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Plants depend on light signals to modulate many aspects of their development and optimize their photosynthetic capacity. Phytochromes (phys), a family of photoreceptors, initiate a signal transduction pathway that alters expression of a large number of genes to induce these responses. Recently, phyA and phyB were shown to bind members of a basic helix-loop-helix family of transcription factors called phy-interacting factors (PIFs). PIF1 negatively regulates chlorophyll biosynthesis and seed germination in the dark, and light-induced degradation of PIF1 relieves this negative regulation to promote photomorphogenesis. Here, we report that PIF1 regulates expression of a discrete set of genes in the dark, including protochlorophyllide oxidoreductase (POR), ferrochelatase (FeChII), and heme oxygenase (HO3), which are involved in controlling the chlorophyll biosynthetic pathway. Using ChIP and DNA gel-shift assays, we demonstrate that PIF1 directly binds to a G-box (CACGTG) DNA sequence element present in the PORC promoter. Moreover, in transient assays, PIF1 activates transcription of PORC in a G-box-dependent manner. These data strongly suggest that PIF1 directly and indirectly regulates key genes involved in chlorophyll biosynthesis to optimize the greening process in ARABIDOPSIS:

The aim of this study was to assess the effects on lipids and safety during a 12-week reversal period after 18 months of treatment with anacetrapib. The cholesteryl ester transfer protein inhibitor anacetrapib was previously shown to reduce low-density lipoprotein cholesterol by 39.8% (estimated using the Friedewald equation) and increase high-density lipoprotein (HDL) cholesterol by 138.1%, with an acceptable side-effect profile, in patients with or at high risk for coronary heart disease in the Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial. A total of 1,398 patients entered the 12-week reversal-phase study, either after completion of the active-treatment phase or after early discontinuation of the study medication. In patients allocated to anacetrapib, placebo-adjusted mean percentage decreases from baseline were observed at 12 weeks off the study drug for Friedewald-calculated low-density lipoprotein cholesterol (18.6%), non-HDL cholesterol (17.6%), and apolipoprotein B (10.2%); placebo-adjusted mean percentage increases were observed for HDL cholesterol (73.0%) and apolipoprotein A-I (24.5%). Residual plasma anacetrapib levels (about 40% of on-treatment apparent steady-state trough levels) were also detected 12 weeks after cessation of anacetrapib. No clinically important elevations in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the reversal phase. Preliminary data from a small cohort (n = 30) revealed the presence of low concentrations of anacetrapib in plasma 2.5 to 4 years after the last anacetrapib dose. In conclusion, after the cessation of active treatment, anacetrapib plasma lipid changes and drug levels decreased to approximately 40% of on-treatment trough levels at 12 weeks after dosing, but modest HDL cholesterol elevations and low drug concentrations were still detectable 2 to 4 years after the last dosing.

Steven McCarroll, Joel Hirschhorn and colleagues identify eight common structural forms of the human amylase locus. They measured amylase gene copy number in ~3,500 individuals and detected no association with BMI and obesity. Hundreds of genes reside in structurally complex, poorly understood regions of the human genome 1 , 2 , 3 . One such region contains the three amylase genes ( AMY2B , AMY2A and AMY1 ) responsible for digesting starch into sugar. Copy number of AMY1 is reported to be the largest genomic influence on obesity 4 , although genome-wide association studies for obesity have found this locus unremarkable. Using whole-genome sequence analysis 3 , 5 , droplet digital PCR 6 and genome mapping 7 , we identified eight common structural haplotypes of the amylase locus that suggest its mutational history. We found that the AMY1 copy number in an individual's genome is generally even (rather than odd) and partially correlates with nearby SNPs, which do not associate with body mass index (BMI). We measured amylase gene copy number in 1,000 obese or lean Estonians and in 2 other cohorts totaling ∼3,500 individuals. We had 99% power to detect the lower bound of the reported effects on BMI 4 , yet found no association.

Background/Aims: Short stature is a common reason for presentation to pediatric endocrinology clinics. However, for most patients, no cause for the short stature can be identified. As genetics plays a strong role in height, we sought to identify known and novel genetic causes of short stature. Methods: We recruited 14 children with severe short stature of unknown etiology. We conducted whole exome sequencing of the patients and their family members. We used an analysis pipeline to identify rare non-synonymous genetic variants that cause the short stature. Results: We identified a genetic cause of short stature in 5 of the 14 patients. This included cases of floating-harbor syndrome, Kenny-Caffey syndrome, the progeroid form of Ehlers-Danlos syndrome, as well as 2 cases of the 3-M syndrome. For the remaining patients, we have generated lists of candidate variants. Conclusions: Whole exome sequencing can help identify genetic causes of short stature in the context of defined genetic syndromes, but may be less effective in identifying novel genetic causes of short stature in individual families. Utilized in the clinic, whole exome sequencing can provide clinically relevant diagnoses for these patients. Rare syndromic causes of short stature may be underrecognized and underdiagnosed in pediatric endocrinology clinics.

This study tested prefrontal and hippocampal functions in a sample of 28 school-aged (M = 14.7 years, SD = 2.7) individuals with Down syndrome (DS) compared with 28 (M = 4.9 years, SD = .75) typically developing children individually matched on mental age (MA). Both neuropsychological domains were tested with multiple behavioral measures. Benchmark measures of verbal and spatial function demonstrated that this DS sample was similar to others in the literature. The main finding was a significant Group x Domain interaction effect indicating differential hippocampal dysfunction in the group with DS. However, there was a moderate partial correlation (r = .54, controlling for chronological age) between hippocampal and prefrontal composite scores in the DS group, and both composites contributed unique variance to the prediction of MA and adaptive behavior in that group. In sum, these results indicate a particular weakness in hippocampal functions in DS in the context of overall cognitive dysfunction. It is interesting that these results are similar to what has been found in a mouse model of DS. Such a model will make it easier to understand the neurobiological mechanisms that lead to the development of hippocampal dysfunction in DS.

Standard testing for disease evaluation in B-cell acute lymphoblastic leukemia (B-ALL) includes examination of the bone marrow and cerebrospinal fluid. Radiographic or functional imaging are indicated when clinical signs of non-CNS extramedullary disease are present but are not standard in the relapsed/refractory setting. We describe two cases of patients with relapsed/refractory B-ALL with prior exposure to blinatumomab and/or inotuzumab ozogamicin presenting for CAR-T cell treatment. Both patients were thought to only have minimal residual disease (MRD) at the pre-CAR disease assessment, with MRD of 6,648 (0.66%) and 100 (0.01%) cells per million cells, respectively, as measured by next-generation sequencing (NGS) in their bone marrows. Both patients for distinct reasons unrelated to non-CNS extra-medullary (EM) symptoms had PET-MRIs prior to lymphodepletion and CAR T cell infusion. In both cases patients were found to have significant bulky subclinical EM disease that required changes in clinical management. In the newly-emergent era of antigen-targeted immunotherapy, it is foundational that incidence and relapse patterns following targeted therapy are well-understood. Herein we contribute to a growing body of literature addressing this fundamental clinical gap and highlight a future role for formal prospective imaging studies to better establish response, toxicity and relapse patterns following CAR-T cell therapy in EM B-ALL.

Statins are the first-line therapy for the prevention and treatment of atherosclerotic vascular disease; however, various other lipid-lowering agents can provide additional beneficial effects when to statin therapy or alternatives for patients who are intolerant to statins. In this Review, Antonio Gotto Jr and Jennifer Moon discuss the mechanisms of action, indications, and clinical data for existing pharmacotherapies for lipid modification, as well as trials of investigational agents that are being developed for cardiovascular risk reduction. The widespread clinical use of statins has contributed to significant reductions in the rate of cardiovascular morbidity and mortality over the past 3 decades, and statins are considered first-line therapy for the prevention and treatment of atherosclerotic vascular disease. Nevertheless, various other lipid-lowering agents can provide clinical benefit by supplementing or augmenting statin therapy in patients with severe hypercholesterolaemia or mixed dyslipidaemia, or by providing an alternative for patients who are intolerant to statins. Bile acid resins and niacin were prescribed for lipid modification for years before the introduction of the statins, and new data continue to emerge regarding their use in different patient groups and for specific conditions. Ezetimibe can be appropriate for patients whose primary lipid abnormality is an elevated LDL-cholesterol level, whereas the fibrates seem to be most beneficial in patients with low levels of HDL cholesterol and elevated triglycerides. At the end of 2012 and the beginning of 2013, the first microsomal triglyceride transfer protein inhibitor, lomitapide, and the first antisense therapy to target apolipoprotein B, mipomersen, were approved for the treatment of individuals with extremely elevated LDL-cholesterol levels caused by homozygous familial hypercholesterolaemia. Although two agents in the experimental class of cholesteryl ester transfer protein inhibitors have failed to show a benefit in clinical trials, newer drugs in this class could provide an additional strategy to address residual cardiovascular risk in patients treated with statins. Key Points Statin therapy is the mainstay of lipid-lowering treatment, but residual cardiovascular risk remains unacceptably high in patients with coronary heart disease receiving optimal statin therapy Patients with statin intolerance, mixed dyslipidaemia, or an extremely elevated LDL-cholesterol level might benefit from additional LDL-cholesterol lowering therapies, or agents that favourably modify HDL-cholesterol and triglyceride levels Bile acid resins and ezetimibe can be used with or without statins to reduce LDL-cholesterol levels, although the clinical benefit of ezetimibe awaits the results of a randomized clinical trial Patients with homozygous familial hypercholesterolaemia might benefit from lomitapide, a microsomal triglyceride transfer protein inhibitor, and mipomersen, an antisense inhibitor of apolipoprotein B synthesis Niacin and fibrates help correct lipid abnormalities and can reduce cardiovascular risk in patients with a low HDL-cholesterol level, high triglyceride levels, or both Results of clinical trials with experimental cholesteryl ester transfer protein inhibitors are eagerly anticipated, and are expected to provide valuable data on the clinical benefit of pharmacologically raising HDL cholesterol

Primary nonautoimmune hyperthyroidism is a rare cause of neonatal hyperthyroidism. This results from an activating mutation in the thyrotropin-receptor (TSHR). It can be inherited in an autosomal dominant manner or occur sporadically as a de novo mutation. Affected individuals display a wide phenotype from severe neonatal to mild subclinical hyperthyroidism. We describe a 6-month-old boy with a de novo mutation in the TSHR gene who presented with accelerated growth, enlarging head circumference, tremor and thyrotoxicosis. Genomic DNA from the patient's and parents' peripheral blood leukocytes was extracted. Exons 9 and 10 of the TSHR gene were amplified by PCR and sequenced. Sequencing exon 10 of the TSHR gene revealed a novel heterozygous missense mutation substituting cytosine to adenine at nucleotide position 1534 in the patient's peripheral blood leukocytes. This leads to a substitution of leucine to methionine at amino acid position 512. The mutation was absent in the parents. In silico modeling by PolyPhen-2 and SIFT predicted the mutation to be deleterious. The p.Leu512Met mutation (c.1534C>A) of the TSHR gene has not been previously described in germline or somatic mutations. This case presentation highlights the possibility of mild thyrotoxicosis in affected individuals and contributes to the understanding of sporadic non-autoimmune primary hyperthyroidism.

Inhibition of cholesteryl ester transfer protein is a strategy under investigation for raising HDL cholesterol levels and addressing residual cardiovascular risk after effective reduction of LDL cholesterol. In the Phase III DEFINE trial conducted in patients with or at high risk for coronary heart disease, anacetrapib reduced LDL cholesterol levels by 39.8% after 24 weeks compared with placebo and demonstrated an acceptable safety profile through 76 weeks of treatment (the primary end points). Anacetrapib caused a placebo-adjusted 138.1% increase in HDL cholesterol levels, with no alterations in blood pressure, aldosterone or electrolytes. The trial also provided reassurance that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with a previous cholesteryl ester transfer protein inhibitor. Sustained effects on lipids were observed 12 weeks following cessation of anacetrapib treatment. Anacetrapib is being evaluated in an ongoing cardiovascular outcomes trial.