CD7-deleted hematopoietic stem cells can restore immunity after CAR T cell therapy

Targeting T cell malignancies with universal CD7-targeting chimeric antigen receptor T cells (UCART7) can lead to profound immune deficiency due to loss of normal T and NK cells. While a small population of endogenous CD7- T cells exists, these cells are unlikely to be able to repopulate the entire immune repertoire after UCART7 treatment, as they are limited in number and proliferative capacity. To rescue T and NK cells after UCART7, we created hematopoietic stem cells genetically deleted for CD7 (CD7-KO HSCs). CD7-KO HSCs were able to engraft immunodeficient mice and differentiate into T and NK cells lacking CD7 expression. CD7-KO T and NK cells could perform effector functions as robustly as control T and NK cells. Furthermore, CD7-KO T cells were phenotypically and functionally distinct from endogenous CD7- T cells, indicating that CD7-KO T cells can supplement immune functions lacking in CD7- T cells. Mice engrafted with CD7-KO HSCs maintained T and NK cell numbers after UCART7 treatment, while these were significantly decreased in control mice. These studies support the development of CD7-KO HSCs to augment host immunity in patients with T cell malignancies after UCART7 treatment

Improving the use of crop models for risk assessment and climate change adaptation

Crop models are used for an increasingly broad range of applications, with a commensurate proliferation of methods. Careful framing of research questions and development of targeted and appropriate methods are therefore increasingly important. In conjunction with the other authors in this special issue, we have developed a set of criteria for use of crop models in assessments of impacts, adaptation and risk. Our analysis drew on the other papers in this special issue, and on our experience in the UK Climate Change Risk Assessment 2017 and the MACSUR, AgMIP and ISIMIP projects. The criteria were used to assess how improvements could be made to the framing of climate change risks, and to outline the good practice and new developments that are needed to improve risk assessment. Key areas of good practice include: i. the development, running and documentation of crop models, with attention given to issues of spatial scale and complexity; ii. the methods used to form crop-climate ensembles, which can be based on model skill and/or spread; iii. the methods used to assess adaptation, which need broadening to account for technological development and to reflect the full range options available. The analysis highlights the limitations of focussing only on projections of future impacts and adaptation options using pre-determined time slices. Whilst this long-standing approach may remain an essential component of risk assessments, we identify three further key components: 1. Working with stakeholders to identify the timing of risks. What are the key vulnerabilities of food systems and what does crop-climate modelling tell us about when those systems are at risk? 2. Use of multiple methods that critically assess the use of climate model output and avoid any presumption that analyses should begin and end with gridded output. 3. Increasing transparency and inter-comparability in risk assessments. Whilst studies frequently produce ranges that quantify uncertainty, the assumptions underlying these ranges are not always clear. We suggest that the contingency of results upon assumptions is made explicit via a common uncertainty reporting format; and/or that studies are assessed against a set of criteria, such as those presented in this paper

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead