BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations

A transition from fetal hemoglobin (HbF) to adult hemoglobin (HbA) normally occurs within a few months after birth. Increased production of HbF after this period of infancy ameliorates clinical symptoms of the major disorders of adult ß-hemoglobin: ß-thalassemia and sickle cell disease. The transcription factor BCL11A silences HbF and has been an attractive therapeutic target for increasing HbF levels; however, it is not clear to what extent BCL11A inhibits HbF production or mediates other developmental functions in humans. Here, we identified and characterized 3 patients with rare microdeletions of 2p15-p16.1 who presented with an autism spectrum disorder and developmental delay. Moreover, these patients all exhibited substantial persistence of HbF but otherwise retained apparently normal hematologic and immunologic function. Of the genes within 2p15-p16.1, only BCL11A was commonly deleted in all of the patients. Evaluation of gene expression data sets from developing and adult human brains revealed that BCL11A expression patterns are similar to other genes associated with neurodevelopmental disorders. Additionally, common SNPs within the second intron of BCL11A are strongly associated with schizophrenia. Together, the study of these rare patients and orthogonal genetic data demonstrates that BCL11A plays a central role in silencing HbF in humans and implicates BCL11A as an important factor for neurodevelopment

High aboveground carbon stock of African tropical montane forests

Tropical forests store 40-50 per cent of terrestrial vegetation carbon(1). However, spatial variations in aboveground live tree biomass carbon (AGC) stocks remain poorly understood, in particular in tropical montane forests(2). Owing to climatic and soil changes with increasing elevation(3), AGC stocks are lower in tropical montane forests compared with lowland forests(2). Here we assemble and analyse a dataset of structurally intact old-growth forests (AfriMont) spanning 44 montane sites in 12 African countries. We find that montane sites in the AfriMont plot network have a mean AGC stock of 149.4 megagrams of carbon per hectare (95% confidence interval 137.1-164.2), which is comparable to lowland forests in the African Tropical Rainforest Observation Network(4) and about 70 per cent and 32 per cent higher than averages from plot networks in montane(2,5,6) and lowland(7) forests in the Neotropics, respectively. Notably, our results are two-thirds higher than the Intergovernmental Panel on Climate Change default values for these forests in Africa(8). We find that the low stem density and high abundance of large trees of African lowland forests(4) is mirrored in the montane forests sampled. This carbon store is endangered: we estimate that 0.8 million hectares of old-growth African montane forest have been lost since 2000. We provide country-specific montane forest AGC stock estimates modelled from our plot network to help to guide forest conservation and reforestation interventions. Our findings highlight the need for conserving these biodiverse(9,10) and carbon-rich ecosystems. The aboveground carbon stock of a montane African forest network is comparable to that of a lowland African forest network and two-thirds higher than default values for these montane forests.Peer reviewe

Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study.

peer reviewedAllogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT

• ROTHSCHILD ET AL. Recent Trends in Optical Lithography Recent Trends in Optical Lithography

■ The fast-paced evolution of optical lithography has been a key enabler in the dramatic size reduction of semiconductor devices and circuits over the last three decades. Various methods have been devised to pattern at dimensions smaller than the wavelength used in the process. In addition, the patterning wavelength itself has been reduced and will continue to decrease in the future. As a result, it is expected that optical lithography will remain the technology of choice in lithography for at least another decade. Lincoln Laboratory has played a seminal role in the progress of optical lithography; it pioneered 193-nm lithography, which is used in advanced production, and 157-nm lithography, which is under active development. Lincoln Laboratory also initiated exploration of liquidimmersion lithography and studied the feasibility of 121-nm lithography. Many of the challenges related to practical implementation of short-wavelength optical lithography are materials-related, including engineering of new materials, improving on existing materials, and optimizing their photochemistry. This article examines the technical issues facing optical lithography and Lincoln Laboratory’s contributions toward their resolution. Optical lithography, the technology of patterning, has enabled semiconductor devices to progressively shrink since the inception of integrated circuits more than three decades ago. Throughout the 1980s and 1990s, the trend of miniaturization continued unabated and even accelerated. Current semiconductor devices are being mass produced with 130-nm dense features; by 2007 these devices will have 65-nm dense features. Optical lithography has been, and will remain for the foreseeable future, the critical technology that makes this trend possible. (To learn the fundamentals of optical lithography, see the sidebar entitled “Optical Lithograph

• ROTHSCHILD ET AL. Photolithography at 193 nm Photolithography at 193 nm

■ For the last two decades photolithography has been the principal technology for patterning the progressively smaller and denser features required in microelectronic devices and circuits. In recent years, the increasing sophistication of photolithographic techniques using radiation at wavelengths comparable to the feature size has enabled the mass production of circuits in which critical dimensions are 0.25 μm. The drive to smaller dimensions is expected to continue in the future to critical dimensions of 0.18, 0.13, and even 0.07 μm, which necessitates a shift to radiation at shorter wavelengths. Lincoln Laboratory has been at the forefront of the development of next-generation photolithographic technology, namely, the use of 193-nm laser radiation. This article presents the rationale behind the transition to this new wavelength, and reviews the status of critical issues encountered in its implementation as a manufacturing process. These issues concern the suitability of optical materials and coatings for lens fabrication, the use of photoresists and wafer processing for device fabrication, and the outlook for extending the usefulness of 193-n

BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations

A transition from fetal hemoglobin (HbF) to adult hemoglobin (HbA) normally occurs within a few months after birth. Increased production of HbF after this period of infancy ameliorates clinical symptoms of the major disorders of adult β-hemoglobin: β-thalassemia and sickle cell disease. The transcription factor BCL11A silences HbF and has been an attractive therapeutic target for increasing HbF levels; however, it is not clear to what extent BCL11A inhibits HbF production or mediates other developmental functions in humans. Here, we identified and characterized 3 patients with rare microdeletions of 2p15-p16.1 who presented with an autism spectrum disorder and developmental delay. Moreover, these patients all exhibited substantial persistence of HbF but otherwise retained apparently normal hematologic and immunologic function. Of the genes within 2p15-p16.1, only BCL11A was commonly deleted in all of the patients. Evaluation of gene expression data sets from developing and adult human brains revealed that BCL11A expression patterns are similar to other genes associated with neurodevelopmental disorders. Additionally, common SNPs within the second intron of BCL11A are strongly associated with schizophrenia. Together, the study of these rare patients and orthogonal genetic data demonstrates that BCL11A plays a central role in silencing HbF in humans and implicates BCL11A as an important factor for neurodevelopment

Local endothelial dna repair defect causes aging-resembling endothelial-specific dysfunction

We previously identified genomic instability as a causative factor for vascular aging. In the present study determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 DNA repair in mice (EC-KO mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared to WT. EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared to WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide were intact. EC-KO showed increased superoxide production compared to WT, as measured in lung tissue, rich in endothelial cells. Arterial systolic blood pressure was increased at 3 months, but normal at 5 months, at which age cardiac output was decreased. Since no further signs of cardiac dysfunction were detected this decrease might be an adaptation to prevent an increase of blood pressure. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived nitric oxide. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung

Does less frequent routine monitoring of patients on a stable, fully suppressed cART regimen lead to an increased risk of treatment failure?

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease