IGERT: Sensor Science, Engineering, and Informatics

This Sensor Science, Engineering and Informatics (SSEI) IGERT program will provide multidisciplinary doctoral training in the area of sensor systems ranging from the science and engineering of new materials and sensing mechanisms to the interpretation of sensor data. The design and management of effective sensor systems requires a holistic understanding of how information is collected, stored, integrated, evaluated, and communicated within sensing systems and to decision makers in diverse application contexts. The SSEI IGERT weaves together three research focus areas: (1) Sensor Materials and Devices, (2) Sensor Systems and Networks, and (3) Sensor Informatics. The intellectual merit of the project includes education and research activities that are designed to ensure a feedback loop so that SSEI IGERT trainees are able to transform new knowledge from sensor-generated data to further development of sensor systems and networks and advances in sensor materials and devices, and vice versa. Innovative components of the program include (1) development and use of a testbed prototype that will require interdisciplinary interaction across the three research areas; (2) a tight integration of the social, legal, ethical, and economic dimensions of sensing environments in both research and training, (3) expanded relationships with companies and federal laboratories engaged in sensor research, (4) international collaborations, and (5) synergistic integration with sensor science and engineering education at the middle, high school, and undergraduate level. The broader impacts of the SSEI IGERT program are a new breed of scientists and engineers who will be versatile in dealing with the diverse technical components that contribute to sensing systems, knowledgeable in the legal, social, and ethical contexts of heavily sensed environments, and aware of the human values that must be preserved, protected and promoted within such systems. IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries

POGZ Is Required for Silencing Mouse Embryonic β-like Hemoglobin and Human Fetal Hemoglobin Expression

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesFetal globin genes are transcriptionally silenced during embryogenesis through hemoglobin switching. Strategies to derepress fetal globin expression in the adult could alleviate symptoms in sickle cell disease and β-thalassemia. We identified a zinc-finger protein, pogo transposable element with zinc-finger domain (POGZ), expressed in hematopoietic progenitor cells. Targeted deletion of Pogz in adult hematopoietic cells in vivo results in persistence of embryonic β-like globin expression without affecting erythroid development. POGZ binds to the Bcl11a promoter and erythroid-specific intragenic regulatory regions. Pogz+/- mice show elevated embryonic β-like globin expression, suggesting that partial reduction of Pogz expression results in persistence of embryonic β-like globin expression. Knockdown of POGZ in primary human CD34+ progenitor cell-derived erythroblasts reduces BCL11A expression, a known repressor of embryonic β-like globin expression, and increases fetal hemoglobin expression. These findings are significant, since new therapeutic targets and strategies are needed to treat β-globin disorders.Frederick National Laboratory for Cancer Research, NIH intramural research program of the NHLBI, NIH intramural research program of the NIDDK, NIH USUH

BCL11A enhancer edited hematopoietic stem cells persist in rhesus monkeys without toxicity

Gene editing of the erythroid-specific BCL11A enhancer in hematopoietic stem and progenitor cells (HSPCs) from sickle cell disease (SCD) patients induces fetal hemoglobin (HbF) without detectable toxicity as assessed by mouse xenotransplant. Here, we evaluated autologous engraftment and HbF induction potential of erythroid-specific BCL11A enhancer edited HSPCs in four non-human primates. We utilized a single guide RNA (sgRNA) with identical human and rhesus target sequences to disrupt a GATA1 binding site at the BCL11A +58 erythroid enhancer. Cas9 protein and sgRNA ribonucleoprotein complex (RNP) was electroporated into rhesus HSPCs, followed by autologous infusion after myeloablation. We found that gene edits persisted in peripheral blood (PB) and bone marrow (BM) for up to 101 weeks similarly for BCL11A enhancer or control locus (AAVS1) targeted cells. Biallelic BCL11A enhancer editing resulted in robust gamma-globin induction, with the highest levels observed during stress erythropoiesis. Indels were evenly distributed across PB and BM lineages. Off-target edits were not observed. Non-homologous end-joining repair alleles were enriched in engrafting HSCs. In summary, we find that edited HSCs can persist for at least 101 weeks post-transplant, and biallelic edited HSCs provide substantial HbF levels in PB red blood cells, together supporting further clinical translation of this approach

The medical student

The Medical Student was published from 1888-1921 by the students of Boston University School of Medicine

The Regulation of Skeletal Muscle Protein Turnover during the Progression of Cancer Cachexia in the ApcMin/+ Mouse

Muscle wasting that occurs with cancer cachexia is caused by an imbalance in the rates of muscle protein synthesis and degradation. The ApcMin/+ mouse is a model of colorectal cancer that develops cachexia that is dependent on circulating IL-6. However, the IL-6 regulation of muscle protein turnover during the initiation and progression of cachexia in the ApcMin/+ mouse is not known. Cachexia progression was studied in ApcMin/+ mice that were either weight stable (WS) or had initial (≤5%), intermediate (6–19%), or extreme (≥20%) body weight loss. The initiation of cachexia reduced %MPS 19% and a further ∼50% with additional weight loss. Muscle IGF-1 mRNA expression and mTOR targets were suppressed with the progression of body weight loss, while muscle AMPK phosphorylation (Thr 172), AMPK activity, and raptor phosphorylation (Ser 792) were not increased with the initiation of weight loss, but were induced as cachexia progressed. ATP dependent protein degradation increased during the initiation and progression of cachexia. However, ATP independent protein degradation was not increased until cachexia had progressed beyond the initial phase. IL-6 receptor antibody administration prevented body weight loss and suppressed muscle protein degradation, without any effect on muscle %MPS or IGF-1 associated signaling. In summary, the %MPS reduction during the initiation of cachexia is associated with IGF-1/mTOR signaling repression, while muscle AMPK activation and activation of ATP independent protein degradation occur later in the progression of cachexia. IL-6 receptor antibody treatment blocked cachexia progression through the suppression of muscle protein degradation, while not rescuing the suppression of muscle protein synthesis. Attenuation of IL-6 signaling was effective in blocking the progression of cachexia, but not sufficient to reverse the process

Gene therapy for sickle cell disease: moving from the bench to the bedside.

Gene therapy as a potential cure for sickle cell disease (SCD) has long been pursued, given that this hemoglobin (Hb) disorder results from a single point mutation. Advances in genomic sequencing have increased the understanding of Hb regulation, and discoveries of molecular tools for genome modification of hematopoietic stem cells have made gene therapy for SCD possible. Gene-addition strategies using gene transfer vectors have been optimized over the past few decades to increase expression of normal or antisickling globins as strategies to ameliorate SCD. Many hurdles had to be addressed before clinical translation, including collecting sufficient stem cells for gene modification, increasing expression of transferred genes to a therapeutic level, and conditioning patients in a safe manner that enabled adequate engraftment of gene-modified cells. The discovery of genome editors that make precise modifications has further advanced the safety and efficacy of gene therapy, and a rapid movement to clinical trial has undoubtedly been supported by lessons learned from optimizing gene-addition strategies. Current gene therapies being tested in clinical trial require significant infrastructure and expertise, given that cells must be harvested from and chemotherapy administered to patients who often have significant organ dysfunction and that gene-modification takes place ex vivo in specialized facilities. For these therapies to realize their full potential, they would have to be portable, safe, and efficient, to make an in vivo–based approach attractive. In addition, adequate resources for SCD screening and access to standardized care are critically important for gene therapy to be a viable treatment option for SCD

Tortoise and hare win for SCD

Bernaudin and colleagues report, in this issue of Blood, the long-term results of the largest study of related myeloablative stem-cell transplantation for sickle cell disease (SCD). Their results show that slow, steady improvements over time, along with the addition of rabbit anti–thymocyte globulin (ATG) to the conditioning regimen, combine to produce an event-free survival (EFS) of 95.3%. They argue that for children with a suitable sibling-matched donor, myeloablative transplantation should be considered the standard of care in those at high risk for stroke