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In the twenty-second century, Glennora Morgan's father has been working on a project that will allow him to penetrate the Rift border and retrieve Glennora's mother; but now that he has succeeded the Authority is suddenly trying to kill them both, and Glennora and her friend Kevin must flee into the Magisterium to escape them.

First of all, being engaged in the community at every level. First of all, if I were President, we would have never been there. [...] the more you roll up your sleeves and get involved the better it will become. Because it's about all of us taking charge of our own community to solve our mutual problems.

Twenty years after the start of the war that caused the Collapse, fifteen-year-old Stephen, his father, and grandfather travel post-Collapse America scavenging, but when his grandfather dies and his father decides to risk everything to save the lives of two strangers, Stephen's life is turned upside down.

They said the merger talks center on how to structure a deal that would allow KPMG to buy Andersen's foreign affiliates and other portions of the company that might not carry liability from its audit of Enron Corp. Already, Andersen partner firms in Spain, Chile and Canada have talked about arranging separate mergers. KPMG would acquire the U.S. operations of Andersen at a later date, once its Enron liabilities were determined, sources familiar with the talks said. Andersen is seeing a daily erosion of major clients. On Friday, Sara Lee Corp., Brunswick Corp., and Northeast Utilities joined the list of about 50 companies that have dismissed Andersen since December.

\"Lucy Weaver has her future all figured out. Make an appearance at prom, ditch graduation, and then head out on an epic road trip with her boyfriend, Luke. But when everyone's phones start to ring halfway through the dance, Lucy knows something terrible has happened--something big. Decades of climate change have left the world teetering on the brink--entire cities drowned, violent extremism on the rise, millions of refugees with nowhere to turn. Is this the night it finally slips over the edge?\"-- Provided by publisher.

Sir, - In \"Jewish neutrality on Israel,\" (September 2), Barbara Sofer stated that \"most (American Jews) don't care\" about Israel, and \"few of my fellow Jews feel love or family affiliation with the Jewish state.\" Her conclusions were based on the National Jewish Democratic Council Frequency Questionnaire in which 15% of respondents indicated that Israel was one of two issues \"most important to you in deciding how to vote for a candidate for president.\"

People with type 2 diabetes are at risk of cognitive impairment and brain atrophy. We aimed to compare the effects on cognitive function and brain volume of intensive versus standard glycaemic control. The Memory in Diabetes (MIND) study was done in 52 clinical sites in North America as part of Action to Control Cardiovascular Risk in Diabetes (ACCORD), a double two-by-two factorial parallel group randomised trial. Participants (aged 55–80 years) with type 2 diabetes, high glycated haemoglobin A 1c (HbA 1c) concentrations (>7·5%; >58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive glycaemic control targeting HbA 1c to less than 6·0% (42 mmol/mol) or a standard strategy targeting HbA 1c to 7·0–7·9% (53–63 mmol/mol). Randomisation was via a centralised web-based system and treatment allocation was not masked from clinic staff or participants. We assessed our cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, at baseline and at 20 and 40 months. We assessed total brain volume (TBV), our primary brain structure outcome, with MRI at baseline and 40 months in a subset of participants. We included all participants with follow-up data in our primary analyses. In February, 2008, raised mortality risk led to the end of the intensive treatment and transition of those participants to standard treatment. We tested our cognitive function hypotheses with a mixed-effects model that incorporated information from both the 20 and 40 month outcome measures. We tested our MRI hypotheses with an ANCOVA model that included intracranial volume and factors used to stratify randomisation. This study is registered with ClinicalTrials.gov, number NCT00182910. We consecutively enrolled 2977 patients (mean age 62·5 years; SD 5·8) who had been randomly assigned to treatment groups in the ACCORD study. Our primary cognitive analysis was of patients with a 20-month or 40-month DSST score: 1378 assigned to receive intensive treatment and 1416 assigned to receive standard treatment. Of the 614 patients with a baseline MRI, we included 230 assigned to receive intensive treatment and 273 assigned to receive standard treatment in our primary MRI analysis at 40 months. There was no significant treatment difference in mean 40-month DSST score (difference in mean 0·32, 95% CI −0·28 to 0·91; p=0·2997). The intensive-treatment group had a greater mean TBV than the standard-treatment group (4·62, 2·0 to 7·3; p=0·0007). Although significant differences in TBV favoured the intensive treatment, cognitive outcomes were not different. Combined with the non-significant effects on other ACCORD outcomes, and increased mortality in participants in the intensive treatment group, our findings do not support the use of intensive therapy to reduce the adverse effects of diabetes on the brain in patients with similar characteristics to those of our participants. US National Institute on Aging and US National Heart, Lung, and Blood Institute.

The Lung Cancer Master Protocol (Lung-MAP; S1400) is a completed biomarker-driven master protocol designed to address an unmet need for better therapies for squamous non-small-cell lung cancer. Lung-MAP (S1400) was created to establish an infrastructure for biomarker screening and rapid regulatory intent evaluation of targeted therapies and was the first biomarker-driven master protocol initiated with the US National Cancer Institute (NCI). Lung-MAP (S1400) was done within the National Clinical Trials Network of the NCI using a public–private partnership. Eligible patients were aged 18 years or older, had stage IV or recurrent squamous non-small-cell lung cancer, had previously been treated with platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. The study included a screening component using the FoundationOne assay (Foundation Medicine, Cambridge, MA, USA) for next-generation sequencing, and a clinical trial component with biomarker-driven substudies and non-match substudies for patients who were ineligible for biomarker-driven substudies. Patients were pre-screened and received their substudy assignment upon progression, or they were screened at progression and received their substudy assignment upon completion of testing. Patients could enrol onto additional substudies after progression on a substudy. The study is registered with ClinicalTrials.gov, NCT02154490, and all research related to Lung-MAP (S1400) is completed. Between June 16, 2014, and Jan 28, 2019, 1864 patients enrolled and 1841 (98·9%) submitted tissue. 1674 (90·9%) of 1841 patients had biomarker results, and 1404 (83·9%) of 1674 patients received a substudy assignment. Of the assigned patients, 655 (46·7%) registered to a substudy. The biomarker-driven substudies evaluated taselisib (targeting PIK3CA alterations), palbociclib (cell cycle gene alterations), AZD4547 (FGFR alteration), rilotumumab plus erlotinib (MET), talazoparib (homologous recombination repair deficiency), and telisotuzumab vedotin (MET). The non-match substudies evaluated durvalumab, and nivolumab plus ipilimumab for anti-PD-1 or anti-PD-L1-naive disease, and durvalumab plus tremelimumab for anti-PD-1 or anti-PD-L1 relapsed disease. Combining data from the substudies, ten (7·0%) of 143 patients responded to targeted therapy, 53 (16·8%) of 315 patients responded to anti-PD-1 or anti-PD-L1 therapy for immunotherapy-naive disease, and three (5·4%) of 56 responded to docetaxel in the second line of therapy. Median overall survival was 5·9 months (95% CI 4·8–7·8) for the targeted therapy groups, 7·7 months (6·7–9·2) for the docetaxel groups, and 10·8 months (9·4–12·3) for the anti-PD-1 or anti-PD-L1-containing groups. Median progression-free survival was 2·5 months (95% CI 1·7–2·8) for the targeted therapy groups, 2·7 months (1·9–2·9) for the docetaxel groups, and 3·0 months (2·7–3·9) for the anti-PD-1 or anti-PD-L1-containing groups. Lung-MAP (S1400) met its goal to quickly address biomarker-driven therapy questions in squamous non-small-cell lung cancer. In early 2019, a new screening protocol was implemented expanding to all histological types of non-small-cell lung cancer and to add focus on immunotherapy combinations for anti-PD-1 and anti-PD-L1 therapy-relapsed disease. With these changes, Lung-MAP continues to meet its goal to focus on unmet needs in the treatment of advanced lung cancers. US National Institutes of Health, and AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health.

Adoptive cellular therapy using chimeric antigen receptor (CAR) T cell therapies have produced significant objective responses in patients with CD19+ hematological malignancies, including durable complete responses. Although the majority of clinical trials to date have used autologous patient cells as the starting material to generate CAR T cells, this strategy poses significant manufacturing challenges and, for some patients, may not be feasible because of their advanced disease state or difficulty with manufacturing suitable numbers of CAR T cells. Alternatively, T cells from a healthy donor can be used to produce an allogeneic CAR T therapy, provided the cells are rendered incapable of eliciting graft versus host disease (GvHD). One approach to the production of these cells is gene editing to eliminate expression of the endogenous T cell receptor (TCR). Here we report a streamlined strategy for generating allogeneic CAR T cells by targeting the insertion of a CAR transgene directly into the native TCR locus using an engineered homing endonuclease and an AAV donor template. We demonstrate that anti-CD19 CAR T cells produced in this manner do not express the endogenous TCR, exhibit potent effector functions in vitro, and mediate clearance of CD19+ tumors in an in vivo mouse model. MacLeod and colleagues use a homing endonuclease and an AAV vector to insert an anti-CD19 CAR into the TRAC gene to create universal allogeneic CAR T cells. Targeted insertion of a CAR transgene may allow the generation of more homogeneous CAR T cell products with more predictable safety and efficacy profiles.

Metagenomes encode an enormous diversity of proteins, reflecting a multiplicity of functions and activities 1 , 2 . Exploration of this vast sequence space has been limited to a comparative analysis against reference microbial genomes and protein families derived from those genomes. Here, to examine the scale of yet untapped functional diversity beyond what is currently possible through the lens of reference genomes, we develop a computational approach to generate reference-free protein families from the sequence space in metagenomes. We analyse 26,931 metagenomes and identify 1.17 billion protein sequences longer than 35 amino acids with no similarity to any sequences from 102,491 reference genomes or the Pfam database 3 . Using massively parallel graph-based clustering, we group these proteins into 106,198 novel sequence clusters with more than 100 members, doubling the number of protein families obtained from the reference genomes clustered using the same approach. We annotate these families on the basis of their taxonomic, habitat, geographical and gene neighbourhood distributions and, where sufficient sequence diversity is available, predict protein three-dimensional models, revealing novel structures. Overall, our results uncover an enormously diverse functional space, highlighting the importance of further exploring the microbial functional dark matter. A computational approach to generate reference-free protein families from the sequence space in metagenomes reveals an enormously diverse functional space.