Heterocyclic polymers have gained enormous attention for their unique functionalities and wide applications. In contrast with the well-studied polymer systems with five- or six-membered heterocycles, ...functional polymers with readily openable small-ring heterocycles have rarely been explored due to their large synthetic difficulty. Herein, a facile one-pot multicomponent polymerization to such polymers is developed. A series of functional polymers with multisubstituted and heteroatom-rich azetidine frameworks are efficiently generated at room temperature in high atom economy from handy monomers. The four-membered azetidine rings in the polymer skeletons can be easily transformed into amide and amidine moieties via a fast and efficient acid-mediated ring-opening reaction, producing brand-new polymeric materials with distinctive properties. All the as-prepared azetidine-containing polymers exhibit intrinsic visible luminescence in the solid state under long-wavelength UV irradiation even without conventionally conjugated structures. Such unconventional luminescence is attributed to the clusteroluminogens formed by through-space electronic interactions of heteroatoms and phenyl rings. All the obtained polymers show excellent optical transparency, high and tunable refractive indices, low optical dispersions and good photopatternability, which make them promising materials in various advanced electronic and optoelectronic devices. The ring-opened polymers can also function as a lysosome-specific fluorescent probe in biological imaging.
FOXM1 is implicated in genotoxic drug resistance but its role and mechanism of action remain unclear. Here, we establish that γH2AX foci, indicative of DNA double-strand breaks (DSBs), accumulate in ...a time-dependent manner in the drug-sensitive MCF-7 cells but not in the resistant counterparts in response to epirubicin. We find that FOXM1 expression is associated with epirubicin sensitivity and DSB repair. Ectopic expression of FOXM1 can increase cell viability and abrogate DSBs sustained by MCF-7 cells following epirubicin, owing to an enhancement in repair efficiency. Conversely, alkaline comet and γH2AX foci formation assays show that Foxm1-null cells are hypersensitive to DNA damage, epirubicin and γ-irradiation. Furthermore, we find that FOXM1 is required for DNA repair by homologous recombination (HR) but not non-homologous end joining (NHEJ), using HeLa cell lines harbouring an integrated direct repeat green fluorescent protein reporter for DSB repair. We also identify BRIP1 as a direct transcription target of FOXM1 by promoter analysis and chromatin-immunoprecipitation assay. In agreement, depletion of FOXM1 expression by small interfering RNA downregulates BRIP1 expression at the protein and mRNA levels in MCF-7 and the epirubicin-resistant MCF-7 Epi(R) cells. Remarkably, the requirement for FOXM1 for DSB repair can be circumvented by reintroduction of BRIP1, suggesting that BRIP1 is an important target of FOXM1 in DSB repair. Indeed, like FOXM1, BRIP1 is needed for HR. These data suggest that FOXM1 regulates BRIP1 expression to modulate epirubicin-induced DNA damage repair and drug resistance.
Worldwide, programs to control mastitis are implemented using different strategies to reach farmers. Even though education materials and best practices may be technically optimal, they need to be ...used to be successful. Thus, effective communication with farmers is essential in order to change their behavior and to improve their farm management. During a Dutch national mastitis control program, a substantial number of farmers seemed to be hard to reach with information on udder health. Consequently, this study was designed to provide insight into the attitude and motivation of such farmers. In the period of October 2007 to July 2008, 24 in-depth, semistructured interviews were conducted with farmers whose veterinarians considered to be difficult to approach with advice on udder health management (8 practices, 3 farmers from each practice). The interviews included questions about the farms and the farmers, their attitude and behavior regarding mastitis, and their information sources and social environment. The results show that so-called hard-to-reach farmers were not always badly informed about udder health and did not always experience problems with mastitis. These ostensibly unreachable farmers were not a homogeneous group, but rather could be divided into 4 categories based on their trust in external information sources regarding mastitis and their orientation toward the outside world: proactivists, do-it-yourselfers, wait-and-see-ers, and reclusive traditionalists. There are ample opportunities to reach hard-to-reach farmers, provided that the communication strategies are tailored to their specific needs. There is especially much to gain in communication with do-it-yourselfers and wait-and-see-ers, but this demands a more proactive role on the part of veterinarians and extension specialists. Different types of farmers need to be approached in different ways and through different channels with information on udder health. Consequently, this study can contribute to the optimization of future programs designed to control and prevent diseases.
Lipid droplets are highly associated with obesity, diabetes, inflammatory disorders, and cancer. A reliable two-photon dye for specific lipid droplets imaging in live cells and live tissues at ...ultralow concentration has rarely been reported. In this work, four new aggregation-induced emission luminogens (AIEgens) based on the naphthalene core were designed and synthesized for specific two-photon lipid droplet staining. The new molecules, namely, NAP AIEgens, exhibit large Stokes shift (>110 nm), high solid-state fluorescence quantum yield (up to 30%), good two-photon absorption cross section (45–100 GM at 860 nm), high biocompatibility, and good photostability. They could specifically stain lipid droplets at ultralow concentration (50 nM) in a short time of 15 min. Such ultralow concentration is the lowest value for lipid droplets staining in live cells reported so far. In vitro and ex vivo two-photon imaging of lipid droplets in live cells and live mice liver tissues were successfully demonstrated. In addition, selective visualization of lipid droplets in live mice liver tissues could be achieved at a depth of about 70 μm. These excellent properties render them as promising candidates for investigating lipid droplet-associated physiological and pathological processes in live biological samples.
The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development
. The central melanocortin system ...acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure
. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.
Background Prudent use of antibiotics is important to prevent antibiotic resistance in humans and in animals. For this reason politicians demanded a decrease of total antibiotic use and of use of ...critically important antibiotics in animal husbandry in the Netherlands. In the dairy sector the use of antibiotics almost halved in the years 2009-2015, with a decrease of the use of critically important antibiotics to very low levels. Theory of behaviour change To realize a sustainable decrease in antibiotic usage, the mindset towards the subject was considered crucial. Based on several models from social psychology, the RESET Mindset Model was used. This model contains the most important cues to change human behaviour, being Rules and regulations, Education and information, Social pressure, Economics, and Tools. To change behaviour of groups in order to reach a tipping point, it is of utmost importance to not choose among the different cues, but to use them all. Changing antibiotic usage in dairy cattle In order to decrease antibiotic usage in dairy cattle in the Netherlands several actions, obliged as well as voluntary, were undertaken. An independent veterinary medicine authority was founded that became active for all animal sectors. In the dairy sector a national database on antibiotic usage called MediRund was developed, which made transparency and benchmarking on antibiotic usage at the national and the herd level possible. Several other activities are described, such as herd health and treatment plans, selective dry cow therapy, and the strong limitation on the use of critically important antibiotics. Antibiotic usage at the herd level, referred to as the 'antibiotic number', became an important and socially accepted herd level parameter. RESET the dairy farmer's mindset on antibiotic usage The actions undertaken worked through different cues, all part of the RESET Mindset Model. As such, different types of dairy farmers sensitive to different types of cues were motivated to change their behaviour. Conclusion Antibiotic usage in dairy cattle in the Netherlands decreased significantly by intense cooperation between the most important stakeholders in the dairy chain, taking communication seriously and applying the RESET Mindset Model.
Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal ...carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.
Worldwide, programs to improve udder health are implemented using communication tools and methods that inform and persuade dairy farmers. This study evaluated 2 communication strategies used in a ...mastitis control program in the Netherlands. To improve farmers’ udder health management, tools such as instruction cards, treatment plans, checklists and software were developed following an argument-based comprehensive “central route.” These tools were used during on-farm study group meetings for farmers organized by veterinarians and also during individual veterinarian–farmer interactions. The second strategy aimed at adopting a single management practice to increase the use of milking gloves during milking. This approach followed a straightforward “peripheral” route that used implicit persuasion techniques. Results of an online survey of 374 Dutch dairy farmers showed that most farmers were able and willing to use the educational management tools to increase udder health on their farms. They evaluated the tools positively regardless of the mastitis problems on their farms. This seems to indicate that the central route of communication is most effective when farmers are motivated to work on udder health in general. Results of repeated random telephone surveys before, during, and after the campaign on the use of milking gloves showed that the use of gloves increased from 20.9 to 42.0% of the respondents. Respondents’ opinions about milking gloves also changed favorably, indicating that a relatively short peripheral campaign on a single action can have a sustained effect on farmers’ behavior. Both communication strategies seem to be potentially successful in disseminating knowledge to a specific target group of farmers and in changing that group's behavior. However, to reach as many farmers as possible, the strategies should be combined. When optimizing these strategies, both the farmers’ motivation to work on udder health and the aim of the campaign should be considered. When aiming to improve general udder health management, the central route seems to be effective if farmers are already motivated to optimize their udder health management. For farmers who are less motivated to work on udder health, the peripheral route seems to be most effective when aiming to change a single management practice. The evaluated communication strategies are examples of how management practices to control mastitis can be effectively communicated to farmers. As such, this study contributes to optimizing future programs to control and prevent diseases.
Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker ...test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95-1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset or at-risk individuals. The predictive performance achieved by the panel was excellent for identifying USA military personnel (AUC: 0.90 (0.86-0.95)) and help-seeking prodromal individuals (AUC: 0.82 (0.71-0.93)) who developed schizophrenia up to 2 years after baseline sampling. The performance increased further using the latter cohort following the incorporation of CAARMS (Comprehensive Assessment of At-Risk Mental State) positive subscale symptom scores into the model (AUC: 0.90 (0.82-0.98)). The current findings may represent the first successful step towards a test that could address the clinical need for early intervention in psychiatry. Further developments of a combined molecular/symptom-based test will aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention before overt disease onset.
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