The response of the maize nitrate transport system to nitrogen demand and supply across the lifecycle

The definitive version is available at www.newphytologist.comAn understanding of nitrate (NO3-) uptake throughout the lifecycle of plants, and how this process responds to nitrogen (N) availability, is an important step towards the development of plants with improved nitrogen use efficiency (NUE). NO3- uptake capacity and transcript levels of putative high- and low-affinity NO3- transporters (NRTs) were profiled across the lifecycle of dwarf maize (Zea mays) plants grown at reduced and adequate NO3-. Plants showed major changes in high-affinity NO3- uptake capacity across the lifecycle, which varied with changing relative growth rates of roots and shoots. Transcript abundances of putative high-affinity NRTs (predominantly ZmNRT2.1 and ZmNRT2.2) were correlated with two distinct peaks in high-affinity root NO3- uptake capacity and also N availability. The reduction in NO3- supply during the lifecycle led to a dramatic increase in NO3- uptake capacity, which preceded changes in transcript levels of NRTs, suggesting a model with short-term post-translational regulation and longer term transcriptional regulation of NO3- uptake capacity. These observations offer new insight into the control of NO3- uptake by both plant developmental processes and N availability, and identify key control points that may be targeted by future plant improvement programmes to enhance N uptake relative to availability and/or demand.Trevor Garnett, Vanessa Conn, Darren Plett, Simon Conn, Juergen Zanghellini, Nenah Mackenzie, Akiko Enju, Karen Francis, Luke Holtham, Ute Roessner, Berin Boughton, Antony Bacic, Neil Shirley, Antoni Rafalski, Kanwarpal Dhugga, Mark Tester, and Brent N. Kaise

Can Fire and Rescue Services and the National Health Service work together to improve the safety and wellbeing of vulnerable older people? Design of a proof of concept study

Older adults are at increased risk both of falling and of experiencing accidental domestic fire. In addition to advanced age, these adverse events share the risk factors of balance or mobility problems, cognitive impairment and socioeconomic deprivation. For both events, the consequences include significant injury and death, and considerable socioeconomic costs for the individual and informal carers, as well as for emergency services, health and social care agencies.Secondary prevention services for older people who have fallen or who are identifiable as being at high risk of falling include NHS Falls clinics, where a multidisciplinary team offers an individualised multifactorial targeted intervention including strength and balance exercise programmes, medication changes and home hazard modification. A similar preventative approach is employed by most Fire and Rescue Services who conduct Home Fire Safety Visits to assess and, if necessary, remedy domestic fire risk, fit free smoke alarms with instruction for use and maintenance, and plan an escape route. We propose that the similarity of population at risk, location, specific risk factors and the commonality of preventative approaches employed could offer net gains in terms of feasibility, effectiveness and acceptability if activities within these two preventative approaches were to be combined

Screening and social prescribing in healthcare and social services to address housing issues among children and families: a systematic review

ObjectivesHousing is a social determinant of health that impacts the health and well-being of children and families. Screening and referral to address social determinants of health in clinical and social service settings has been proposed to support families with housing problems. This study aims to identify housing screening questions asked of families in healthcare and social services, determine validated screening tools and extract information about recommendations for action after screening for housing issues.MethodsThe electronic databases MEDLINE, PsycINFO, EMBASE, Ovid Emcare, Scopus and CINAHL were searched from 2009 to 2021. Inclusion criteria were peer-reviewed literature that included questions about housing being asked of children or young people aged 0-18 years and their families accessing any healthcare or social service. We extracted data on the housing questions asked, source of housing questions, validity and descriptions of actions to address housing issues.ResultsForty-nine peer-reviewed papers met the inclusion criteria. The housing questions in social screening tools vary widely. There are no standard housing-related questions that clinical and social service providers ask families. Fourteen screening tools were validated. An action was embedded as part of social screening activities in 27 of 42 studies. Actions for identified housing problems included provision of a community-based or clinic-based resource guide, and social prescribing included referral to a social worker, care coordinator or care navigation service, community health worker, social service agency, referral to a housing and child welfare demonstration project or provided intensive case management and wraparound services.ConclusionThis review provides a catalogue of housing questions that can be asked of families in the clinical and/or social service setting, and potential subsequent actions

TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.This work was supported by funding from the Medical Research Council and the European Research Council (ERC, 281847) (A.P.J.), the Lister Institute for Preventative Medicine (A.P.J. and G.S.S.), Medical Research Scotland (L.S.B.), German Federal Ministry of Education and Research (BMBF, 01GM1404) and E-RARE network EuroMicro (B.W), Wellcome Trust (M. Hurles), CMMC (P.N.), Cancer Research UK (C17183/A13030) (G.S.S. and M.R.H), Swiss National Science Foundation (P2ZHP3_158709) (O.M.), AIRC (12710) and ERC/EU FP7 (CIG_303806) (S.S.), Cancer Research UK (C6/A11224) and ERC/EU FP7 (HEALTH-F2- 2010-259893) (A.N.B. and S.P.J.).This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches