RNA targeting with CRISPR–Cas13

RNA has important and diverse roles in biology, but molecular tools to manipulate and measure it are limited. For example, RNA interference1-3 can efficiently knockdown RNAs, but it is prone to off-target effects4, and visualizing RNAs typically relies on the introduction of exogenous tags5. Here we demonstrate that the class 2 type VI6,7 RNA-guided RNA-targeting CRISPR-Cas effector Cas13a8(previously known as C2c2) can be engineered for mammalian cell RNA knockdown and binding. After initial screening of 15 orthologues, we identified Cas13a from Leptotrichia wadei (LwaCas13a) as the most effective in an interference assay in Escherichia coli. LwaCas13a can be heterologously expressed in mammalian and plant cells for targeted knockdown of either reporter or endogenous transcripts with comparable levels of knockdown as RNA interference and improved specificity. Catalytically inactive LwaCas13a maintains targeted RNA binding activity, which we leveraged for programmable tracking of transcripts in live cells. Our results establish CRISPR-Cas13a as a flexible platform for studying RNA in mammalian cells and therapeutic development.National Institute of Mental Health (U.S.) (Grant 5DP1-MH100706)National Institute of Mental Health (U.S.) (Grant 1R01-MH110049

The cost of proactive interference is constant across presentation conditions

Proactive interference (PI) severely constrains how many items people can remember. For example, Endress and Potter (2014a) presented participants with sequences of everyday objects at 250 ms/picture, followed by a yes/no recognition test. They manipulated PI by either using new images on every trial in the unique condition (thus minimizing PI among items), or by re-using images from a limited pool for all trials in the repeated condition (thus maximizing PI among items). In the low-PI unique condition, the probability of remembering an item was essentially independent of the number of memory items, showing no clear memory limitations; more traditional working memory-like memory limitations appeared only in the high-PI repeated condition. Here, we ask whether the effects of PI are modulated by the availability of long-term memory (LTM) and verbal resources. Participants viewed sequences of 21 images, followed by a yes/no recognition test. Items were presented either quickly (250 ms/image) or sufficiently slowly (1500 ms/image) to produce LTM representations, either with or without verbal suppression. Across conditions, participants performed better in the unique than in the repeated condition, and better for slow than for fast presentations. In contrast, verbal suppression impaired performance only with slow presentations. The relative cost of PI was remarkably constant across conditions: relative to the unique condition, performance in the repeated condition was about 15% lower in all conditions. The cost of PI thus seems to be a function of the relative strength or recency of target items and interfering items, but relatively insensitive to other experimental manipulations

Migrant and refugee populations: a public health and policy perspective on a continuing global crisis.

The 2015-2017 global migratory crisis saw unprecedented numbers of people on the move and tremendous diversity in terms of age, gender and medical requirements. This article focuses on key emerging public health issues around migrant populations and their interactions with host populations. Basic needs and rights of migrants and refugees are not always respected in regard to article 25 of the Universal Declaration of Human Rights and article 23 of the Refugee Convention. These are populations with varying degrees of vulnerability and needs in terms of protection, security, rights, and access to healthcare. Their health status, initially conditioned by the situation at the point of origin, is often jeopardised by adverse conditions along migratory paths and in intermediate and final destination countries. Due to their condition, forcibly displaced migrants and refugees face a triple burden of non-communicable diseases, infectious diseases, and mental health issues. There are specific challenges regarding chronic infectious and neglected tropical diseases, for which awareness in host countries is imperative. Health risks in terms of susceptibility to, and dissemination of, infectious diseases are not unidirectional. The response, including the humanitarian effort, whose aim is to guarantee access to basic needs (food, water and sanitation, healthcare), is gripped with numerous challenges. Evaluation of current policy shows insufficiency regarding the provision of basic needs to migrant populations, even in the countries that do the most. Governments around the world need to rise to the occasion and adopt policies that guarantee universal health coverage, for migrants and refugees, as well as host populations, in accordance with the UN Sustainable Development Goals. An expert consultation was carried out in the form of a pre-conference workshop during the 4th International Conference on Prevention and Infection Control (ICPIC) in Geneva, Switzerland, on 20 June 2017, the United Nations World Refugee Day

Corporate reputation past and future: a review and integration of existing literature and a framework for future research

The concept of corporate reputation is steadily growing in interest among management researchers and practitioners. In this article, we trace key milestones in the development of reputation literature over the past six decades to suggest important research gaps as well as to provide contextual background for a subsequent integration of approaches and future outlook. In particular we explore the need for better categorised outcomes; a wider range of causes; and a deeper understanding of contingencies and moderators to advance the field beyond its current state while also taking account of developments in the macro business environment. The article concludes by presenting a novel reputation framework that integrates insights from reputation theory and studies, outlines gaps in knowledge and offers directions for future research

Dehydrogenative Photoredox Catalyzed Synthesis of Indolyl Δ2-Isoxazolines via a Formal C(sp3)−H Functionalization

The discovery of a dehydrogenative photoredox catalyzed formal C(sp3)−H intramolecular cyclization of indolyl-oximes to generate indolyl Δ2-isoxazolines is reported. In contrast to the current state-of-the-art, the reaction avoids the use of super stoichiometric chemical oxidants and high reaction temperatures and is proposed to operate via two sequential single electron oxidation events

Correlates of video games playing among adolescents in an Islamic country

<p>Abstract</p> <p>Background</p> <p>No study has ever explored the prevalence and correlates of video game playing among children in the Islamic Republic of Iran. This study describes patterns and correlates of excessive video game use in a random sample of middle-school students in Iran. Specifically, we examine the relationship between video game playing and psychological well-being, aggressive behaviors, and adolescents' perceived threat of video-computer game playing.</p> <p>Methods</p> <p>This cross-sectional study was performed with a random sample of 444 adolescents recruited from eight middle schools. A self-administered, anonymous questionnaire covered socio-demographics, video gaming behaviors, mental health status, self-reported aggressive behaviors, and perceived side effects of video game playing.</p> <p>Results</p> <p>Overall, participants spent an average of 6.3 hours per week playing video games. Moreover, 47% of participants reported that they had played one or more intensely violent games. Non-gamers reported suffering poorer mental health compared to excessive gamers. Both non-gamers and excessive gamers overall reported suffering poorer mental health compared to low or moderate players. Participants who initiated gaming at younger ages were more likely to score poorer in mental health measures. Participants' self-reported aggressive behaviors were associated with length of gaming. Boys, but not girls, who reported playing video games excessively showed more aggressive behaviors. A multiple binary logistic regression shows that when controlling for other variables, older students, those who perceived less serious side effects of video gaming, and those who have personal computers, were more likely to report that they had played video games excessively.</p> <p>Conclusion</p> <p>Our data show a curvilinear relationship between video game playing and mental health outcomes, with "moderate" gamers faring best and "excessive" gamers showing mild increases in problematic behaviors. Interestingly, "non-gamers" clearly show the worst outcomes. Therefore, both children and parents of non-game players should be updated about the positive impact of moderate video gaming. Educational interventions should also be designed to educate adolescents and their parents of the possible harmful impact of excessive video game playing on their health and psychosocial functioning.</p

Primary care provider perceptions of intake transition records and shared care with outpatient cardiac rehabilitation programs

Abstract Background While it is recommended that records are kept between primary care providers (PCPs) and specialists during patient transitions from hospital to community care, this communication is not currently standardized. We aimed to assess the transmission of cardiac rehabilitation (CR) program intake transition records to PCPs and to explore PCPs' needs in communication with CR programs and for intake transition record content. Method 144 PCPs of consenting enrollees from 8 regional and urban Ontario CR programs participated in this cross-sectional study. Intake transition records were tracked from the CR program to the PCP's office. Sixty-six PCPs participated in structured telephone interviews. Results Sixty-eight (47.6%) PCPs received a CR intake transition record. Fifty-eight (87.9%) PCPs desired intake transition records, with most wanting it transmitted via fax (n = 52, 78.8%). On a 5-point Likert scale, PCPs strongly agreed that the CR transition record met their needs for providing patient care (4.32 ± 0.61), with 48 (76.2%) reporting that it improved their management of patients' cardiac risk. PCPs rated the following elements as most important to include in an intake transition record: clinical status (4.67 ± 0.64), exercise test results (4.61 ± 0.52), and the proposed patient care plan (4.59 ± 0.71). Conclusions Less than half of intake transition records are reaching PCPs, revealing a large gap in continuity of patient care. PCP responses should be used to develop an evidence-based intake transition record, and procedures should be implemented to ensure high-quality transitional care

Total Catch of a Red-Listed Marine Species Is an Order of Magnitude Higher than Official Data

Accurate information on total catch and effort is essential for successful fisheries management. Officially reported landings, however, may be underestimates of total catch in many fisheries. We investigated the fishery for the nationally red-listed European lobster (Homarus gammarus) in south-eastern Norway. Probability-based strip transect surveys were used to count buoys in the study area in combination with catch per unit effort data obtained independently from volunteer catch diaries, phone interviews, and questionnaires. We estimate that recreational catch accounts for 65% of total catch in the study area. Moreover, our results indicate that only a small proportion (24%) of lobsters landed commercially were sold through the legal market and documented. Total estimated lobster catch was nearly 14 times higher than reported officially. Our study highlights the need for adequate catch monitoring and data collection efforts in coastal areas, presents a clear warning to resource managers that illegal, unreported and unregulated (IUU) fisheries in coastal areas should not be ignored, and shows the potential impact of recreational fisheries

Fine-Scale Movements of the Broadnose Sevengill Shark and Its Main Prey, the Gummy Shark

Information on the fine-scale movement of predators and their prey is important to interpret foraging behaviours and activity patterns. An understanding of these behaviours will help determine predator-prey relationships and their effects on community dynamics. For instance understanding a predator's movement behaviour may alter pre determined expectations of prey behaviour, as almost any aspect of the prey's decisions from foraging to mating can be influenced by the risk of predation. Acoustic telemetry was used to study the fine-scale movement patterns of the Broadnose Sevengill shark Notorynchus cepedianus and its main prey, the Gummy shark Mustelus antarcticus, in a coastal bay of southeast Tasmania. Notorynchus cepedianus displayed distinct diel differences in activity patterns. During the day they stayed close to the substrate (sea floor) and were frequently inactive. At night, however, their swimming behaviour continually oscillated through the water column from the substrate to near surface. In contrast, M. antarcticus remained close to the substrate for the entire diel cycle, and showed similar movement patterns for day and night. For both species, the possibility that movement is related to foraging behaviour is discussed. For M. antarcticus, movement may possibly be linked to a diet of predominantly slow benthic prey. On several occasions, N. cepedianus carried out a sequence of burst speed events (increased rates of movement) that could be related to chasing prey. All burst speed events during the day were across the substrate, while at night these occurred in the water column. Overall, diel differences in water column use, along with the presence of oscillatory behaviour and burst speed events suggest that N. cepedianus are nocturnal foragers, but may opportunistically attack prey they happen to encounter during the day

Flomoxef and fosfomycin in combination for the treatment of neonatal sepsis in the setting of highly prevalent antimicrobial resistance.

BACKGROUND: Neonatal sepsis is a serious bacterial infection of neonates, globally killing up to 680 000 babies annually. It is frequently complicated by antimicrobial resistance, particularly in low- and middle-income country (LMIC) settings with widespread resistance to the WHO's recommended empirical regimen of ampicillin and gentamicin. OBJECTIVES: We assessed the utility of flomoxef and fosfomycin as a potential alternative empirical regimen for neonatal sepsis in these settings. METHODS: We studied the combination in a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment and chequerboard assays. We further assessed the combination using clinically relevant regimens in the HFIM with six Enterobacterales strains with a range of flomoxef/fosfomycin MICs. RESULTS: Pharmacokinetic/pharmacodynamic modelling of the HFIM experimental output, along with data from chequerboard assays, indicated synergy of this regimen in terms of bacterial killing and prevention of emergence of fosfomycin resistance. Flomoxef monotherapy was sufficient to kill 3/3 strains with flomoxef MICs ≤0.5 mg/L to sterility. Three of three strains with flomoxef MICs ≥8 mg/L were not killed by fosfomycin or flomoxef monotherapy; 2/3 of these were killed with the combination of the two agents. CONCLUSIONS: These data suggest that flomoxef/fosfomycin could be an efficacious and synergistic regimen for the empirical treatment of neonatal sepsis in LMIC settings with prevalent antimicrobial resistance. Our HFIM results warrant further assessment of the flomoxef/fosfomycin combination in clinical trials