from emergency granulopoiesis, leading to a prolonged expansion of circulating neutrophils that promotes immunity. Fungal colonization after either rewilding or oral inoculation of laboratory mice with Candida albicans induced persistent expansion of myeloid progenitors in the bone marrow. This increase in granulopoiesis conferred greater long-term protection from bloodstream infection by gram-positive bacteria than by the trained immune response evoked by transient exposure to the fungal cell wall component ß-glucan. Consequently, introducing fungi into laboratory mice may restore aspects of leukocyte development and provide a better model for humans and free-living mammals that are constantly exposed to environmental fungi.

Differentiation, regulation and function of regulatory T cells in non-lymphoid tissues and tumors.

Regulatory T cells (Tregs) play a substantial role in inhibiting excessive immune response. A large number of studies have focused on the tissue homeostasis maintenance and remodeling characteristics of Tregs in non-lymphoid tissues, such as the skin, colon, lung, brain, muscle, and adipose tissues. Herein, we overview the kinetics of Treg migration to non-lymphoid tissues and adaptation to the specific tissue microenvironment through the development of tissue-specific chemokine receptors, transcription factors, and phenotypes. Additionally, tumor-infiltrating Tregs (Ti-Tregs) play an important role in tumor generation and immunotherapy resistance. The phenotypes of Ti-Tregs are related to the histological location of the tumor and there is a large overlap between the transcripts of Ti-Tregs and those of tissue-specific Tregs. We recapitulate the molecular underpinnings of tissue-specific Tregs, which might shed new light on Treg-based therapeutic targets and biomarkers for inflammatory diseases and cancer.

L-Fucose increases the fucosylation of colorectal cancer cells via promoting the accumulation of serine.

Fucosylation, a kind of posttranslational modification, has been identified as a key regulator of health, with alterations in this process serving as an indicator of diseases such as colorectal cancer. L-Fucose, an essential substrate of fucosylation, was reported to possess anticancer potential and increase fucosylation. However, the association between its tumour-inhibitory effect and its ability to regulate fucosylation was not fully understood. Herein, we demonstrate that the simultaneous inhibitory effect of L-fucose on cancer cell growth and enhanced fucosylation occurred only in certain colorectal cancer cells (HCT-116 cells) but not in normal cells (HCoEpic cells), which may be related to the induction of pro-apoptotic fucosylated proteins by L-fucose in HCT-116 cells. RNA-seq analysis showed that upregulation of the transcription levels of serine biosynthesis genes (e.g. PSAT1) and decreased levels of genes involved in serine consumption with supplemental L-fucose were also unique to HCT-116 cells. Increased serine concentrations only in HCT-116 cells and increased α1,3/6-fucosylation in CRC cells induced by exogenous serine also verified that L-fucose enhanced fucosylation via promoting intracellular serine accumulation. Additionally, the knockdown of PSAT1 and serine-deficiency impaired fucosylation. Notably, PSAT1 knockdown weakened the inhibitory effect of L-fucose on cell proliferation and migration. Interestingly, simultaneous increased levels of α1,3/6-fucosylation and PSAT1 transcription were also identified in colorectal tumor tissues of CRC patients. Together, these results uncover a novel role of serine synthesis and PSAT1 in the regulation of fucosylation and provide insights into the potential application of L-fucose in CRC therapy.

Marine-Derived Natural Product HDYL-GQQ-495 Targets P62 to Inhibit Autophagy.

Autophagy is widely implicated in pathophysiological processes such as tumors and metabolic and neurodegenerative disorders, making it an attractive target for drug discovery. Several chemical screening approaches have been developed to uncover autophagy-modulating compounds. However, the modulation capacity of marine compounds with significant pharmacological activities is largely unknown. We constructed an EGFPKI-LC3B cell line using the CRISPR/Cas9 knock-in strategy in which green fluorescence indicated endogenous autophagy regulation. Using this cell line, we screened a compound library of approximately 500 marine natural products and analogues to investigate molecules that altered the EGFP fluorescence. We identified eight potential candidates that enhanced EGFP fluorescence, and HDYL-GQQ-495 was the leading one. Further validation with immunoblotting demonstrated that cleaved LC3 was increased in dose- and time-dependent manners, and the autophagy adaptor P62 showed oligomerization after HDYL-GQQ-495 treatment. We also demonstrated that HDYL-GQQ-495 treatment caused autophagy substrate aggregation, which indicated that HDYL-GQQ-495 serves as an autophagy inhibitor. Furthermore, HDYL-GQQ-495 induced Gasdermin E (GSDME) cleavage and promoted pyroptosis. Moreover, HDYL-GQQ-495 directly combined with P62 to induce P62 polymerization. In P62 knockout cells, the cleavage of LC3 or GSDME was blocked after HDYL-GQQ-495 treatment. The EGFPKI-LC3B cell line was an effective tool for autophagy modulator screening. Using this tool, we found a novel marine-derived compound, HDYL-GQQ-495, targeting P62 to inhibit autophagy and promote pyroptosis.

HPV vaccination, information sources, and acculturation among Chinese college students aged 18-26 in the United States.

Human papillomavirus (HPV) vaccination behaviors among Chinese college students (CCS) in the United States are affected by social determinants of health. Using a self-report questionnaire and a snowball sampling technique, this cross-sectional study investigated (a) HPV vaccination practices; (b) primary social networking platforms and preferred means of receiving HPV information; and (c) the influence of acculturation on HPV vaccination, HPV information sources, and social networking use among 213 CCS aged 18-26 in the United States. About half (50.7%) had received one to three doses of an HPV vaccine, and 91.7% had received their first dose. The most popular social networking platforms were WeChat (69.5%), Instagram (58.7%), text messaging (55.4%), and Facebook (47.4%). Preferred means of receiving future HPV information included the internet, online social networking, and health professionals. Participants with high Asian identification (AI) were less likely to receive the HPV vaccine than those with high Western identification. Participants with high AI were more likely to use WeChat for their social networking but less likely to use US-based social media platforms. Acculturation, preferred social networking platforms, and sources and communication of HPV (i.e., health professionals, family members, schoolteachers, friends) influenced participants' HPV vaccination. To promote equity of access to health messages and increase HPV vaccination, future efforts should pay attention to CCS with high AI and incorporate their cultural beliefs and practices. Given that nonprofessionals (e.g., family, friends) were influential factors in HPV vaccination, it is critical to tailor interventions for CCS to the recipients and their social circles.

Generation of hydroxyl radical-activatable ratiometric near-infrared bimodal probes for early monitoring of tumor response to therapy.

Tumor response to radiotherapy or ferroptosis is closely related to hydroxyl radical (•OH) production. Noninvasive imaging of •OH fluctuation in tumors can allow early monitoring of response to therapy, but is challenging. Here, we report the optimization of a diene electrochromic material (1-Br-Et) as a •OH-responsive chromophore, and use it to develop a near-infrared ratiometric fluorescent and photoacoustic (FL/PA) bimodal probe for in vivo imaging of •OH. The probe displays a large FL ratio between 780 and 1113 nm (FL780/FL1113), but a small PA ratio between 755 and 905 nm (PA755/PA905). Oxidation of 1-Br-Et by •OH decreases the FL780/FL1113 while concurrently increasing the PA755/PA905, allowing the reliable monitoring of •OH production in tumors undergoing erastin-induced ferroptosis or radiotherapy.

Malignant transformation of abdominal wall endometriosis: A systematic review of the epidemiology, diagnosis, treatment, and outcomes.

Malignant transformation of abdominal wall endometriosis (AWE) is rare. The clinical characteristics and treatment of malignant transformation of AWE are not well known. Therefore, in this review, we performed a thorough search for malignant transformation of AWE on MEDLINE and Web of Science from their inception to May 2021. In total, the data of 46 patients with malignant transformation of AWE were retrieved, and all the data on these patients were collected. After reviewing and analyzing the clinical parameters, we found that cesarean scar was the most common site of malignant transformation of AWE, and the most common pathological type of malignant transformation of AWE was clear cell cancer, followed by endometrioid adenocarcinoma. The main symptoms of malignant transformation of AWE included an abdominal nodule or mass, and ultrasonography was the first choice for diagnosis. The most widely accepted treatment was surgical resection of local lesions with adjunctive chemotherapy and/or radiotherapy, and the overall survival of patients with malignant transformation of AWE was poor. In conclusion, malignant transformation of AWE is rare, and the prognosis is poor. Thus, improving abdominal surgical technology and avoiding iatrogenic ectopia and implantation of the endometrium are necessary to prevent malignant transformation of AWE.

An intestinal organoid-based platform that recreates susceptibility to T-cell-mediated tissue injury.

A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T-cell-mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that cocultured allogeneic T cells kill Atg16L1-mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T-cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues.

Transvaginal salpingo-oophorectomy with gasless laparoscopy - an optional pure natural orifice transluminal endoscopic surgery.

OBJECTIVES: To establish the appropriate technique for salpingo-oophorectomy via transvaginal natural orifice transluminal endoscopic surgery (NOTES), under gasless laparoscopy. MATERIAL AND METHODS: Ten patients with clinical indication underwent gasless laparoscopic transvaginal salpingo-oophorectomy with concurrent vaginal hysterectomy. An abdominal-wall lifting device was used after removal of the uterus, and the adnexa was removed trans-vaginally by gasless laparoscopy. The perioperative clinical data, such as operative duration, volume of blood loss, morbidity, intraoperative and postoperative complications, and length of hospital stay, were retrospectively analyzed. RESULTS: All procedures were successfully done, without any intraoperative or major postoperative complications, and no additional transabdominal ports were required. The salpingo-oophorectomy part of the procedure was completed in approximately 11-40 minutes, with minimal blood loss. All of the patients were discharged, scar-free, 2-4 days after surgery. CONCLUSIONS: Transvaginal NOTES with gasless laparoscopy is a feasible and safe surgical technique in cases involving difficult vaginal salpingo-oophorectomy, which avoids conversion to an abdominal route.

Clinical evaluation of transvaginal myomectomy surgery: a retrospective study of 138 cases.

OBJECTIVES: The aim of this study was to evaluate the safety, feasibility, and effectiveness of transvaginal myomectomy surgery. MATERIAL AND METHODS: We conducted a retrospective study in Shengjing Hospital of China Medical University. In all, 138 patients underwent transvaginal myomectomy from March 2009 to March 2019. The perioperative clinical data, suchas position and size of myomas, operative duration, blood loss, intraoperative and postoperative complications, and hospitalizationtime were retrospectively analyzed. RESULTS: All transvaginal myomectomies were performed without conversion to laparotomy. The mean vaginal operatingtime was 56.0 (± 17.2) minutes. The mean operative estimated blood loss was 89.2 (± 36.8) mL. No significant intraoperativecomplications occurred. The median time of intestinal function recovery after operation was 1 day (range 1-4 days).The median time of hospital stay was 4 days (range 3-10 days); 12 (8.7%) patients experienced postoperative morbidity. CONCLUSIONS: Transvaginal myomectomy is a minimally invasive surgery that can be performed without leaving a scar onthe body surface. It can be performed safely and effectively by a skilled surgeon in cases with a specific surgical indicationfor this approach.

Aspergiolides A and B: Core Structural Establishment and Synthesis of Structural Analogues.

The core structure of marine natural products aspergiolides A (1a) and B (1b) was achieved via a concise, two-step procedure with satisfactory yield. Based on this protocol, a natural products mimic library containing 25 structural simplified analogues of 1a was then constructed. Several prepared analogues showed potential cytotoxic activity against five different tumor cell lines, and compound 7bb, in particular, exhibited cytotoxicity comparable to that of 1a.

Enhanced removal of organic matter and typical disinfection byproduct precursors in combined iron-carbon micro electrolysis-UBAF process for drinking water pre-treatment.

The organic matter and two types of disinfection byproduct (DBP) precursors in micro-polluted source water were removed using an iron-carbon micro-electrolysis (ICME) combined with up-flow biological aerated filter (UBAF) process. Two pilot-scale experiments (ICME-UBAF and UBAF alone) were used to investigate the effect of the ICME system on the removal of organic matter and DBP precursors. The results showed that ICME pretreatment removed 15.6% of dissolved organic matter (DOM) and significantly improved the removal rate in the subsequent UBAF process. The ICME system removed 31% of trichloromethane (TCM) precursors and 20% of dichloroacetonitrile (DCAN) precursors. The results of measurements of the molecular weight distribution and hydrophilic fractions of DOM and DBP precursors showed that ICME pretreatment played a key role in breaking large-molecular-weight organic matter into low-molecular-weight components, and the hydrophobic fraction into hydrophilic compounds, which was favorable for subsequent biodegradation by UBAF. Three-dimensional fluorescence spectroscopy (3D-EEM) further indicated that the ICME system improved the removal of TCM and DCAN precursors. The biomass analysis indicated the presence of a larger and more diverse microbial community in the ICME-UBAF system than for the UBAF alone. The high-throughput sequencing results revealed that domination of the genera Sphingomonas, Brevundimonas and Sphingorhabdus contributed to the better removal of organic matter and two types of DBP precursors. Also, Nitrosomonas and Pseudomonas were beneficial for ammonia removal.

AS1041, a Novel Synthesized Derivative of Marine Natural Compound Aspergiolide A, Arrests Cell Cycle, Induces Apoptosis, and Inhibits ERK Activation in K562 Cells.

AS1041 is a novel synthesized anthraquinone lactone derivative of marine natural compound aspergiolide A (ASP-A) with new structure skeleton and marked cytotoxicity in cancer cells. To study its cytotoxicity in detail, we evaluated its activity on human K562 chronic myelogenous leukemia cells and investigated the related molecule mechanisms. AS1041 significantly inhibited the proliferation and colony formation of K562 cells. Moreover, AS1041 arrested cell cycle progression at G2/M phase in a concentration-dependent manner, and also caused concentration- and time-dependent induction of apoptosis. In addition, the molecular mechanisms investigation showed that AS1041 did not localize in the cellular nucleus and did not affect topoisomerases I or II. However, AS1041 could inactivate extracellular signal-regulated kinase (ERK) and contribute to AS1041-induced apoptosis. We concluded that AS1041 was cytotoxic to K562 leukemia cells and the cytotoxicity related to the cell cycle arrest, apoptosis induction, and ERK inhibition. These results implied that AS1041 was a novel derivative of ASP-A with significant cytotoxicity to chronic myelogenous leukemia cells and may have therapeutic potential for the treatment of cancer and leukemia.

Catch and Release of Cytokines Mediated by Tumor Phosphatidylserine Converts Transient Exposure into Long-Lived Inflammation.

Immune cells constantly survey the host for pathogens or tumors and secrete cytokines to alert surrounding cells of these threats. In vivo, activated immune cells secrete cytokines for several hours, yet an acute immune reaction occurs over days. Given these divergent timescales, we addressed how cytokine-responsive cells translate brief cytokine exposure into phenotypic changes that persist over long timescales. We studied melanoma cell responses to transient exposure to the cytokine interferon γ (IFNγ) by combining a systems-scale analysis of gene expression dynamics with computational modeling and experiments. We discovered that IFNγ is captured by phosphatidylserine (PS) on the surface of viable cells both in vitro and in vivo then slowly released to drive long-term transcription of cytokine-response genes. This mechanism introduces an additional function for PS in dynamically regulating inflammation across diverse cancer and primary cell types and has potential to usher in new immunotherapies targeting PS and inflammatory pathways.