Nanozymes have emerged as enzyme-mimicking nanomaterials to overcome the low stability and high cost of some natural enzymes. The design and fabrication of nanozymes with superior performance to natural enzymes are in urgent demand. Single-atom catalysts offer the unique characteristics of maximum atomic utilization, and are an excellent candidate for nanozymes. However, most of the reported synthesis methods for single-atom catalysts require the preparation of supports for single-atom catalysts in advance, which requires multiple steps and calcination in a high temperature atmosphere. Herein, Cu-N-C single-atom nanozymes (Cu-N-C SAzymes) were successfully designed via a one-pot solvothermal method. Cu-N-C SAzymes exhibited excellent peroxidase-mimicking activity that is superior to some other related nanoparticles. The mechanism study revealed that H2O2 was catalyzed by Cu-N-C SAzymes to generate reactive oxygen species. Furthermore, based on the excellent peroxidase-mimicking activity of the Cu-N-C SAzymes, a simple and sensitive detection method for H2O2 and glucose has been developed.In this article, we report a novel dual on/off thrombin fluorescence aptasensor by combining the energy driven target induced strand displacement reaction and a non-enzyme catalyst recycling DNA machine. Firstly, the specific binding of an aptamer strand and thrombin induce the release of a catalyst which was used as a DNA machine trigger. Subsequently, the catalyst as the trigger initiated the DNA machine through nucleic acid hybridization and branch migration of the DNA machine, resulting in the DNA substrate melting and re-hybridization. In such a working model, the DNA machine achieved cooperative control of the circular strand displacement reaction, realizing catalyst recycling and dual-amplification. The fluorescence signal change of FAM and ROX accumulation had a good linear relationship with the thrombin concentration in the range of 1 fM to 1 nM. On account of catalyst recycling and dual recognition, the detection limit for thrombin was determined to be as low as 0.45 fM (S/N = 3).This biosensor also showed good selectivity for thrombin without being affected by some other proteins, such as PSA, lysozyme etc. Moreover, this assay can be applied to the detection of thrombin in diluted human serum.Injectable, drug-releasing hydrogel scaffolds with multifunctional properties including hemostasis and anti-bacterial activity are essential for successful wound healing; however, designing ideal materials is still challenging. Herein, we demonstrate the fabrication of a biodegradable, temperature-pH dual responsive supramolecular hydrogel (SHG) scaffold based on sodium alginate/poly(N-vinyl caprolactam) (AG/PVCL) through free radical polymerization and the subsequent chemical and ionic cross-linking. A natural therapeutic molecule, tannic acid (TA)-incorporated SHG (AG/PVCL-TA), was also fabricated and its hemostatic and wound healing efficiency were studied. In the AG/PVCL-TA system, TA acts as a therapeutic molecule and also substitutes as an effective gelation binder. Notably, the polyphenol-arm structure and diverse bonding abilities of TA can hold polymer chains through multiple bonding and co-ordinate cross-linking, which were vital in the formation of the mechanically robust AG/PVCL-TA. The SHG formation was successfully balanced by varying the composition of SA, VCL, TA and cross-linkers. The AG/PVCL-TA scaffold was capable of releasing a therapeutic dose of TA in a sustained manner under physiological temperature-pH conditions. AG/PVCL-TA displayed excellent free radical scavenging, anti-inflammatory, anti-bacterial, and cell proliferation activity towards the 3T3 fibroblast cell line. The wound healing performance of AG/PVCL-TA was further confirmed in skin excision wound models, which demonstrated the potential application of AG/PVCL-TA for skin regeneration and rapid wound healing.A sensitive As(iii) ion detection method has been developed based on ion-mediated self-assembly of cysteine (Cys)-capped quantum dots (QDs), and fluorescence self-quenching. A variety of Cys-capped core/shell CdTe/CdS QDs were prepared via hydrothermal methods. Based on the coordination binding between the As(iii) ion and cystine groups anchored on the QDs, addition of As(iii) ions led to self-assembly of the Cys-capped QDs, which was accompanied by fluorescence self-quenching. The fluorescence response was attributed to the exciton energy transfer of the QD aggregates. The ion-mediated fluorescence quenching was further exploited for quantitative determination of As(iii) ions in water. A limit of detection (LOD) of 10 ng L-1 (3σ method) and a linear range from 14 to 70 ng L-1 were obtained for the sensing of As(iii) ions. The system was evaluated using a series of interference targets, and demonstrated high selectivity after addition of mask agents. Finally, the proposed method was successfully employed for the detection of As(iii) in a real water sample. The method was sensitive and specific, and shows great promise in quantitative determination of heavy metal ions in lakes and rivers.Fludarabine, cyclophosphamide, and rituximab (FCR) is highly effective initial therapy for younger patients with chronic lymphocytic leukemia (CLL); however, most eventually relapse. Duvelisib is a delta/gamma PI3K inhibitor approved for relapsed/refractory CLL. We conducted an investigator-initiated, phase 1b/2 study of duvelisib + FCR (DFCR) as initial treatment for CLL patients aged ≤65. A standard 3 + 3 design included two dose levels of duvelisib (25 mg qd and 25 mg bid). Duvelisib was given for 1 week, then with standard FCR added for up to six 28-day cycles, then up to 2 years of duvelisib maintenance. Thirty-two patients were enrolled. The phase 2 dose of duvelisib was identified as 25 mg bid. Hematologic toxicity was common, and all-grade non-hematologic toxicities included transaminitis (28%), febrile neutropenia (22%), pneumonia (19%), and colitis (6%). The best overall response rate by ITT was 88% (56% CR/CRi and 32% PR). The best rate of bone marrow undetectable minimal residual disease (BM-uMRD) by ITT was 66%. The rate of CR with BM-uMRD at end of combination treatment (primary endpoint) was 25%. Three-year PFS and OS are 73 and 93%, respectively. DFCR is active as initial therapy of younger CLL patients. Immune-mediated and infectious toxicities occurred and required active management.We assessed the epidemiologic progress against childhood and adolescent acute lymphoblastic leukaemia (ALL) in the Netherlands over a 26 year period. ALL patients less then 18 years were selected from the Netherlands Cancer Registry and the Dutch Childhood Oncology Group. Trend analyses were performed over time and by age group and ALL subtype. Between 1990 and 2015, 2997 ALL patients were diagnosed, i.e. 115 patients (range 87-147) per year. Overall incidence remained stable at 37 per million children, despite increases for B-cell precursor ALL (BCP-ALL) at age 10-14 years (AAPC + 1.4%, p = 0.04) and T-cell ALL at 15-17 years (AAPC + 3.7%, p = 0.01). Five-year survival increased from 80% in 1990-94 to 91% in 2010-15 (p  less then  0.01). Mortality decreased by 4% annually (p  less then  0.01). Patients 15-17 years were increasingly treated in a paediatric oncology centre, from 35% in 1990-94 to 87% in 2010-15 and experienced a 70% reduction of risk of death compared to those treated outside such a centre (p  less then  0.01). Significant progress against childhood ALL has been made in the Netherlands, visible by improved survival rates coinciding with declining mortality rates. These outcomes were accompanied by stable incidence rates, despite increases for BCP-ALL at age 10-14 years and T-cell ALL at age 15-17 years.EZH1 and EZH2 are enzymatic components of polycomb repressive complex (PRC) 2, which catalyzes histone H3K27 tri-methylation (H3K27me3) to repress the transcription of PRC2 target genes. We previously reported that the hematopoietic cell-specific Ezh2 deletion (Ezh2Δ/Δ) induced a myelodysplastic syndrome (MDS)-like disease in mice. We herein demonstrated that severe PRC2 insufficiency induced by the deletion of one allele Ezh1 in Ezh2-deficient mice (Ezh1+/-Ezh2Δ/Δ) caused advanced dyserythropoiesis accompanied by a differentiation block and enhanced apoptosis in erythroblasts. p53, which is activated by impaired ribosome biogenesis in del(5q) MDS, was specifically activated in erythroblasts, but not in hematopoietic stem or progenitor cells in Ezh1+/-Ezh2Δ/Δ mice. Cdkn2a, a major PRC2 target encoding p19Arf, which activates p53 by inhibiting MDM2 E3 ubiquitin ligase, was de-repressed in Ezh1+/-Ezh2Δ/Δ erythroblasts. The deletion of Cdkn2a as well as p53 rescued dyserythropoiesis in Ezh1+/-Ezh2Δ/Δ mice, indicating that PRC2 insufficiency caused p53-dependent dyserythropoiesis via the de-repression of Cdkn2a. Since PRC2 insufficiency is often involved in the pathogenesis of MDS, the present results suggest that p53-dependent dyserythropoiesis manifests in MDS in the setting of PRC2 insufficiency.The remarkable success of immune checkpoint inhibitors demonstrates the potential of tumour-specific CD8+ T cells to prevent and treat cancer. Although the number of lives saved by immunotherapy mounts, only a relatively small fraction of patients are cured. Here, we review two of the factors that limit the application of CD8+ T cell immunotherapies difficulties in identifying tumour-specific peptides presented by MHC class I molecules and the ability of tumour cells to impair antigen presentation as they evolve under T cell selection. We describe recent advances in understanding how peptides are generated from non-canonical translation of defective ribosomal products, relate this to the dysregulated translation that is a feature of carcinogenesis and propose dysregulated translation as an important new source of tumour-specific peptides. We discuss how the synthesis and function of components of the antigen-processing and presentation pathway, including the recently described immunoribosome, are manipulated by tumours for immunoevasion and point to common druggable targets that may enhance immunotherapy.An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

In the current study, we explore the feasibility of detecting exfoliated prostate cancer cells in urine using an RNA in situ hybridization (RISH) assay. We hypothesized that robust and specific labeling of prostate cancer cells could be achieved in post-digital rectal examination (DRE) urine samples using RISH.

We focused on method development, optimization, and analytical evaluation of RISH-based detection of prostate cancer in urine. We optimized a sample collection, processing, and target detection workflow for urine cytology specimens in conjunction with RNA target detection by RISH. We screened a panel of 11 prostate-specific RNA targets, and selected NKX3-1 and PRAC1 as markers for cells of prostate origin and PCA3 as a marker of prostate malignancy. Following analytical validation of a multiplexed NKX3-1/PRAC1/PCA3 assay, we evaluated whether prostate cancer cells can be detected in a pilot cohort of 19 post-DRE specimens obtained from men diagnosed with prostate cancer.

Using cytology specimens s proof-of-principle study provides evidence supporting the application of RISH as a potential noninvasive tool for prostate cancer detection.Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line antiandrogen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on antiandrogen therapies is only 8-19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR signaling in regulating the transcriptome of prostate cancer cells. The ression and development of resistance to treatment with bicalutamide and enzalutamide.Non-small cell lung cancer (NSCLC) is the major cause of cancer-associated death worldwide, but its underlying mechanisms remain to be fully elucidated. Long noncoding RNAs (lncRNAs) are known to play an important role in the aberrant regulation of gene expression in many cancers, including NSCLC. Here, we investigated the involvement of the lncRNA KTN1-AS1 in NSCLC. We found that KTN1-AS1 expression was upregulated in NSCLC tissue and was positively associated with poor prognosis. KTN1-AS1 knockdown inhibited cell growth and proliferation, increased apoptosis, and modulated the expression of cell cycle- and apoptosis-related proteins (cyclin A1, cyclin-dependent kinase 2, Bcl2, and Bax) in NSCLC cell lines and tumour xenografts in nude mice. KTN1-AS1 bound to and directly regulated the expression of miR-130a-5p. Notably, miR-130a-5p overexpression suppressed NSCLC cell proliferation and increased apoptosis in vitro and in vivo, and this effect was reversed by KTN1-AS1 overexpression. Finally, we showed that KTN1-AS1 modulated the expression of 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a miR-130a-5p target and key regulator of autophagy in NSCLC cells. Taken together, our results suggest that the KTN1-AS1/miR-130a-5p/PDPK1 pathway may be a potential therapeutic target for NSCLC.The original version of this Article contained an error in the spelling of the author Chan FL, which was incorrectly given as leung Chan F. This has now been corrected in both the PDF and HTML versions of the Article.After publication of this Article, the Authors noticed errors in some of the Figures. In Figures 2e, 2f-g, 4a, 4j, 5a and 6b, unmatched β-actin was inadvertently used as loading control for the immunoblots. These have been corrected using repeat data from a similar set of samples and the revised Figures containing matched β-actin and their respective quantification data are included below. In Figure 7a, the same image was inadvertently used to represent tumors 3 and 5 in the control group. This error has been corrected using original images of tumors 3 and 5 in the control group. Additional corrections have been made in the Article and Figure legends to enhance the clarity of the description. NAD was replaced by NADP. NAD/NADP was replaced by NADP/NADPH. The description of the antibody source and dilution for the antigens PFKFB4 (Abcam, 11000), G6PD, and HK1 (Cell Signaling, 11,000) have been included in the Methods section for Western Blot. The legend for Figure 4e and 4j has been updated. The HTML and PDF versions of this Article have been corrected. The scientific conclusions of this paper have not been affected.Glioma reported to be refractory to EGFR tyrosine kinase inhibitor is the most common malignant tumor in central nervous system. Our research showed the low expression of miR-450a-5p and high expression of EGFR in glioma tissues. MiR-450a-5p was also observed to synergize with gefitinib to inhibit the proliferation, migration and invasion and induce the apoptosis and autophagy of glioma cells. Furthermore, miR-450a-5p was demonstrated to target 3’UTR of EGFR, and regulated EGFR-induced PI3K/AKT/mTOR signaling pathway. Moreover, the above effects induced by miR-450a-5p in glioma cells were reversed by WIPI1 silencing. The inhibition role of miR-450a-5p on glioma growth was also confirmed in vivo by subcutaneous and intracranial tumor xenografts. Therefore, we conclude that miR-450a-5p synergizes with gefitinib to inhibit the glioma tumorigenesis through inducing autophagy by regulating the EGFR-induced PI3K/AKT/mTOR signaling pathway, thereby enhancing the drug sensitivity of gefitinib.COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.

In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728.

Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts one with 2685 CHD cases versus 4370 . These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies.

We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2.

A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.

A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.

Biallelic CAD variants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment.

Retrospective case series of 20 patients.

Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients.

We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.

We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.

Health-care practitioners’ (HCPs) preferences for returning secondary findings (SFs) will influence guideline compliance, shared decision-making, and patient health outcomes. This study aimed to estimate HCPs’ preferences and willingness to support the return (WTSR) of SFs in Canada.

A discrete choice experiment estimated HCPs’ preferences for the following attributes disease risk, clinical utility, health consequences, prior experience, and patient preference. We analyzed responses with an error component mixed logit model and predicted WTSR using scenario analyses.

Two hundred fifty participants of 583 completed the questionnaire (completion rate 42.9%). WTSR was significantly influenced by patient preference and SF outcome characteristics. HCPs’ WTSR was 78% (95% confidence interval 74-81%) when returning SFs with available medical treatment, high penetrance, severe health consequences, and patient’s preference for return. Genetics professionals had a higher WTSR than HCPs of other types when returning SFs with clinical utility and patient preference to know. HCPs >55 years of age were more likely to return SFs compared with younger HCPs.

This study identified factors that influence WTSR of SFs and indicates that HCPs make tradeoffs between patient preference and other outcome characteristics. The results can inform clinical scenarios and models aiming to understand shared decision-making, patient and family opportunity to benefit, and cost-effectiveness.

This study identified factors that influence WTSR of SFs and indicates that HCPs make tradeoffs between patient preference and other outcome characteristics. The results can inform clinical scenarios and models aiming to understand shared decision-making, patient and family opportunity to benefit, and cost-effectiveness.

Copy-number variants (CNVs) of uncertain clinical significance are routinely reported in a clinical setting only when exceeding predetermined reporting thresholds, typically based on CNV size. Given that very few genes are associated with triplosensitive phenotypes, it is not surprising that many interstitial duplications <1 Mb are found to be inherited and anticipated to be of limited or no clinical significance.

In an effort to further refine our reporting criteria to maximize diagnostic yield while minimizing the return of uncertain variants, we performed a retrospective analysis of all clinical microarray cases reported in a 10-year window. A total of 1112 reported duplications had parental follow-up, and these were compared by size, RefSeq gene content, and inheritance pattern. De novo origin was used as a rough proxy for pathogenicity.

Approximately 6% of duplications 500 kb-1 Mb were de novo observations, compared with approximately 14% for 1-2 Mb duplications (p = 0.0005). On average, de novo duplications had higher gene counts than inherited duplications.

Our data reveal limited diagnostic utility for duplications of uncertain significance <1 Mb. Considerations for revised reporting criteria are discussed and are applicable to CNVs detected by any genome-wide exploratory methodology, including exome/genome sequencing.

Our data reveal limited diagnostic utility for duplications of uncertain significance less then 1 Mb. Considerations for revised reporting criteria are discussed and are applicable to CNVs detected by any genome-wide exploratory methodology, including exome/genome sequencing.The conspicuous bright golden to orange-reddish coloration of species of the basidiomycete genus Laetiporus is a hallmark feature of their fruiting bodies, known among mushroom hunters as the „chicken of the woods”. This report describes the identification of an eight-domain mono-modular highly reducing polyketide synthase as sole enzyme necessary for laetiporic acid biosynthesis. Heterologous pathway reconstitution in both Aspergillus nidulans and Aspergillus niger verified that LpaA functions as a multi-chain length polyene synthase, which produces a cocktail of laetiporic acids with a methyl-branched C26-C32 main chain. Laetiporic acids show a marked antifungal activity on Aspergillus protoplasts. Given the multiple products of a single biosynthesis enzyme, our work underscores the diversity-oriented character of basidiomycete natural product biosynthesis.Inadequate vitamin D nutritional status is prevalent worldwide and has been associated with autoimmune disorders, heart disease, deadly cancers, insulin resistance, inflammation, neurological disorders, adverse outcomes in pregnancy, and increased risk for mortality. Expert recommendations for vitamin D intake differ between governmental agencies and practice guidelines from medical societies due to differences in the definition of vitamin D deficiency, insufficiency and sufficiency based on serum 25-hydroxyvitamin D [25(OH)D] concentrations. In addition, separate health promotion bodies also provide targeted recommendations for the prevention of specific disorders such as reducing risk for developing some cancers and autoimmune diseases. We review and provide perspectives regarding various recommendations from the Institute of Medicine (IOM, United States) and Health Canada, the European Food Safety Authority (EFSA), the Scientific Advisory Committee on Nutrition (SACN; United Kingdom), the World Health Organization, the Endocrine Society and other expert groups by life stage as a guide intended for clinician use.Green tea is commonly consumed in China, Japan, and Korea and certain parts of North Africa and is gaining popularity in other parts of the world. The aim of this review was to objectively evaluate the existing evidence related to green tea consumption and various health outcomes, especially cancer, cardiovascular disease and diabetes. This review captured evidence from meta-analyses as well as expert reports and recent individual studies. For certain individual cancer sites endometrial, lung, oral and ovarian cancer, and non-Hodgkins lymphoma the majority of meta-analyses observed an inverse association with green tea. Mixed findings were observed for breast, esophageal, gastric, liver and a mostly null association for colorectal, pancreatic, and prostate cancer. No studies reported adverse effects from green tea related to cancer although consuming hot tea has been found to possibly increase the risk of esophageal cancer and concerns of hepatotoxity were raised as a result of high doses of green tea. The literature overall supports an inverse association between green tea and cardiovascular disease-related health outcomes. The evidence for diabetes-related health outcomes is less convincing, while the included meta-analyses generally suggested an inverse association between green tea and BMI-related and blood pressure outcomes. Fewer studies investigated the association between green tea and other health outcomes such as cognitive outcomes, dental health, injuries and respiratory disease. This review concludes that green tea consumption overall may be considered beneficial for human health.The COVID-19 pandemic and the resulting social changes that were required to slow the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) have resulted in lockdowns across many countries and led to substantial numbers of people being quarantined. For single people, their opportunities to meet a partner were completely lost. For couples who lived apart, this meant that they were not able to see their partner for many months. However, by contrast, for cohabiting couples, lockdown meant that they were forced to spend 24 h a day with each other, and perhaps their children or housemates, for months at a time. As lockdowns have loosened around the world, the possibility of a second wave arises, and lockdowns are being reinstated in many regions. The prospect of potential long-term lockdowns means that adjusting to this new normal in relationships is an important consideration. In this Viewpoint, three specialists in sexology and psychology discuss the effects of lockdown on intimacy and consider how it can be considered an opportunity as well as an obstacle for making love in the time of corona.Discarding by fisheries is one of the most wasteful human marine activities, yet we have few estimates of its scale. Reliable estimates of global discards are essential for sustainable fisheries management. Using United Nations Food and Agriculture Organization databases on country-specific landings, we estimated the discard rate and magnitude for global marine and estuarine capture fisheries using fishery-specific discard rates derived from direct observations and global gear-specific discard rates estimated within a Bayesian modelling framework. An estimated 9.1 million tonnes are discarded annually (95% uncertainty interval 7-16 M t)-or 10.8% of the global catch (95% UI 10-12%). Encouragingly, this is about half of the annual global discard rate estimated in the late 1980s. Trawl fisheries, especially demersal otter trawls, warrant intensified efforts to reduce discards. Periodic benchmarks of global discards are needed to assess the performance of reduction efforts.Depression and anxiety are common comorbidities in breast cancer patients. Whether depression and anxiety are associated with breast cancer progression or mortality is unclear. Herein, based on a systematic literature search, 17 eligible studies involving 282,203 breast cancer patients were included. The results showed that depression was associated with cancer recurrence [1.24 (1.07, 1.43)], all-cause mortality [1.30 (1.23, 1.36)], and cancer-specific mortality [1.29 (1.11, 1.49)]. However, anxiety was associated with recurrence [1.17 (1.02, 1.34)] and all-cause mortality [1.13 (1.07, 1.19)] but not with cancer-specific mortality [1.05 (0.82, 1.35)]. Comorbidity of depression and anxiety is associated with all-cause mortality [1.34 (1.24, 1.45)] and cancer-specific mortality [1.45 (1.11, 1.90)]. Subgroup analyses demonstrated that clinically diagnosed depression and anxiety, being female and of younger age ( less then 60 years), and shorter follow-up duration (≤5 years) were related to a poorer prognosis. Our study highlights the critical role of depression/anxiety as an independent factor in predicting breast cancer recurrence and survival. Further research should focus on a favorable strategy that works best to improve outcomes among breast cancer patients with mental disorders.Since the beginning of the coronavirus disease 2019 (COVID-19) outbreak initiated on the Diamond Princess Cruise Ship at Yokohama harbor in February 2020, we have been doing our best to treat COVID-19 patients. In animal experiments, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) are reported to suppress the downregulation of angiotensin converting enzyme 2 (ACE2), and they may inhibit the worsening of pathological conditions. We aimed to examine whether preceding use of ACEIs and ARBs affected the clinical manifestations and prognosis of COVID-19 patients. One hundred fifty-one consecutive patients (mean age 60 ± 19 years) with polymerase-chain-reaction proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who were admitted to six hospitals in Kanagawa Prefecture, Japan, were analyzed in this multicenter retrospective observational study. Among all COVID-19 patients, in the multiple regression analysis, older age (age ≥ 65 years) was significantly associated with the primary composite outcome (odds ratio (OR) 6.63, 95% confidence interval (CI) 2.28-22.78, P  less then  0.001), which consisted of (i) in-hospital death, (ii) extracorporeal membrane oxygenation, (iii) mechanical ventilation, including invasive and noninvasive methods, and (iv) admission to the intensive care unit. In COVID-19 patients with hypertension, preceding ACEI/ARB use was significantly associated with a lower occurrence of new-onset or worsening mental confusion (OR 0.06, 95% CI 0.002-0.69, P = 0.02), which was defined by the confusion criterion, which included mild disorientation or hallucination with an estimation of medical history of mental status, after adjustment for age, sex, and diabetes. In conclusion, older age was a significant contributor to a worse prognosis in COVID-19 patients, and ACEIs/ARBs could be beneficial for the prevention of confusion in COVID-19 patients with hypertension.HIV-associated neurocognitive deficits include impaired speed-of-information processing (SIP) and motor functions. There is lack of Cameroonian adult norms for assessing SIP or motor functions. This study of 683 Cameroonians (320 HIV+, 363 HIV-) establishes demographically-adjusted norms for six SIP [Wechsler-Adult-Intelligence-Scale (WAIS)-III Digit Symbol (WAIS-IIIDS) and Symbol Search (WAIS-IIISS), Stroop Color-Naming, Stroop Word-Reading, Trail-Making Test-A (TMT-A), Color Trails-1 (CTT1)], and two motor function [Grooved Pegboard-dominant (GP-DH) and non-dominant (GP-NDH) hands] tests. We assessed viral effects on SIP and motor functions. HIV-infected persons had significantly lower (worse) T scores on GP-DH, WAIS-IIIDS, Stroop Word-Reading, TMT-A; lower motor and SIP summary T scores. Significantly higher proportion of cases (20.7%) than controls (10.3%) had impaired SIP. Male cases had better T scores than female cases on GP-NDH, WAIS-IIIDS, WAIS-IIISS, TMT-A, CTT1; better SIP summary T scores. Antiretroviral therapy (ART) was associated with significantly better T scores on GP-NDH, WAIS-IIIDS, Stroop Color-Naming; better motor and SIP summary T scores. Cases with higher CD4 had better T scores on WAIS-IIIDS, TMT-A, CTT1; better SIP summary T scores. Overall, we demonstrate that HIV infection in Cameroon is associated with deficits in SIP and motor functions; ART and higher CD4 are associated with better cognitive performance. We provide SIP and psychomotor functions normative standards, which will be useful for neurobehavioral studies in Cameroon of diseases affecting the brain.Long non-coding RNA (lncRNA) is characterized by biological function in diverse cancers. LncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) is well acknowledged to regulate various cancers, while its role in bladder cancer remains unclear. In the present study, we aimed at probing into the impact and detailed mechanisms of KCNQ1OT1 in bladder cancer progression. In this study, we demonstrated that KCNQ1OT1 expression in bladder cancer tissues was notably up-regulated compared with in normal adjacent tissues, and KCNQ1OT1 modulated the malignant phenotypes of bladder cancer cells. Moreover, it was validated that KCNQ1OT1 could specifically bind to miR-218-5p and reduce its expression. Overexpressed miR-218-5p would inhibit the proliferation and metastasis of bladder cancer cells while facilitating apoptosis. In terms of Mechanism, Heparan Sulfate-Glucosamine 3-Sulfotransferase 3B1 (HS3ST3B1) was validated as a target gene of miR-218-5p, and could be regulated by KCNQ1OT1 indirectly. In conclusion, KCNQ1OT1 can promote the progression of bladder cancer through regulation of miR-218-5p/HS3ST3B1, which is expected to serve as a new therapeutic target for bladder cancer.Fibre optic technology is rapidly evolving, driven mainly by telecommunication and sensing applications. Excellent reliability of the manufacturing processes and low cost have drawn ever increasing attention to fibre-based sensors, e.g. for studying mechanical response/limitations of aerospace composite structures. Here, a vector bending and orientation distinguishing curvature sensor, based on asymmetric coupled multi-core fibre, is proposed and experimentally demonstrated. By optimising the mode coupling effect of a seven core multi-core fibre, we have achieved a sensitivity of – 1.4 nm/° as a vector bending sensor and – 17.5 nm/m-1 as a curvature sensor. These are the highest sensitivities reported so far, to the best of our knowledge. In addition, our sensor offers several advantages such as repeatability of fabrication, wide operating range and small size and weight which benefit its sensing applications.Measuring handgrip strength is the initial step to diagnose sarcopenia. To investigate whether the serum creatinine (Cr)/cystatin C (CysC) ratio could serve as a case-finding tool for low handgrip strength, we conducted a diagnostic accuracy study. Adults (aged ≥ 40 years) with normal renal function were recruited. Trained nurses collected blood samples and conducted the anthropometric measurements and handgrip strength test. The serum concentrations of Cr, CysC, and other biomarkers were measured. We recruited 1098 men and 1241 women. The Cr/CysC ratio was significantly associated with AWGS-defined low handgrip strength among men and women. The areas under the receiver operating characteristic curves were 0.79 among men and 0.78 among women for using the Cr/CysC ratio to identify AWGS-defined low handgrip strength. We set the Cr/CysC ratio cut-off values at  less then  8.9 among men and  less then  8.0 among women. The corresponding sensitivity values were 64.9% among men and 63.1% among women, while the specificity values were 83.7% among men and 77.5% among women. In conclusion, the Cr/CysC ratio is positively and linearly associated with handgrip strength and may be helpful for screening low handgrip strength in Chinese middle-aged and older adults dwelling in communities.Deep-sea hydrothermal plumes are considered natural laboratories for understanding ecological and biogeochemical interactions. Previous studies focused on interactions between microorganisms and inorganic, reduced hydrothermal inputs including sulfur, hydrogen, iron, and manganese. However, little is known about transformations of organic compounds, especially methylated, sulfur-containing compounds, and petroleum hydrocarbons. Here, we reconstructed nine gammaproteobacterial metagenome-assembled genomes, affiliated with Methylococcales, Methylophaga, and Cycloclasticus, from three hydrothermal ecosystems. We present evidence that these three groups have high transcriptional activities of genes encoding cycling of C1-compounds, petroleum hydrocarbons, and organic sulfur in hydrothermal plumes. This includes oxidation of methanethiol, the simplest thermochemically-derived organic sulfur, for energy metabolism in Methylococcales and Cycloclasticus. Together with active transcription of genes for thiosulfate and methane oxidation in Methylococcales, these results suggest an adaptive strategy of versatile and simultaneous use of multiple available electron donors. Meanwhile, the first near-complete MAG of hydrothermal Methylophaga aminisulfidivorans and its transcriptional profile point to active chemotaxis targeting small organic compounds. Petroleum hydrocarbon-degrading Cycloclasticus are abundant and active in plumes of oil spills as well as deep-sea vents, suggesting that they are indigenous and effectively respond to stimulus of hydrocarbons in the deep sea. These findings suggest that these three groups of Gammaproteobacteria transform organic carbon and sulfur compounds via versatile and opportunistic metabolism and modulate biogeochemistry in plumes of hydrothermal systems as well as oil spills, thus contributing broad ecological impact to the deep ocean globally.Perturbed ecosystems may undergo rapid and non-linear changes, resulting in 'regime shifts’ to an entirely different ecological state. The need to understand the extent, nature, magnitude and reversibility of these changes is urgent given the profound effects that humans are having on the natural world. General ecosystem models, which simulate the dynamics of ecosystems based on a mechanistic representation of ecological processes, provide one novel way to project ecosystem changes across all scales and trophic levels, and to forecast impact thresholds beyond which irreversible changes may occur. We model ecosystem changes in four terrestrial biomes subjected to human removal of plant biomass, such as occurs through agricultural land-use change. We find that irreversible, non-linear responses commonly occur where removal of vegetation exceeds 80% (a level that occurs across nearly 10% of the Earth’s land surface), especially for organisms at higher trophic levels and in less productive ecosystems. Very large, irreversible changes to ecosystem structure are expected at levels of vegetation removal akin to those in the most intensively used real-world ecosystems. Our results suggest that the projected twenty-first century rapid increases in agricultural land conversion may lead to widespread trophic cascades and in some cases irreversible changes to ecosystem structure.Perturbations in fatty acid (FA) metabolism as well as thinning of the cerebral cortex have been associated with cognitive decline in the elderly. Predominant FAs in the brain are docosahexaenoic acid (DHA) and arachidonic acid (ARA). Approximately 2-8% of esterified DHA and 3-5% of esterified ARA in the brain are replaced daily. DHA and ARA are derivatives of 18-carbon essential FAs, α-linolenic acid and linoleic acid, that must be imported into the brain from the circulation. In blood, FAs are primarily transported in triacylglycerols (TAGs) from which they can be released at the blood-brain-barrier and transported inside the brain. We show that circulating levels of TAGs carrying 18-carbon FAs are positively associated with cortical thickness in middle-aged adults. These associations are stronger in cortical regions with higher expression of genes regulating long-chain FA metabolism and cellular membranes, and cortical thickness in the same regions may be related to cognitive performance.Graft failure (GF) is a life-threatening complication after allogeneic stem cell transplantation. Although salvage cord blood transplantation (CBT) is a curative therapy for GF, the optimal immunosuppression after salvage CBT remains unknown. Using nationwide registration data, we compared the transplant outcomes of patients who developed GF and underwent salvage CBT using immunosuppressants, including calcineurin (CNI) alone (n = 177); CNI plus methotrexate (CNI+MTX, n = 150); and CNI plus mycophenolate mofetil (CNI+MMF, n = 161). The CNI+MMF group, in comparison with the CNI+MTX and CNI alone groups, demonstrated better neutrophil recovery at 30 days (62.7 vs. 42.7 vs. 53.1%, P  less then  0.001); better overall survival (OS) at 12 months (48.4 vs. 33.5 vs. 28.3%, P  less then  0.001); and lower non-relapse mortality (NRM) at 12 months (35.2 vs. 53.9 vs. 56.5%, P  less then  0.001). On multivariate analysis, CNI+MMF had the best neutrophil recovery (hazard ratio (HR), 1.71; P  less then  0.001) and OS (HR, 0.64; P = 0.002) and the lowest NRM (HR, 0.53; P  less then  0.001). Hemorrhage was relatively less frequent in the CNI+MMF group. CNI+MMF can be a promising immunosuppressant regimen after salvage CBT for GF, with better engraftment and survival outcomes, compared with CNI alone and CNI+MTX.Island birds that were victims of anthropic extinctions were often more specialist species, having evolved their most distinctive features in isolation, making the study of fossil insular birds most interesting. Here we studied a fossil cranium of the 'giant’ extinct scops owl Otus murivorus from Rodrigues Island (Mascarene Islands, southwestern Indian Ocean), to determine any potential unique characters. The fossil and extant strigids were imaged through X-ray microtomography, providing 3D views of external and internal (endocast, inner ear) cranial structures. Geometric morphometrics and analyses of traditional measurements yielded new information about the Rodrigues owl’s evolution and ecology. Otus murivorus exhibits a 2-tier „lag behind” phenomenon for cranium and brain evolution, both being proportionately small relative to increased body size. It also had a much more developed olfactory bulb than congeners, indicating an unexpectedly developed olfactory sense, suggesting a partial food scavenging habit. In addition, O. murivorus had the eyes placed more laterally than O. sunia, the species from which it was derived, probably a side effect of a small brain; rather terrestrial habits; probably relatively fearless behavior; and a less vertical posture (head less upright) than other owls (this in part an allometric effect of size increase). These evolutionary features, added to gigantism and wing reduction, make the extinct Rodrigues owl’s evolution remarkable, and with multiple causes.Very few population-based studies have examined the epidemiology of Wilson’s disease (WD). We investigated the epidemiology of WD using the National Health Insurance Service (NHIS) database in South Korea. We analyzed not only the statistical variables of WD, but also those of WD-related diseases. WD patients were identified with the relevant International Classification of Diseases-10 code out of 50.5 million people. We used the NHIS database from 2009 to 2016 and analyzed the incidence rate, prevalence, and clinical symptoms of WD. A total of 1,333 patients were identified. The average annual incidence rate was 3.8 per million person-years. The prevalence was 38.7 per million people. The mean diagnostic age was 26.1 ± 17.2 with earlier diagnosis in men (P = 0.0003). Among the patients, 988 (74.1%) had hepatic symptoms, 510 (38.3%) had neurologic symptoms, and 601 (45.1%) had psychiatric symptoms. Before the diagnosis of WD, 350 (26.3%) had neurologic symptoms, and 427 (32%) had psychiatric symptoms. The annual mortality rate was 0.7%. Age, liver cirrhosis, and liver failure correlated with a fatal prognosis (P  less then  0.05). Many patients showed neurologic and psychiatric symptoms before they were diagnosed with WD. Prognosis correlated with age, liver cirrhosis, and liver failure.Alteration in extracellular matrix (ECM) in adipose tissues (AT) has been associated with insulin resistance, diabetes and obesity. We investigated whether selected biomarkers of ECM remodeling in AT in healthy subjects associated with the amount and distribution of AT and with glucometabolic variables. Subcutaneous AT and fasting blood samples from 103 middle-aged healthy non-obese men were used. AT gene expression and circulating levels of the biomarkers were quantified. Distribution of AT was assessed by computed tomography, separated into subcutaneous, deep subcutaneous and visceral AT. Insulin sensitivity was measured by glucose clamp technique. Metalloproteinase (MMP)-9, tissue inhibitor of MMP (TIMP)-1 and plasminogen activator inhibitor (PAI)-1 expression in AT correlated significantly to the amount of AT in all compartments (rs = 0.41-0.53, all p ≤ 0.01), and to insulin sensitivity, insulin, C-peptide, waist circumference and body mass index (BMI) (rs = 0.25-0.57, all p ≤ 0.05). MMP-9 was 5.3 fold higher in subjects with insulin sensitivity below median (p = 0.002) and 3.1 fold higher in subjects with BMI above median level (p = 0.013). In our healthy non-obese middle-aged population AT-expressed genes, central in remodeling of ECM, associated strongly with the amount of abdominal AT, overweight and insulin sensitivity, indicating AT-remodeling to play a role also in non-obese individuals. The remodeling process seems furthermore to associate significantly with glucometabolic disturbances.Trial registration ClinicalTrials.gov, NCT01412554. Registered 9 August 2011, https//clinicaltrials.gov/ct2/show/NCT01412554?term=NCT01412554 .An amendment to this paper has been published and can be accessed via a link at the top of the paper.Membrane fluidity plays an important role in many cell functions such as cell adhesion, and migration. In stem cell lines membrane fluidity may play a role in differentiation. Here we report the use of viscosity-sensitive fluorophores based on a BODIPY core, termed „molecular rotors”, in combination with Fluorescence Lifetime Imaging Microscopy, for monitoring of plasma membrane viscosity changes in mesenchymal stem cells (MSCs) during osteogenic and chondrogenic differentiation. In order to correlate the viscosity values with membrane lipid composition, the detailed analysis of the corresponding membrane lipid composition of differentiated cells was performed by time-of-flight secondary ion mass spectrometry. Our results directly demonstrate for the first time that differentiation of MSCs results in distinct membrane viscosities, that reflect the change in lipidome of the cells following differentiation.Two of the important traits for wheat yield are tiller and fertile tiller number, both of which have been thought to increase cereal yield in favorable and unfavorable environments. A total of 6,349 single nucleotide polymorphism (SNP) markers from the 15 K wheat Infinium array were employed for genome-wide association study (GWAS) of tillering number traits, generating a physical distance of 14,041.6 Mb based on the IWGSC wheat genome sequence. GWAS analysis using Fixed and random model Circulating Probability Unification (FarmCPU) identified a total of 47 significant marker-trait associations (MTAs) for total tiller number (TTN) and fertile tiller number (FTN) in Iranian bread wheat under different water regimes. After applying a 5% false discovery rate (FDR) threshold, a total of 13 and 11 MTAs distributed on 10 chromosomes were found to be significantly associated with TTN and FTN, respectively. Linked single nucleotide polymorphisms for IWB39005 (2A) and IWB44377 (7A) were highly significantly associated (FDR  less then  0.01) with TTN and FTN traits. Moreover, to validate GWAS results, meta-analysis was performed and 30 meta-QTL regions were identified on 11 chromosomes. The integration of GWAS and meta-QTLs revealed that tillering trait in wheat is a complex trait which is conditioned by the combined effects of minor changes in multiple genes. The information provided by this study can enrich the currently available candidate genes and genetic resources pools, offering evidence for subsequent analysis of genetic adaptation of wheat to different climatic conditions of Iran and other countries.