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Found 34923 matches. Displaying 141-150
Anderson CJ, Bredvik K, Burstein SR, Davis C, Meadows SM, Dash J, Case L, Milner TA, Kawamata H, Zuberi A, Piersigilli A, Lutz C, Manfredi G
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ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response

ACTA NEUROPATHOLOGICA 2019 JUL; 138(1):103-121
Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), a mitochondrial protein of unknown function, cause a disease spectrum with clinical features of motor neuron disease, dementia, myopathy and cardiomyopathy. To investigate the pathogenic mechanisms of CHCHD10, we generated mutant knock-in mice harboring the mouse-equivalent of a disease-associated human S59L mutation, S55L in the endogenous mouse gene. CHCHD10(S55L) mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Critically, CHCHD10 accumulates in aggregates with its paralog CHCHD2 specifically in affected tissues of CHCHD10(S55L) mice, leading to aberrant organelle morphology and function. Aggregates induce a potent mitochondrial integrated stress response (mtISR) through mTORC1 activation, with elevation of stress-induced transcription factors, secretion of myokines, upregulated serine and one-carbon metabolism, and downregulation of respiratory chain enzymes. Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10(S55L)-dependent disease pathology is not caused by loss-of-function. Overall, CHCHD10(S55L) mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation.
Bredbenner K
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One Ph. D., hold the pastries

SCIENCE 2019 JUL 5; 365(6448):94-94
I never thought I would spend so much of my time and money setting up still-life–worthy displays of flaky croissants and shiny fruit for people who are judging my science, and that of my colleagues. Yet that's the expectation: At my university, and many others, students bring food to our thesis committee meetings and defenses, adding to the already sky-high pressure. My first taste of it came 5 years ago, for my first committee meeting. I prepared furiously. I meticulously proofread my written proposal and aligned all the figures. My slides all used the same font. I had even prepared some extra slides to address possible questions my judges might ask. Even so, I was sure the meeting was doomed—because I didn't know how to make coffee.
Doria JW, Forgacs PB
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Incidence, Implications, and Management of Seizures Following Ischemic and Hemorrhagic Stroke

Purpose of ReviewIn this review, we summarize the recent literature regarding the incidence and treatment of seizures arising after ischemic and hemorrhagic strokes. Additionally, we identify open questions in guidelines and standard clinical care to aid future studies aiming to improve management of seizures in post-stroke patients.Recent FindingsStudies demonstrate an increasing prevalence of seizures following strokes, probably a consequence of advances in post-stroke management and expanding use of continuous EEG monitoring. Post-stroke seizures are associated with longer hospitalization and increased mortality; therefore, prevention and timely treatment of seizures are important. The standard of care is to treat recurrent seizures with anti-epileptic drugs (AEDs) regardless of the etiology. However, there are no established guidelines currently for prophylactic use of AEDs following a stroke.SummaryThe prevalence of post-stroke seizures is increasing. Further studies are needed to determine the risk factors for recurrent seizures and epilepsy after strokes and optimal treatment strategies.
Hammer MJ, Paul SM, Steinberg A, Eckardt P, Barton-Burke M, Miaskowski C
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Trajectories of Fasting Blood Glucose in Autologous Hematopoietic Cell Transplantation

CANCER NURSING 2019 JUL-AUG; 42(4):307-313
Background Patients who receive autologous hematopoietic cell transplantation (HCT) for the treatment of hematologic malignancies are at risk of serious adverse outcomes including infections and death. Hyperglycemia following the HCT is associated with increased risk of these adverse outcomes. However, limited information is available on demographic and clinical characteristics that contribute to changes in blood glucose levels following HCT. Objective The objective of this study was to determine the trajectories of fasting blood glucose (FBG) levels as well as the demographic and clinical characteristics that predicted interindividual differences in these FBG trajectories. Methods A sample of adult patients with hematologic malignancies who were scheduled to receive autologous HCT (n = 53) was enrolled in the study. Patients with preexisting diabetes were excluded. Demographic and clinical characteristics were abstracted from electronic medical records. Morning fasting laboratory tests (ie, FBG and absolute neutrophil counts) were obtained. Data were analyzed using hierarchical linear modeling from the day of HCT (day 0) through 14 days post-HCT. Results Among 8 characteristics evaluated, pre-HCT FBG was associated with variability in both the initial levels and the trajectories of FBG. Body mass index was only associated with initial levels of FBG. Conclusions The large amount of interindividual variability in the trajectories of FBG levels following autologous HCT suggests that glucose control in these patients warrants ongoing assessments and preemptive tailoring.
Cook B
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Discovery of a Small Molecule Promoting Mouse and Human Osteoblast

CELL CHEMICAL BIOLOGY 2019 JUL 18; 26(7):926-935.e6
Disorders of bone healing and remodeling are indications with an unmet
Der E, Suryawanshi H, Morozov P, Kustagi M, Goilav B, Ranabathou S, Izmirly P, Clancy R, Belmont HM, Koenigsberg M, Mokrzycki M, Rominieki H, Graham JA, Rocca JP, Bornkamp N, Jordan N, Schulte E, Wu M, Pullman J, Slowikowski K, Raychaudhuri S, Guthridge J, James J, Buyon J, Tuschl T, Putterman C, Anolik J, Apruzzese W, Arazi A, Berthier C, Brenner M, Connery S, Cunningham M, Dall'Era M, Davidson A, Fava A, Fonseka C, Furie R, Goldman D, Gupta R, Guthridge J, Hacohen N, Hildeman D, Hoover P, Hsu R, Kado R, Kalunian K, Kamen D, Kretzler M, Maecker H, Massarotti E, McCune W, McMahon M, Park M, Payan-Schober F, Pendergraft W, Petri M, Pichavant M, Rao D, Utz P, Waguespack D, Wofsy D, Zhang F
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Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways

NATURE IMMUNOLOGY 2019 JUL; 20(7):915-927
The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.
Wang WS, Ishibashi J, Trefely S, Shao ML, Cowan AJ, Sakers A, Lim HW, O'Connor S, Doan MT, Cohen P, Baur JA, King MT, Veech RL, Won KJ, Rabinowitz JD, Snyder NW, Gupta RK, Seale P
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A PRDM16-Driven Metabolic Signal from Adipocytes Regulates Precursor Cell Fate

CELL METABOLISM 2019 JUL 2; 30(1):174-189.e5
The precursor cells for metabolically beneficial beige adipocytes can alternatively become fibrogenic and contribute to adipose fibrosis. We found that cold exposure or beta 3-adrenergic agonist treatment of mice decreased the fibrogenic profile of precursor cells and stimulated beige adipocyte differentiation. This fibrogenic-to-adipogenic transition was impaired in aged animals, correlating with reduced adipocyte expression of the transcription factor PRDM16. Genetic loss of Prdm16 mimicked the effect of aging in promoting fibrosis, whereas increasing PRDM16 in aged mice decreased fibrosis and restored beige adipose development. PRDM16-expressing adipose cells secreted the metabolite beta-hydroxybutyrate (BHB), which blocked precursor fibrogenesis and facilitated beige adipogenesis. BHB catabolism in precursor cells, mediated by BDH1, was required for beige fat differentiation in vivo. Finally, dietary BHB supplementation in aged animals reduced adipose fibrosis and promoted beige fat formation. Together, our results demonstrate that adipocytes secrete a metabolite signal that controls beige fat remodeling.
Nam AS, Kim KT, Chaligne R, Izzo F, Ang C, Taylor J, Myers RM, Abu-Zeinah G, Brand R, Omans ND, Alonso A, Sheridan C, Mariani M, Dai X, Harrington E, Pastore A, Cubillos-Ruiz JR, Tam W, Hoffman R, Rabadan R, Scandura JM, Abdel-Wahab O, Smibert P, Landau DA
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Somatic mutations and cell identity linked by Genotyping of Transcriptomes.

NATURE 2019 JUL 18; 571(7765):355-360
Defining the transcriptomic identity of malignant cells is challenging in the absence of surface markers that distinguish cancer clones from one another, or from admixed non-neoplastic cells. To address this challenge, here we developed Genotyping of Transcriptomes (GoT), a method to integrate genotyping with high-throughput droplet-based single-cell RNA sequencing. We apply GoT to profile 38,290 CD34+ cells from patients with CALR-mutated myeloproliferative neoplasms to study how somatic mutations corrupt the complex process of human haematopoiesis. High-resolution mapping of malignant versus normal haematopoietic progenitors revealed an increasing fitness advantage with myeloid differentiation of cells with mutated CALR. We identified the unfolded protein response as a predominant outcome of CALR mutations, with a considerable dependency on cell identity, as well as upregulation of the NF-κB pathway specifically in uncommitted stem cells. We further extended the GoT toolkit to genotype multiple targets and loci that are distant from transcript ends. Together, these findings reveal that the transcriptional output of somatic mutations in myeloproliferative neoplasms is dependent on the native cell identity.
Estrogens receptors (ER) are involved in several sociosexual behaviors and fear responses. In particular, the ER alpha is important for sexual behaviors, whereas ER beta modulates anxiolytic responses. Using shRNA directed either against the ER alpha or the ER beta RNAs (or containing luciferase control) encoded within an adeno-associated viral vector, we silenced these receptors in the ventromedial nucleus of the hypothalamus (VMN) and the central amygdala (CeA). We exposed ovariectomized female rats, sequentially treated with estradiol benzoate and progesterone, to five stimuli, previously reported to elicit positive and negative affect. The subjects were housed in groups of 4 females and 3 males in a seminatural environment for several days before hormone treatment. We analyzed the frequency of a large number of behavior patterns. In addition, we performed analyses of co-occurrence in order to detect changes in the structure of behavior after infusion of the vectors. Silencing the ER alpha in the VMN disrupted lordosis and showed some anxiolytic properties in aversive situations, whereas silencing of the ER beta in this structure had no effect. This was also the case after silencing the ER alpha in the CeA. Silencing of the ER beta in this structure increased risk assessment, an expression of anxiety, and increased olfactory exploration of the environment. We hypothesize that the ER beta in the CeA has an important role in the well-established anxiolytic effects of estrogens, and that it may modulate arousal level. Furthermore, it seems that the ER alpha in the VMN is anxiogenic in aversive or threatening situations, in agreement with other studies.
Fava VM
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Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and

Type-1 reactions (T1R) are pathological inflammatory episodes and main