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Emmanuel Perrodin-Njoku,1 Sowmya R Rao,2 Regina M Wang,3 Christopher J Moreland,4 Poorna Kushalnagar1 1Center for Deaf Health Equity, Gallaudet University, Washington, DC, USA; 2Department of Global Health, Boston University School of Public Health, Boston, MA, USA; 3Family Medicine and Public Health, University of California San Diego, San Diego, CA, USA; 4Dell Medical School, University of Texas at Austin, Austin, TX, USACorrespondence: Poorna Kushalnagar, Gallaudet University, 800 Florida Avenue NE, Hall Memorial Building, Washington, DC, 20002, USA, Email poorna.kushalnagar@gallaudet.eduPurpose: Some deaf and hard-of-hearing (DHH) individuals face health information barriers, increasing their risk of diabetes mellitus (DM) and subsequent cancer development. This study examines if health-related quality of life (HRQoL) and deaf patient-reported outcomes (DHH-QoL) mediate the relationship between DM diagnosis and cancer screening adherence among DHH individuals.Patients and Methods: In a cross-sectional study, US DHH adults assigned female at birth answered questions on cervical and breast cancer screenings from the ASL-English bilingual Health Information National Trends Survey (HINTS-ASL) and the PROMIS (Patient Reported Outcome Measurement Information System) Deaf Profile measure’s Communication Health and Global Health domains. Odds ratios (OR) and 95% confidence intervals (CI) were obtained from multivariable logistic and linear regression models, examining the association between DM, DHH-QoL, and cancer screening adherence, adjusting for other covariates and HRQoL. A Baron and Kenny causal mediation analysis was used. A two-sided p < 0.05 indicated significance.Results: Most respondents were White (66.4%), heterosexual (66.2%), did not have DM (83.9%), had health insurance (95.5%), and adhered to pap smears (75.7%) and mammograms (76.9%). The average (standard deviation) DHH-QoL score was 50.9 (8.6). Those with DM had lower HRQoL scores (46.2 (9.5) vs 50.2 (8.8); p < 0.0001) than those without. Non-significant multivariable models indicate that those with DM were more adherent to pap testing (OR: 1.48; 95% CI: 0.72, 3.03; p = 0.285) and mammograms (2.18; 95% CI: 0.81, 5.88; p = 0.122), with DHH-QoL scores slightly increasing them to 1.53 (0.74, 3.16; p = 0.250) for pap testing and 2.55 (0.91, 7.13; p = 0.076) for mammograms. DHH-QoL was significantly associated with mammograms (p = 0.027), with 6% increased adherence per unit increase in the score. Overall, HRQoL and DHH-QoL were not significant mediators.Conclusion: While HRQoL/DHH-QoL in DHH individuals with DM does not mediate cancer screening adherence, higher DHH-QoL scores are associated with it. DHH-focused health literacy and communication training can improve cancer-related outcomes.Keywords: deaf, cancer screening, sign language, hearing loss, diabetes

Background: Telecare may provide an alternative to maintaining post-acute stroke care services in making benefit to both the providers and the stroke survivors, although study is needed to investigate its feasibility and effectiveness in integrating this innovative delivery mode into a routine., Objectives: The objectives of this study are to assess the feasibility and effectiveness of telecare consultations in a nurse-led post-acute stroke clinic., Methods: A pre- and post-test one group quasi-experimental design was adopted. Subjects were recruited in the clinic and received three secondary stroke care consultations in 3 months via telecare from stroke nurses. Data were collected at pre- and post-intervention. A Wilcoxon signed-rank test was used to compare the two time-points for differences in effectiveness., Results: Ninety-two stroke survivors participated. The drop-out rate was 27%. The majority perceived the programme as time-friendly and cost-saving and as alleviating their health-related worries. At the 3-month follow-up, notable improvements were observed in the activities of daily living and the strength domain of stroke-specific quality of life., Conclusions: Integrating telecare consultations within nurse-led stroke clinics is a feasible and acceptable strategy for monitoring the health and fostering the self-care abilities of individuals following their discharge from hospital after an acute stroke episode., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

In 2021, the severe acute respiratory syndrome coronavirus 2 Delta variant rapidly proliferated and became dominant. Some but not all research evidence supports that Delta was associated with increased maternal risk. The purpose of this study was to determine whether Delta was associated with risk for cardiac and respiratory complications in a national sample. Of an estimated 3,495,188 delivery hospitalizations in 2021, 1.8% of pre-Delta deliveries ( n  = 29,580; January-June) and 2.1% of Delta-period deliveries ( n  = 37,545; July-December) had a coronavirus disease 2019 (COVID-19) diagnosis. The Delta period was associated with increased adjusted odds of respiratory complications (adjusted odds ratio [aOR] = 1.54, 95% CI: 1.41, 1.69) and cardiac severe maternal morbidity (SMM; aOR = 1.54, 95% CI: 1.40, 1.69). Among deliveries with a COVID-19 diagnosis, the Delta period was associated with a higher incidence of respiratory complications (8.4 vs. 3.7%) and cardiac SMM (8.4 vs. 3.5%; p  < 0.01 for both). These findings corroborate prior clinical studies suggesting that the Delta strain was associated with an increased maternal population-level clinical burden. KEY POINTS: · The Delta strain was associated with an increased maternal population-level clinical burden.. · The Delta period was associated with an increased risk for cardiac and respiratory complications.. · Among deliveries with a COVID-19 diagnosis, the Delta period was associated with increased risk.., Competing Interests: T.W. serves as a consultant on the medical advisory board for Delfina, Inc. A.F. is supported by funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant nos.: 1UG3HD111247, 1R01HD104943, and other grants); however, this funding was not used to support this research. A.F. has served on an advisory board for Sage and Biogen., (Thieme. All rights reserved.)

Background: Reduction mammaplasty improves the quality of life by providing functional and aesthetic benefits to women with macromastia. This study contributes to the existing literature on socioeconomic and clinical barriers to referral for plastic surgery procedures by focusing specifically on reduction mammaplasty., Methods: Patients with macromastia were identified via a chart review in a single institution from 2021-2022. The treatment pathway for each patient was characterized by reception of referral, completion of plastic surgery consultation, and eventual reception of surgery. After controlling for clinical covariates, multivariate logistic regression was applied to quantify the independent impact of race, insurance, and language status on the completion of surgery (p < 0.05)., Results: The final patient cohort included 425 women with macromastia. Among the 151 patients who were first seen by a primary care physician, 64 (42%) completed an initial plastic surgery consultation. Among all patients, 160 (38%) eventually underwent reduction mammaplasty. Multivariate regression predictions indicated a lower likelihood of completing breast reduction surgery in patients with current smoking history (OR: 0.08, 95% CI: 0.01-0.59) and higher body mass index (BMI) (OR: 0.94, 95% CI: 0.90-0.97) (p < 0.05). Minority race and ethnicity, private insurance status, and primary language status were not significant predictors of this outcome (p > 0.05)., Conclusions: In this study, the socioeconomic variables were not independent predictors of breast reduction surgery completion. However, the association of minority race and ethnicity and nonprivate insurance status with the most common reasons for breast reduction deferral suggest an indirect influence of socioeconomic status on the treatment pathway., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the prevalence, intervention methods and effect of arteriovenous graft (AVG) stenosis. Methods: The clinical data of patients who received AVG in the Blood Purification Center, the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2022 were retrospectively analyzed. The patency rate, prevalence and intervention effect of AVG stenosis were analyzed. Results: A total of 475 patients aged (55.5±11.8) years were included, and there were 193 male cases (40.6%) and 282 female cases (59.4%). The patients were followed up for [ M ( Q 1 , Q 3 )] 19 (12, 30) months, and the primary, assisted primary and secondary patency were 14 (5, 27), 27 (13, 55), and 59 (33, 65) months, respectively. There were 799 access events which needed intervention, with a total standardized intervention rate of 0.90 per patient-year. Totally, 431(53.9%, 431/799) stenosis events occurred in 207 AVG. Among 422 AVG stenosis events with complete clinical data, 57.8% (244/422) were multi-site stenosis and 42.2% (178/422) were single-site stenosis. The most common sites of stenosis were graft-vein anastomosis (47.6%, 340/715), venous outflows (22.7%, 162/715), and puncture zone (20.0%, 143/715). In the 414 stenosis with intact follow-up data, 90.8% (376/414) were treated by balloon angioplasty, 8.5% (35/414) received covered stent insertion, and 0.7% (3/414) were intervened by open surgery. Clinical success rate was 98.1% (406/414). The primary patency time after endovascular treatment was 6 (4, 12) months. Covered stent significantly increased post-intervention primary patency time compared withballoon angioplasty [6 (3, 7) months vs 3 (1, 4) months, P =0.020]. Conclusions: Stenosis is the most common complication of AVG, and the most common sites are graft-vein anastomosis, venous outflows, and puncture zone. Intervention of AVG stenosis has a high clinical success rate, and a relatively low post-intervention patency. Covered stent insertion improves the post-intervention patency of AVG, which has a poor effect using balloon expansion.

Purpose: To analyze the effects of fixed appliance and invisible appliance without bracket on anterior tooth root and alveolar bone in patients with mild to moderate overcrowding of Class Ⅰmalocclusion., Methods: A total of 120 patients with mild to moderate dental crowding were selected from January 2018 to February 2022,and divided into control group and experimental group by random number table method, with 60 cases in each group. The control group was treated with traditional fixed appliance, while the experimental group was treated with invisible appliance without bracket. Cone-beam CT(CBCT) was taken before and 12 months after treatment to measure the root length and alveolar bone height and thickness of maxillary central incisor teeth, height of alveolar bone of anterior teeth lip and lingual side and cusp teeth in both groups. Statistical analysis was performed with SPSS 22.0 software package., Results: The root length changes of maxillary central incisor, lateral incisor and cusp teeth in the experimental group were significantly lower than those in the control group before and after treatment(P＜0.05). The alveolar bone height changes in the labial side and lingual palatine side of upper anterior teeth, labial side and lingual palatine side of inferior anterior teeth in the experimental group before and after treatment were significantly lower than those in the control group(P＜0.05). The thickness changes of labiolingual alveolar bone at the neck, middle root and apex of upper and inferior anterior teeth in the experimental group were significantly lower than those in the control group before and after treatment(P＜0.05)., Conclusions: Compared with fixed appliance, invisible appliance without bracket can reduce root resorption and the loss of alveolar bone height and thickness in the treatment of Class I patients with mild to moderate dental crowding.

Introduction: The deaf and hard of hearing (DHH) community experiences lower cancer screening rates than the general population. Cancer worry and fatalism can influence cancer screening, along with race, and the interaction of intrinsic factors with DHH health behavior needs to be investigated., Objectives: The study examines the association of the intersection of race and hearing status with cancer worry and fatalism., Methods: This study analyzed cross-sectional survey data from NCI HINTS-ASL (for DHH adults) and NCI HINTS (for hearing adults). Multivariable logistic regression models were used to assess (i) the association of race-hearing status intersection with cancer worry and fatalism, as well as (ii) the relationship between hearing status and outcomes within each race., Results: The study found that the overall interaction between race and hearing status was significantly associated with both high cancer worry and fatalism, with African American (AA)/Black and Asian/Other having higher odds of worry [1.17 (0.83, 1.64); 1.19 (0.85, 1.66), respectively] and other groups having lower worry than White hearing ( P < 0.0001), and all deaf having less concern about cancer fatalism ( P < 0.0001). Within each racial group, White DHH respondents had lower odds of cancer worry [aOR (95% CI): 0.72 (0.58, 0.91); P < 0.01] and fatalism [0.55 (0.46, 0.67); P < 0.0001] compared to White hearing respondents, while DHH AA/Black [1.89 (1.06, 3.37); P = 0.03], Asian/Other [2.39 (1.06, 3.37); P = 0.03], and Hispanic [1.95 (1.18, 3.22); P < 0.01] respondents had significantly higher odds of cancer worry and lower odds of cancer fatalism [Black: 0.50 (0.23, 1.09); P = 0.07; Asian/Other: [0.68 (0.42, 1.09); P = 0.10]; Hispanic: [0.69 (0.40, 1.17)]; P = 0.16] compared to their hearing counterparts., Conclusion: DHH individuals have different odds of experiencing cancer worry and fatalism compared to their hearing counterparts. Inclusion of individuals with sensory disabilities in a larger cancer study sample enriches the diversity of perspectives, ensuring that the findings reflect a broader range of experiences and needs. More research into contributory factors in the signing DHH population is needed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: This study aimed to investigate the prevalence and risk factors for carbapenem-resistant Enterobacterales colonisation/infection at admission and acquisition among patients admitted to the intensive care unit., Research Methodology/design: A prospective and multicentre study., Setting: This study was conducted in 24 intensive care units in Anhui, China., Main Outcome Measures: Demographic and clinical data were collected, and rectal carbapenem-resistant Enterobacterales colonisation was detected by active screening. Multivariate logistic regression models were used to analyse factors associated with colonisation/infection with carbapenem-resistant Enterobacterales at admission and acquisition during the intensive care unit stay., Results: There were 1133 intensive care unit patients included in this study. In total, 5.9% of patients with carbapenem-resistant Enterobacterales colonisation/infection at admission, and of which 56.7% were colonisations. Besides, 8.5% of patients acquired carbapenem-resistant Enterobacterales colonisation/infection during the intensive care stay, and of which 67.6% were colonisations. At admission, transfer from another hospital, admission to an intensive care unit within one year, colonisation/infection/epidemiological link with carbapenem-resistant Enterobacterales within one year, and exposure to any antibiotics within three months were risk factors for colonisation/infection with carbapenem-resistant Enterobacterales. During the intensive care stay, renal disease, an epidemiological link with carbapenem-resistant Enterobacterales, exposure to carbapenems and beta-lactams/beta-lactamase inhibitors, and intensive care stay of three weeks or longer were associated with acquisition., Conclusion: The prevalence of colonisation/infection with carbapenem-resistant Enterobacterales in intensive care units is of great concern and should be monitored systematically. Particularly for the 8.5% prevalence of carbapenem-resistant Enterobacterales acquisition during the intensive care stay needs enhanced infection prevention and control measures in these setting. Surveillance of colonisation/infection with carbapenem-resistant Enterobacterales at admission and during the patient's stay represents an early identification tool to prevent further transmission of carbapenem-resistant Enterobacterales., Implications for Clinical Practice: Carbapenem-resistant Enterobacterales colonization screening at admission and during the patient's stay is an important tool to control carbapenem-resistant Enterobacterales spread in intensive care units., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Chronic thyrotoxic myopathy (CTM) is a common, easily neglected complication of hyperthyroidism. There are currently no standard diagnostic criteria for CTM, and the ultrasonic characteristics of CTM-affected skeletal muscle remain unclear. Herein, we aimed to evaluate hyperthyroid patients for CTM by ultrasound and identify ultrasonic muscle parameter cutoffs for CTM diagnosis., Materials and Methods: Each participant underwent ultrasonography. The original (muscle thickness (MT), pennation angle (PA), and cross-sectional area (CSA)) and corrected (MT/height (HT), MT/body mass index (BMI), CSA/HT, and CSA/BMI) parameters of the vastus lateralis and vastus medialis (VM) were evaluated. The diagnostic effectiveness of ultrasound for predicting CTM was determined using receiver operating characteristic (ROC) curve analysis. Our study included 203 participants: 67 CTM patients (18 males, 49 females), 67 non-CTM patients (28 males, 39 females) and 69 healthy controls (20 males, 49 females)., Results: The CTM group had lower muscular ultrasonic and anthropometric parameters, higher thyroid hormone and thyroid-stimulating hormone receptor antibody (TRAb) levels, and a longer duration of hyperthyroidism than the non-CTM group (P < 0.05). The VM-PA, VM-CSA, VM-CSA/HT, and VM-CSA/BMI were lower in females than in males (P < 0.05). Free thyroxine (FT4) and TRAb both showed significant negative correlations with VM-MT, VM-MT/HT, VM-CSA, and VM-CSA/HT (P < 0.05). VM-MT/BMI and VM-CSA/HT, respectively, best predicted male and female CTM (AUC = 0.84, 0.85; cutoff ≤ 0.07, < 4.01)., Conclusion: Ultrasound measurement of muscular parameters, especially in the VM, is a valid and feasible way of diagnosing and characterizing possible CTM in hyperthyroidism.

Objective: To analyze factors associated with intestinal acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation(allo-HSCT) in children and to develop a prediction model for intestinal aGVHD after allo-HSCT in children., Methods: The clinical data of 62 children who underwent allo-HSCT at the Department of Hematology of the People's Hospital of Xinjiang Uygur Autonomous Region from February 2018 to September 2021 were retrospectively analyzed. Intestinal aGVHD was evaluated according to the Mount Sinai Acute GVHD International Consortium (MAGIC) grading criteria, the variables were screened by LASSO (least absolute shrinkage and selection operator) regression analysis with 10-fold cross-validation, and developed a model for predicting intestinal aGVHD after allo-HSCT in children., Results: A total of 33 (53.2%) of the 62 children developed intestinal aGVHD, of which 25 were degree II and 8 were degree III-IV. The results of screening variables by 10-fold cross-validated LASSO regression showed that the significant variables included ethnic minorities ( OR =7.229; 95% CI : 2.337-22.354), platelet (PLT) ( OR =0.971; 95% CI : 0.932-0.993), uric acid (UA) ( OR =0.971; 95% CI : 0.935-0.988), C-reactive protein (CRP) ( OR =1.217; 95% CI : 1.053-1.545), and viral infection ( OR =10; 95% CI : 3.021-32.668), and these variables were independently associated with intestinal aGVHD in children (all P <0.05). A prediction model was constructed based on above variables. The area under the receiver operating characteristic (ROC) curve (AUC) of the model was calculated, and the AUC value was 0.985 (0.966-1), the Brier score was 0.055. The evaluation showed that the model has a high degree of discrimination and calibration., Conclusion: Ethnic minorities, low PLT, low UA, high CRP, and viral infections are independently associated with intestinal aGVHD in children, and early attention should be paid to these high-risk children.

Bioactive immunomodulatory biomaterials have shown promise for influencing the immune response to promote tissue repair and regeneration. Macrophages and T cells have been associated with this response; however, other immune cell types have been traditionally overlooked. In this study, we investigated the role of mast cells in the regulation of the immune response to decellularized biomaterial scaffolds using a subcutaneous implant model. In mast cell-deficient mice, there was dysregulation of the expected M1 to M2 macrophage transition typically induced by the biomaterial scaffold. Polarization progression deviated in a sex-specific manner with an early transition to an M2 profile in female mice, while the male response was unable to properly transition past a pro-inflammatory M1 state. Both were reversed with adoptive mast cell transfer. Further investigation of the later-stage immune response in male mice determined a greater sustained pro-inflammatory gene expression profile, including the IL-1 cytokine family, IL-6, alarmins, and chemokines. These results highlight mast cells as another important cell type that influences the immune response to pro-regenerative biomaterials., (© 2023. Springer Nature Limited.)

This study evaluated two types of barriers that the authors deemed important to resolve during the early stage of cancer clinical trial exploration by Latinx community members. One was the accessibility of information provided on cancer centers' websites. The other was the telephone responders' clinical trial knowledge and their conveyance of a warm welcome to Latinx callers inquiring about the centers' clinical trials. Simulated clinical trial inquiry calls were made to 17 National Cancer Institute-designated centers in this study. The centers were located in cities where the Latinx community accounted for at least 25% of the population, thereby justifying center-wide efforts to encourage the Latinx community to explore clinical trial participation. A rubric was developed to determine and quantify a Total Score that was partially composed of the accessibility of clinical trial information displayed on each cancer center's website. A research assistant gathered information by posing as a person calling the cancer center to inquire about clinical trials on behalf of a family member with limited English proficiency and evaluated their response using a "mystery shopper" method of data collection. The warmth and sense of welcome conveyed by the telephone responder was also quantified and included in the rubric's Total Score. A perfect Total Score reflected the likely existence of an environment that would encourage Latinx community members to continue exploring clinical trials, i.e., removed or diminished possible barriers. Welcoming characteristics, such as those elements included in the scoring rubric, can be monitored regularly to assure that centers are consistently conveying an optimal sense of welcome to the Latinx community, while also providing accessible clinical trial information. Among the 17 cancer centers, no correlation was found between the size of the Latinx population served and each center's Total Score., (© 2023. The Author(s).)

Uterine clear cell carcinoma (UCCC) is a relatively rare endometrial cancer. There is limited information on its prognosis. This study aimed to develop a predictive model predicting the cancer-specific survival (CSS) of UCCC patients based on data from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2018. A total of 2329 patients initially diagnosed with UCCC were included in this study. Patients were randomized into training and validation cohorts (7:3). Multivariate Cox regression analysis identified that age, tumor size, SEER stage, surgery, number of lymph nodes detected, lymph node metastasis, radiotherapy and chemotherapy were independent prognostic factors for CSS. Based on these factors, a nomogram for predicting the prognosis of UCCC patients was constructed. The nomogram was validated using concordance index (C-index), calibration curves, and decision curve analyses (DCA). The C-index of the nomograms in the training and validation sets are 0.778 and 0.765, respectively. Calibration curves showed good consistency of CSS between actual observations and nomogram predictions, and DCA showed that the nomogram has great clinical utility. In conclusion, a prognostic nomogram was firstly established for predicting the CSS of UCCC patients, which can help clinicians make personalized prognostic predictions and provide accurate treatment recommendations., (© 2023. The Author(s).)

Postmenopausal osteoporosis is one of the most common metabolic diseases in old women, and supplementing estrogen through bioactive substances is one of the important ways to improve menopausal syndrome. Some studies have confirmed that soybean isoflavone has estrogenic activity, and the main active component of soybean isoflavones is isoflavone aglycones. However, few studies have investigated the improvement effect of high-purity soy isoflavone aglycones on postmenopausal osteoporosis. Thus, the effect of different doses of high-purity soybeans isoflavone aglycone on the ovariectomized female osteoporosis rat model was evaluated by oral gavage. The rats were divided into seven experimental groups including SHAM, OVX, EE, SIHP, AFDP-L, AFDP-M, and AFDP-H, which was administered for 60 days from 30 days after ovariectomy. We collected blood from the abdominal aorta of rats on the 30th, 60th, and 90th days respectively, analyzed its serum biochemistry, and took out the femur for micro-CT imaging and bone microstructure parameter analysis. Results showed that the intervention effect of AFDP-H group on osteoporosis rats at 60 and 90 days was similar to that of EE group, and superior to the OVX group, SIHP group, AFDP-L group, AFDP-M group. The AFDP-H group inhibited the decrease in serum bone markers, bone density, trabeculae quantity, trabeculae thickness, and bone volume fraction, and increased the trabecular separation caused by ovariectomy, thereby significantly improving bone microstructure. It also prevented continuous weight gain and increased cholesterol levels in female rats. This study provided theoretical to application of soybean isoflavone aglycone in the intervention of osteoporosis. and confirmed that could replace chemical synthetic estrogen drugs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Yang, Ma, Li, Bian, Fu, Ren, Wang, Shi and Zhang.)

The P-type ATPase ATP7B exports cytosolic copper and plays an essential role in the regulation of cellular copper homeostasis. Mutants of ATP7B cause Wilson disease (WD), an autosomal recessive disorder of copper metabolism. Here, we present cryoelectron microscopy (cryo-EM) structures of human ATP7B in the E1 state in the apo, the putative copper-bound, and the putative cisplatin-bound forms. In ATP7B, the N-terminal sixth metal-binding domain (MBD6) binds at the cytosolic copper entry site of the transmembrane domain (TMD), facilitating the delivery of copper from the MBD6 to the TMD. The sulfur-containing residues in the TMD of ATP7B mark the copper transport pathway. By comparing structures of the E1 state human ATP7B and E2-P i state frog ATP7B, we propose the ATP-driving copper transport model of ATP7B. These structures not only advance our understanding of the mechanisms of ATP7B-mediated copper export but can also guide the development of therapeutics for the treatment of WD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Deficiency of MTAP (MTAP def ) mainly occurs because of homozygous loss of chromosome 9p21, which is the most common copy-number loss in metastatic urothelial cancer (mUC). We characterized the clinical and genomic features of MTAP def mUC in 193 patients treated at MD Anderson Cancer Center (MDACC) and 298 patients from the phase 2 IMvigor210 trial, which investigated atezolizumab in cisplatin-ineligible and platinum-refractory disease. In the MDACC cohort, visceral metastases were significantly more common for MTAP def (n = 48) than for MTAP-proficient (MTAP prof ; n = 145) patients (75% vs 55.2%; p = 0.02). MTAP def was associated with poor prognosis (median overall survival [mOS] 12.3 vs 20.2 mo; p = 0.007) with an adjusted hazard ratio of 1.93 (95% confidence interval 1.35-2.98). Similarly, IMvigor210 patients with MTAP lo (n = 29) had a higher incidence of visceral metastases than those with MTAP hi tumors (n = 269; 86.2% vs 72.5%; p = 0.021) and worse prognosis (mOS 8.0 vs 11.3 mo; p = 0.042). Hyperplasia-associated genes were more frequently mutated in MTAP def tumors (FGFR3: 31% vs 8%; PI3KCA: 31% vs 19%), while alterations in dysplasia-associated genes were less common in MTAP def tumors (TP53: 41% vs 67%; RB1: 0% vs 16%). Our findings support a distinct biology in MTAP def mUC that is associated with early visceral disease and worse prognosis. PATIENT SUMMARY: We investigated the outcomes for patients with the most common gene loss (MTAP gene) in metastatic cancer of the urinary tract. We found that this loss correlates with worse prognosis and a higher risk of metastasis in internal organs. There seems to be distinct tumor biology for urinary tract cancer with MTAP gene loss and this could be a potential target for treatment., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

To determine the suitable planting density and row spacing of short-season cotton suitable for machine picking in the Yellow River Basin of China, we conducted a two-year field experiment in Dezhou during 2018-2019. The experiment followed a split-plot design, with planting density (82500 plants·hm -2 and 112500 plants·hm -2 ) as the main plots and row spacing (equal row spacing of 76 cm, wide-narrow row spacing of 66 cm+10 cm, equal row spacing of 60 cm) as the subplots. We examined the effects of planting density and row spacing on growth and development, canopy structure, seed cotton yield and fiber quality of short-season cotton. The results showed that plant height and LAI under high density treatment were significantly greater than those under low density treatment. The transmittance of the bottom layer was significantly lower than under low density treatment. Plant height under 76 cm equal row spacing was significantly higher than that under 60 cm equal row spacing, while that under wide-narrow row spacing (66 cm +10 cm) was significantly smaller than that under 60 cm equal row spacing in peak bolling stage. The effects of row spacing on LAI varied between the two years, densities, and growth stages. On the whole, the LAI under the wide-narrow row spacing (66 cm+10 cm) was higher, with the curve declining gently after the peak, and it was higher than that in the two cases of equal row spacing in the harvest time. The change in transmittance of the bottom layer presented the opposite trend. Density, row spacing, and their interaction had significant effects on seed cotton yield and its components. In both years, seed cotton yield was the highest (3832 kg·hm -2 in 2018, 3235 kg·hm -2 in 2019) under wide-narrow row spacing (66 cm+10 cm), and it was more stable at high densities. Fiber quality was less affected by density and row spacing. To sum up, the optimal density and row spacing of short-season cotton were as follows: density with 112500 plants·hm -2 and wide-narrow row spacing (66 cm+10 cm).

Green hydrophobically modified butyrylated dextrin (BD) was used to modulate casein (CN). The CN/BD complex nanoparticles were formed at different CN-to-BD mass ratios based on a pH-driven technology. The interaction force, stability, and emulsifying properties of complex nanoparticles were investigated. The nanoparticles had a negative charge and a small particle size (160.03, 152.6, 155.9, 206.13, and 231.67 nm) as well as excellent thermal stability and environmental stability (pH 4.5, 5.5, 6.6, 7.5, 8.5, and 9.5; ionic strength, 50, 100, 200, and 500 mM). Transmission electron microscopy demonstrated the successful preparation of complex nanoparticles and their spherical shape. Fourier transform infrared spectroscopy, fluorescence spectroscopy, and dissociation analysis results showed that the main driving forces of formed CN/BD nanoparticles were hydrogen bonding and hydrophobic interaction. Furthermore, the CN/BD nanoparticles (CN/BD mass ratio, 1:1; weight/weight) exhibited the lowest creaming index, and optical microscopy showed that it has the most evenly dispersed droplets after 7 d of storage, which indicates that the CN/BD nanoparticles had excellent emulsifying properties. Butyrylated dextrin forms complex nanoparticles with CN through hydrogen bonding and hydrophobic interaction to endow CN with superior properties. The results showed that it is possible to use pH-driven technology to form protein-polysaccharide complex nanoparticles, which provides some information on the development of novel food emulsifiers based on protein-polysaccharide nanoparticles. The study provided significant information on the improvement of CN properties and the development of emulsions based on CN., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Introduction: Itch is a common symptom of many skin and systemic diseases. Identifying novel endogenous itch mediators and the downstream signaling pathways involved will contribute to the development of new strategies for the treatment of chronic itch. In the present study, we adopted behavioral testing, patch clamp recording and metabonomics analysis to investigate the role of agmatine in itch and the underlying mechanism., Methods: Behavioral analysis was used to evaluate the establishing of acute and chronic itch mice model, and to test the effects of different drugs or agents on mice itch behavior. Western blotting analysis was used to test the effect of agmatine on phosphorylation of ERK (p-ERK) expression in the spinal cord. Patch clamp recording was used to determine the effect agmatine on the excitability of DRG neurons and the role of ASIC3. Finally, the metabonomics analysis was performed to detect the concentration of agmatine in the affected skin under atopic dermatitis or psoriasis conditions., Results: We fused a mouse model and found that an intradermal injection of agmatine (an endogenous polyamine) into the nape of the neck or cheek induced histamine-independent scratching behavior in a dose-dependent manner. In addition, the ablation of nociceptive C-fibers by resiniferatoxin (RTX) abolished agmatine-induced scratching behavior. However, agmatine-induced itch was not affected by the pharmacological inhibition of either transient receptor potential vanilloid 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1); similar results were obtained from TRPV1 -/- or TRPA1 -/- mice. Furthermore, agmatine-induced itch was significantly suppressed by the administration of acid-sensing ion channel 3 (ASIC3) inhibitors, APETx2 or amiloride. Agmatine also induced the upregulation of p-ERK in the spinal cord; this effect was inhibited by amiloride. Current clamp recording showed that the acute perfusion of agmatine reduced the rheobase and increased the number of evoked action potentials in acute dissociated dorsal root ganglion (DRG) neurons while amiloride reversed agmatine-induced neuronal hyperexcitability. Finally, we identified significantly higher levels of agmatine in the affected skin of a mouse model of atopic dermatitis (AD) when compared to controls, and the scratching behavior of AD mice was significantly attenuated by blocking ASIC3., Discussion: Collectively, these results provide evidence that agmatine is a novel mediator of itch and induces itch via the activation of ASIC3. Targeting neuronal ASIC3 signaling may represent a novel strategy for the treatment of itch., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Xu, Lu, Zhou, Feng, Zhang, Sun, Wang, Liu and Wu.)

Wilson disease (WD) is a hereditary disorder of copper metabolism, resulting from mutations within ATP7B. Early diagnosis is essential for affected individuals. However, there are still patients with clinically suspected WD who do not have detectable pathogenic variants, which makes diagnosis difficult and delays treatment. This study included such patients from the authors' center and screened for the full-length sequence of ATP7B by next-generation sequencing. Newly identified synonymous and intronic variants were then analyzed with in silico tools. A minigene system was constructed to determine the pathogenicity of these variants in terms of splicing and blood RNA extraction, and RT-PCR experiments were performed on several patients to verify the splicing alterations. The phenotypes of the patients were also analyzed. Fourteen suspected pathogenic variants, including nine synonymous and five intronic variants, were detected in 12 patients with clinically suspected WD. Among them, four synonymous variants (c.1050G>A, c.1122C>G, c.3243G>A, and c.4014T>A) and four intronic variants (c.1543 +40G>A, c.1707+6&#95;1707+16del, c.1870-49A>G, and c.2731-67A>G) resulted in splicing changes in ATP7B. After the above analysis, the diagnosis of WD could be confirmed in eight clinically suspected patients with WD who showed a late age of onset., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Birth defects, particularly those that affect development of the heart, are a leading cause of morbidity and mortality in infants and young children. Babies born with heart hypoplasia (heart hypoplasia) disorders often have a poor prognosis. It remains unclear whether cardiomyocytes from hypoplastic hearts retain the potential to recover growth, although this knowledge would be beneficial for developing therapies for heart hypoplasia disorders. The objective of this study was to determine the proliferation and maturation potential of cardiomyocytes from hypoplastic hearts and whether these behaviors are influenced by biochemical signaling from the extracellular matrix (ECM) and cyclic mechanical stretch., Method: Congenital diaphragmatic hernia (CDH)-associated heart hypoplasia was induced in rat fetuses by maternal exposure to nitrofen. Hearts were isolated from embryonic day 21 nitrofen-treated fetuses positive for CDH (CDH+) and from fetuses without nitrofen administration during gestation., Results and Discussion: CDH+ hearts were smaller and had decreased myocardial proliferation, along with evidence of decreased maturity compared to healthy hearts. In culture, CDH+ cardiomyocytes remained immature and demonstrated increased proliferative capacity compared to their healthy counterparts. Culture on ECM derived from CDH+ hearts led to a significant reduction in proliferation for both CDH+ and healthy cardiomyocytes. Healthy cardiomyocytes were dosed with exogenous nitrofen to examine whether nitrofen may have an aberrant effect on the proliferative ability of cardiomyocyte, yet no significant change in proliferation was observed. When subjected to stretch, CDH+ cardiomyocytes underwent lengthening of sarcomeres while healthy cardiomyocyte sarcomeres were unaffected. Taken together, our results suggest that alterations to environmental cues such as ECM and stretch may be important factors in the pathological progression of heart hypoplasia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Watson, Williams, Wang, Perreault, Sullivan, Stoppel and Black.)

Neutrophil extracellular traps (NETs) play crucial roles in atherosclerotic cardiovascular diseases such as acute coronary syndrome (ACS). Our preliminary study shows that oxidized low-density lipoprotein (oxLDL)-induced NET formation is accompanied by an elevated intracellular Cl - concentration ([Cl - ] i ) and reduced cystic fibrosis transmembrane conductance regulator (CFTR) expression in freshly isolated human blood neutrophils. Herein we investigated whether and how [Cl - ] i regulated NET formation in vitro and in vivo. We showed that neutrophil [Cl - ] i and NET levels were increased in global CFTR null (Cftr -/- ) mice in the resting state, which was mimicked by intravenous injection of the CFTR inhibitor, CFTR inh -172, in wild-type mice. OxLDL-induced NET formation was aggravated by defective CFTR function. Clamping [Cl - ] i at high levels directly triggered NET formation. Furthermore, we demonstrated that increased [Cl - ] i by CFTR inh -172 or CFTR knockout increased the phosphorylation of serum- and glucocorticoid-inducible protein kinase 1 (SGK1) and generation of intracellular reactive oxygen species in neutrophils, and promoted oxLDL-induced NET formation and pro-inflammatory cytokine production. Consistently, peripheral blood samples obtained from atherosclerotic ApoE -/- mice or stable angina (SA) and ST-elevation ACS (STE-ACS) patients exhibited increased neutrophil [Cl - ] i and SGK1 activity, decreased CFTR expression, and elevated NET levels. VX-661, a CFTR corrector, reduced the NET formation in the peripheral blood sample obtained from oxLDL-injected mice, ApoE -/- atherosclerotic mice or patients with STE-ACS by lowering neutrophil [Cl - ] i . These results demonstrate that elevated neutrophil [Cl - ] i during the development of atherosclerosis and ACS contributes to increased NET formation via Cl - -sensitive SGK1 signaling, suggesting that defective CFTR function might be a novel therapeutic target for atherosclerotic cardiovascular diseases., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

This study explored the influence of germination and fortification on the functionality and digestibility of brown rice from the perspective of starch structure changes. The surface of germinated brown rice starch appeared some pits and holes under the action of endogenous hydrolase, and the amylose content, relative crystallinity and short-range order of the starch decreased significantly after germination. However, the fortification treatment seemed to intensify the enzymatic hydrolysis of germinated brown rice starch, showing deeper pits, lower short-range order and less double helix structure. These changes in structural characteristics led to a significant decrease in peak viscosity, enthalpy change (ΔH) and starch hydrolysis rate after germination and fortification treatment. As the germination time increased, the trend became more obvious. And the peak viscosity and enthalpy change (ΔH) of fortified brown rice reached the minimum values of 290.89 cP and 13.73 J/g after 34 h of germination, respectively, while the starch hydrolysis rate reached the maximum value of 85.42 %. Overall, the combination of germination and fortification could be an effective method to adjust the functional and digestive characteristics of starch by changing its structural characteristics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

As the native regenerative potential of adult cardiac tissue is limited post-injury, stimulating endogenous repair mechanisms in the mammalian myocardium is a potential goal of regenerative medicine therapeutics. Injection of myocardial matrix hydrogels into the heart post-myocardial infarction (MI) has demonstrated increased cardiac muscle and promotion of pathways associated with cardiac development, suggesting potential promotion of cardiomyocyte turnover. In this study, the myocardial matrix hydrogel was shown to have native capability as an effective reactive oxygen species scavenger and protect against oxidative stress induced cell cycle inhibition in vitro. Encapsulation of cardiomyocytes demonstrated an enhanced turnover in in vitro studies, and in vivo assessments of myocardial matrix hydrogel treatment post-MI showed increased thymidine analog uptake in cardiomyocyte nuclei compared to saline controls. Overall, this study provides evidence that properties of the myocardial matrix material provide a microenvironment mitigating oxidative damage and supportive of cardiomyocytes undergoing DNA synthesis, toward possible DNA repair or cell cycle activation. STATEMENT OF SIGNIFICANCE: Loss of adult mammalian cardiomyocyte turnover is influenced by shifts in oxidative damage, which represents a potential mechanism for improving restoration of cardiac muscle after myocardial infarction (MI). Injection of a myocardial matrix hydrogel into the heart post-MI previously demonstrated increased cardiac muscle and promotion of pathways associated with cardiac development, suggesting potential in promoting proliferation of cardiomyocytes. In this study, the myocardial matrix hydrogel was shown to protect cells from oxidative stress and increase proliferation in vitro. In a rat MI model, greater presence of tissue free thiol content spared from oxidative damage, lesser mitochondrial superoxide content, and increased thymidine analog uptake in cardiomyocytes was found in matrix injected animals compared to saline controls. Overall, this study provides evidence that properties of the myocardial matrix material provide a microenvironment supportive of cardiomyocytes undergoing DNA synthesis, toward possible DNA repair or cell cycle activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. KLC is co-founder, consultant, board member, and holds equity interest in Ventrix, Inc., (Copyright © 2022. Published by Elsevier Ltd.)

Alkaline pectate lyase has developmental prospects in the textile, pulp, paper, and food industries. In this study, we selected BacPelA, the pectin lyase with the highest expression activity from Bacillus clausii, modified and expressed in Escherichia coli BL21(DE3). Through fragment replacement, the catalytic activity of the enzyme was significantly improved. The optimum pH and temperature of the modified pectin lyase (PGLA-rep4) were 11.0 and 70 °C, respectively. It also exhibited a superior ability to cleave methylated pectin. The enzyme activity of PGLA-rep4, measured at 235 nm with 0.2% apple pectin as the substrate, was 554.0 U/mL, and the specific enzyme activity after purification using a nickel column was 822.9 U/mg. After approximately 20 ns of molecular dynamics simulation, the structure of the pectin lyase PGLA-rep4 tended to be stable. The root mean square fluctuation (RMSF) values at the key catalytically active site, LYS168, were higher than those of the wildtype PGLA. In addition, PGLA-rep4 was relatively stable in the presence of metal ions. PGLA-rep4 has good enzymatic properties and activities and maintains a high pH and temperature. This study provides a successful strategy for enhancing the catalytic activity of PGLA-rep4, making it the ultimate candidate for degumming and various uses in the pulp, paper, and textile industries., (© 2022. The Author(s).)

Platelet hyperactivity is essential for thrombus formation in coronary artery diseases (CAD). Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients with cystic fibrosis elevates intracellular Cl - levels ([Cl - ] i ) and enhanced platelet hyperactivity. In this study, we explored whether alteration of [Cl - ] i has a pathological role in regulating platelet hyperactivity and arterial thrombosis formation. CFTR expression was significantly decreased, while [Cl - ] i was increased in platelets from CAD patients. In a FeCl 3 -induced mouse mesenteric arteriole thrombosis model, platelet-specific Cftr-knockout and/or pre-administration of ion channel inhibitor CFTRinh-172 increased platelet [Cl - ] i , which accelerated thrombus formation, enhanced platelet aggregation and ATP release, and increased P2Y 12 and PAR4 expression in platelets. Conversely, Cftr-overexpressing platelets resulted in subnormal [Cl - ] i , thereby decreasing thrombosis formation. Our results showed that clamping [Cl - ] i at high levels or Cftr deficiency-induced [Cl - ] i increasement dramatically augmented phosphorylation (Ser422) of serum and glucocorticoid-regulated kinase (SGK1), subsequently upregulated P2Y 12 and PAR4 expression via NF-κB signaling. Constitutively active mutant S422 D SGK1 markedly increased P2Y 12 and PAR4 expression. The specific SGK1 inhibitor GSK-650394 decreased platelet aggregation in wildtype and platelet-specific Cftr knockout mice, and platelet SGK1 phosphorylation was observed in line with increased [Cl - ] i and decreased CFTR expression in CAD patients. Co-transfection of S422 D SGK1 and adenovirus-induced CFTR overexpression in MEG-01 cells restored platelet activation signaling cascade. Our results suggest that [Cl - ] i is a novel positive regulator of platelet activation and arterial thrombus formation via the activation of a [Cl - ] i -sensitive SGK1 signaling pathway. Therefore, [Cl - ] i in platelets is a novel potential biomarker for platelet hyperactivity, and CFTR may be a potential therapeutic target for platelet activation in CAD., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

In this work, the combination treatment of zinc sulfate fortification and germination was used to increase zinc content and bioavailability of brown rice. The zinc content in brown rice during germination time of 10-34 h gradually increased with the increase of zinc sulfate concentration (0-100 mg/L). Brown rice with zinc fortified concentration of 25 mg/L and germinated for 28 h was recommended, which reached the maximum (26.31%) of zinc bioavailability and met the requirements of recommended dietary intake (RDA) of zinc. The physicochemical and structural characteristics of brown rice under different treatment conditions were compared. As the germination time prolonged, the germination rate (%), total phenol content, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging rate (%) and Gamma-aminobutyric acid content of fortified or unfortified brown rice increased, while the phytic acid content decreased. The fortification treatment improved total phenol content and antioxidant activity of germinated brown rice. The crystalline structure of brown rice was destroyed during germination, but no significant change of crystalline structure caused by zinc sulfate fortification was found. These results could provide valuable reference for the application of germination in the field of brown rice fortification and the preparation of zinc-rich germinated brown rice products., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a small Euphorbiaceae diterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types. The most active compound 6, a lathyrane diterpenoid (5/11/3 ring system), dose-dependently activated hPXR with a high selectivity, and significantly upregulated the expression of hPXR downstream genes CYP3A4 and UGT1A1. In LCA-induced cholestasis mouse model, administration of compound 6 (50 mg· kg -1 . d -1 , ip) for 7 days significantly suppressed liver necrosis and decreased serum levels of AST, ALT, Tbili, ALP, and TBA, ameliorating LCA-induced cholestatic liver injury. We further revealed that compound 6 exerted its anti-cholestatic efficacy via activation of PXR pathway, accelerating the detoxification of toxic BAs and promoting liver regeneration. These results suggest that lathyrane diterpenoids may serve as a promising scaffold for future development of anti-cholestasis drugs., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Background: Wilson's disease (WD) currently lacks a promising indicator that could reflect neurological impairment and monitor treatment outcome. We aimed to investigate whether serum neurofilament light chain (sNfL) functions as a candidate for disease assessment and treatment monitoring of WD., Methods: We assessed preclinical and manifested WD patients' sNfL levels compared to controls and analyzed the differences between patients with various clinical symptoms. We then explored the correlation between clinical scales and sNfL levels. And repeated measurements were performed in 34 patients before and after treatment., Results: WD patients with neurological involvement had significantly higher sNfL levels than both hepatic patients and controls. Positive correlations were found between Unified Wilson's Disease Rating Scale scores and sNfL and between semiquantitative magnetic resonance imaging scales and sNfL levels in WD patients. However, in the treatment follow-up analysis, the trend of sNfL before and after treatment disaccorded with clinical response., Conclusion: These findings suggest that sNfL levels can be an ideal indicator for the severity of neurological involvement but fail to evaluate change in disease condition after treatment. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

The effect of pullulanase enzymatic hydrolysis time on the textural properties of acorn vermicelli was investigated by texture analyzer. And the influencing mechanism was revealed by exploring the physicochemical properties of acorn starch under the optimum enzymatic hydrolysis time by texture analyzer, scanning electron microscopy, X-ray diffraction and brabender viscograph. After acorn starch was hydrolyzed by pullulanase for 14 h, acorn vermicelli had excellent textural properties. In addition, the enzymatic hydrolysis transformed the acorn starch from spherical particles with smooth surface to polygonal particles with rough surface, as well as transformed the crystal structure of acorn starch from C-type to B-type. Compared with native acorn starch, enzyme hydrolyzed acorn starch had higher amylose content, better freeze-thaw stability, lower swelling power and, breakdown viscosity, stronger gel strength and, higher light transmittance. These excellent properties contributed to the exceptional textural properties and quality of acorn vermicelli. The results of this study may provide valuable information on the preparation of acorn vermicelli., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The remarkable advancement of top-down proteomics in the past decade is driven by the technological development in separation, mass spectrometry (MS) instrumentation, novel fragmentation, and bioinformatics. However, the accurate identification and quantification of proteoforms, all clearly-defined molecular forms of protein products from a single gene, remain a challenging computational task. This is in part due to the complicated mass spectra from intact proteoforms when compared to those from the digested peptides. Herein, pTop 2.0 is developed to fill in the gap between the large-scale complex top-down MS data and the shortage of high-accuracy bioinformatic tools. Compared with pTop 1.0, the first version, pTop 2.0 concentrates mainly on the identification of the proteoforms with unexpected modifications or a terminal truncation. The quantitation based on isotopic labeling is also a new function, which can be carried out by the convenient and user-friendly "one-key operation," integrated together with the qualitative identifications. The accuracy and running speed of pTop 2.0 is significantly improved on the test data sets. This chapter will introduce the main features, step-by-step running operations, and algorithmic developments of pTop 2.0 in order to push the identification and quantitation of intact proteoforms to a higher-accuracy level in top-down proteomics., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Ovarian cancer (OV) is the most lethal gynecologic malignancy. One major reason of the high mortality of the disease is due to platinum-based chemotherapy resistance. Increasing evidence reveal the important biological functions and clinical significance of zinc finger proteins (ZNFs) in OV. In the present study, the relationship between the zinc finger protein 76 (ZNF76) and clinical outcome and platinum resistance in patients with OV was explored. We further analyzed ZNF76 expression via multiple gene expression databases and identified its functional networks using cBioPortal. RT-qPCR and IHC assay shown that the ZNF76 mRNA and protein expression were significantly lower in OV tumor than that in normal ovary tissues. A strong relationship between ZNF76 expression and platinum resistance was determined in patients with OV. The low expression of ZNF76 was associated with worse survival in OV. Multivariable analysis showed that the low expression of ZNF76 was an independent factor predicting poor outcome in OV. The prognosis value of ZNF76 in pan-cancer was validated from multiple cohorts using the PrognoScan database and GEPIA 2. A gene-clinical nomogram was constructed by multivariate cox regression analysis, combined with clinical characterization and ZNF76 expression in TCGA. Functional network analysis suggested that ZNF76 was involved in several biology progressions which associated with OV. Ten hub genes (CDC5L, DHX16, SNRPC, LSM2, CUL7, PFDN6, VARS, HSD17B8, PPIL1, and RGL2) were identified as positively associated with the expression of ZNF76 in OV. In conclusion, ZNF76 may serve as a promising prognostic-related biomarker and predict the response to platinum in OV patients., (© 2021 The Author(s).)

These preliminary data from an ongoing first-in-human phase 1/2, open-label study provide proof-of-concept that pluripotent stem cell-derived pancreatic endoderm cells (PEC-01) engrafted in type 1 diabetes patients become islet cells releasing insulin in a physiologically regulated fashion. In this study of 17 subjects aged 22-57 with type 1 diabetes, PEC-01 cells were implanted subcutaneously in VC-02 macroencapsulation devices, allowing for direct vascularization of the cells. Engraftment and insulin expression were observed in 63% of VC-02 units explanted from subjects at 3-12 months post-implant. Six of 17 subjects (35.3%) demonstrated positive C-peptide as early as 6 months post-implant. Most reported adverse events were related to surgical implant or explant procedures (27.9%) or to side-effects of immunosuppression (33.7%). Initial data suggest that pluripotent stem cells, which can be propagated to the desired biomass and differentiated into pancreatic islet-like tissue, may offer a scalable, renewable alternative to pancreatic islet transplants., Competing Interests: M.D., R.M.W., E.J.K., E.P.B., K.A.D., M.J., and H.L.F. are employees of ViaCyte and may have equity interest in ViaCyte, Inc., a privately held company. J.S. and J.W. are consultants for ViaCyte and may have equity interest in ViaCyte. ViaCyte has 850 global and US patents. The remaining authors declare no conflicts of interest. Funding sources for this work included the California Institute for Regenerative Medicine, JDRF, and the Stem Cell Network of Canada. These groups were not involved in the research, the writing, or the decision to submit the manuscript for publication. Authors have not been paid by a pharmaceutical company or other organization to write this article., (© 2021 The Authors.)

Aceruloplasminemia (ACP) is a rare disorder of iron overload resulting from ceruloplasmin (CP) variants. Because of its rarity and heterogeneity, the diagnosis of ACP is often missed or misdiagnosed. Here, we aim to present a clinical spectrum of ACP and raise more attention to the early diagnosis. Whole exome sequencing (WES) was performed in a Chinese female patient suspected with ACP and her clinical data were collected in detail. The PubMed databases was searched for published ACP patients within the last decade, and we present a systematic review of their clinical features with data extracted from these researches. A novel pathogenic variant (c.2689delC) and a known pathogenic variant (c.606dupA) within ceruloplasmin gene were identified in our patient and confirmed the diagnosis of ACP. Then we reviewed 51 ACP patients including the case we reported here. A possible timeline of symptoms was discovered, anemia appears first (29.7 years old on average), followed by diabetes (37.3 years old) and finally neurological symptoms (50.7 years old). The delay in diagnosis was significantly shortened in patients without neurological symptoms. Biochemical triad including anemia, low to undetectable serum ceruloplasmin, low serum iron and/or hyperferritinemia, showed better sensitivity in diagnosis than clinical triad including diabetes, neurological symptoms, and retinal degeneration. Due to the variable symptom spectrum, patients with ACP often visit different departments, which can lead to misdiagnosis. Clinical attention needs to be paid to symptoms and tests that have a warning effect. Prompt diagnosis in the early stage of the disease can be beneficial., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pregnane X receptor (PXR) that orchestrates the intricate network of xeno- and endobiotic metabolism is considered as a promising therapeutic target for cholestasis. In this study, the human PXR (hPXR) agonistic bioassay-guided isolation of Euphorbia lathyris followed by the structural modification led to the construction of a lathyrane diterpenoid library ( 1 - 34 ). Subsequent assay of this library led to the identification of a series of potent hPXR agonists, showing better efficacy than that of typical hPXR agonist, rifampicin. The most active compound, 8 , could dose-dependently activate hPXR at micromolar concentrations and significantly up-regulate the expressions of PXR downstream genes CYP3A4 , CYP2B6 , and MDR1 . The structure-activity relationships (SARs) studied in combination with molecular modeling suggested that acyloxy at C-7 and the presence of 14-carbonyl were essential to the activity. These findings suggested that lathyrane diterpenoids could serve as a new type of hPXR agonist for future anticholestasis drug development., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Ovarian cancer (OV) is the main cause of deaths worldwide in female reproductive system malignancies. Enhancer RNAs (eRNAs) are derived from the transcription of enhancers and has attracted increasing attention in cancers recently. However, the biological functions and clinical significance of eRNAs in OV have not been well described presently. We used an integrated data analysis to identify prognostic-related eRNAs in OV. Tissue-specific enhancer-derived RNAs and their regulating genes were considered as putative eRNA-target pairs using the computational pipeline PreSTIGE. Gene expression profiles and clinical data of OV and 32 other cancer types were obtained from the UCSC Xena platform. Altogether, 71 eRNAs candidates showed significant correlation with overall survival (OS) of OV samples (Kaplan-Meier log-rank test, P<0.05). Among which, 23 were determined to be correlated with their potential target genes (Spearman's r > 0.3, P<0.001). It was found that among the 23 prognostic-related eRNAs, the expression of forkhead box P4 antisense RNA 1 (FOXP4-AS1) had the highest positive correlation with its predicted target gene FOXP4 (Spearman's r = 0.61). Moreover, the results were further validated by RT-qPCR analysis in an independent OV cohort. Our results suggested the eRNA FOXP4-AS1 expression index may be a favorable independent prognostic biomarker candidate in OV., (© 2021 The Author(s).)

Objective: This study aims to evaluate the clinical application value of flash spiral mode of high-pitch dual source CT in carotid, cardiac and cerebral vessels combined one-stop imaging., Patients and Methods: A total of 100 consecutive patients were given carotid, cardiac and cerebral vessels combined one-stop imaging at flash spiral mode of high-pitch dual source CT. 27 patients received DSA examination of carotid and cerebral vessels, and 38 patients received digital subtraction angiography (DSA) examination of the coronary artery at the same time. Carotid, cardiac and cerebral vessels combined one-stop imaging was compared with "golden standard", DSA image., Results: The overall satisfaction rate of coronary arteries, extracranial segment of the carotid artery (CA-E), intracranial segment of the carotid artery (CA-I), and cerebral vessels (anterior, middle, and posterior cerebral artery) were 93%, 99%, 95% and 97% respectively, and the positive rate of hemadostenosis was consistent with DSA. The kappa value indicating consistency of cerebral, carotid and coronary artery vessels was 0.78382, 0.80654, 0.82398, respectively., Conclusions: The method of carotid, cardiac and cerebral vessels combined one-stop imaging by flash spiral mode of high-pitch dual source CT can provide high image quality. It comprehensively evaluates stenosis of carotid, cardiac and cerebral vessels, which is of great importance for early intervention in harmful events of the cardia and cerebrovascular disorder.

Background & Aims: Wilson disease is an autosomal recessive disorder that impairs copper homeostasis and is caused by homozygous or compound heterozygous mutations in ATP7B, which encodes a copper-transporting P-type ATPase. Patients have variable clinical manifestations and laboratory test results, resulting in diagnostic dilemmas. We aimed to identify factors associated with symptoms and features of Wilson disease from a large cohort, over 15 years., Methods: We collected data from 715 patients (529 with symptoms, 146 without symptoms, and 40 uncategorized) and a genetic confirmation of Wilson's disease (mean age of diagnosis, 18.84 years), recruited from 3 hospitals in China from 2004 through 2019. We analyzed clinical data along with serum levels of ceruloplasmin (available from 636 patients), 24-hr urinary copper excretion (collected from 131 patients), Kayser-Fleisher rings (copper accumulation in eyes, with neurologic data from 355 patients), and magnetic resonance imaging (MRI) abnormalities. Differences among the groups were analyzed using 1-way analysis of variance followed by Tukey multiple comparison test., Results: Of the 529 patients with symptoms, 121 had hepatic features, 355 had neurologic features, 28 had osteomuscular features (premature osteoarthritis, skeletal deformities, and pathological bone fractures), and 25 had psychiatric symptoms. Age of onset was significantly younger in patients with hepatic (16.94 ± 1.03 years; P = .0105) or osteomuscular features (13 ± 1.33 years; P = .0001) than patients with neurological features (19.48 ± 0.46 years). Serum levels of ceruloplasmin differed among asymptomatic patients and patients with osteomuscular or neurologic symptoms of Wilson disease. Serum levels of ceruloplasmin ranged from 18.93 mg/L to approximately 120.00 mg/L (quantiles of 0.025 to approximately 0.975). Fifty-one of 131 patients (39%) had urinary copper excretion levels below 100 μg/24 hr; there was significant variation in levels of urinary copper excretion between patients older than 14 years vs 14 years or younger. Of the 355 patients with neurologic features, 244 patients (69%) had abnormal findings from MRI and Kayser-Fleisher rings; only 1 patient with abnormal findings from brain MRI was negative for Kayser-Fleisher rings., Conclusions: Serum level of ceruloplasmin, 24-hour urinary copper excretion, and Kayser-Fleisher rings can be used to identify patients who might have Wilson disease. Patients with serum levels of ceruloplasmin below 120 mg/L and children with urinary copper excretion above 40 μg should undergo genetic testing for Wilson's disease. Patients with movement disorders and brain MRI abnormalities without Kayser-Fleisher rings are not likely to have Wilson disease., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Wilson's disease (WD) is an autosomal recessive disorder caused by ATP7B pathogenic variants. This study aimed to show the geographical distribution and haplotype spectrum of three prevalent pathogenic variants (p.R778L, p.P992L, p.T935M) in mainland Chinese population and clarify whether the founder effect may account for their origins. We firstly summarized the frequency and geographical distribution of p.R778L, p.P992L and p.T935M in 715 WD patients. Then, to construct haplotypes associated with the three variants, Sanger sequencing and microsatellite typing at three dinucleotide-repeat markers (D13S314, D13S301, D13S316) flanking the ATP7B gene were performed in 102 WD families. An obvious regional-specific distribution feature was found in p.T935M. Linkage disequilibrium at the three markers was shown in all the three variants and we found the common haplotypes specific for p.R778L, p.P992L and p.T935M respectively, represented successively by 10-7-7, 10-9-5 and 12-4-8, which all exhibited great significance vs. the control chromosomes ( p < 0.01). Meanwhile, haplotypes for the three variants differed from the studies in other regions to some extent. The common haplotypes we found indicate that three prevalent pathogenic variants emerge due to the founder effect. Furthermore, the study contributes to expand our knowledge of the genetic diversity of WD from a cross-regional perspective.