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Article: Delayed reaction to penicillin in beeswax and peanut oil (P. O. B.) in a child.

MANDEL, E E / BASCH, F P / GREENGARD, J

2008 Volume 65, Issue 3, Page(s) 119–123

MeSH term(s)	Peanut Oil ; Penicillins ; Plant Oils ; Waxes
Chemical Substances	Peanut Oil ; Penicillins ; Plant Oils ; Waxes ; beeswax (2ZA36H0S2V)
Language	English
Publishing date	2008-09-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	1181947-9
ISSN	1769-664X ; 0096-6630 ; 0929-693X
ISSN (online)	1769-664X
ISSN	0096-6630 ; 0929-693X
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Article: Roscovitine: a novel regulator of P/Q-type calcium channels and transmitter release in central neurons.

Yan, Zhen / Chi, Ping / Bibb, James A / Ryan, Timothy A / Greengard, Paul

The Journal of physiology

2002 Volume 540, Issue Pt 3, Page(s) 761–770

Abstract: ... calcium currents was significantly blocked by the P/Q-channel blocker CgTx-MVIIC, indicating ... that the major target of roscovitine is the P/Q-type calcium channel. In mutant mice with targeted deletion ... effect of roscovitine on the P/Q-type calcium channel, the major mediator of action potential-evoked ...

Abstract	Roscovitine is widely used for inhibition of cdk5, a cyclin-dependent kinase expressed predominantly in the brain. A novel function of roscovitine, i.e. an effect on Ca(2+) channels and transmitter release in central neurons, was studied by whole-cell voltage-clamp recordings and time-lapse fluorescence imaging techniques. Extracellular application of roscovitine markedly enhanced the tail calcium current following repolarization from depolarized voltages. This effect was rapid, reversible and dose dependent. Roscovitine dramatically slowed the deactivation kinetics of calcium channels. The deactivation time constant was increased 3- to 6-fold, suggesting that roscovitine could prolong the channel open state and increase the calcium influx. The potentiation of tail calcium currents caused by roscovitine and by the L-channel activator Bay K 8644 was not occluded but additive. Roscovitine-induced potentiation of tail calcium currents was significantly blocked by the P/Q-channel blocker CgTx-MVIIC, indicating that the major target of roscovitine is the P/Q-type calcium channel. In mutant mice with targeted deletion of p35, a neuronal specific activator of cdk5, roscovitine regulated calcium currents in a manner similar to that observed in wild-type mice. Moreover, intracellular perfusion of roscovitine failed to modulate calcium currents. These results suggest that roscovitine acts on extracellular site(s) of calcium channels via a cdk5-independent mechanism. Roscovitine potentiated glutamate release at presynaptic terminals of cultured hippocampal neurons detected with the vesicle trafficking dye FM1-43, consistent with the positive effect of roscovitine on the P/Q-type calcium channel, the major mediator of action potential-evoked transmitter release in the mammalian CNS.
MeSH term(s)	3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology ; Animals ; Calcium Channels, P-Type/drug effects ; Calcium Channels, P-Type/physiology ; Calcium Channels, Q-Type/drug effects ; Calcium Channels, Q-Type/physiology ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Enzyme Inhibitors/pharmacology ; Hippocampus/physiology ; Kinetics ; Membrane Potentials/drug effects ; Mice ; Neurons/physiology ; Patch-Clamp Techniques ; Purines/pharmacology ; Rats ; Roscovitine
Chemical Substances	Calcium Channels, P-Type ; Calcium Channels, Q-Type ; Enzyme Inhibitors ; Purines ; Roscovitine (0ES1C2KQ94) ; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester (71145-03-4) ; Cyclin-Dependent Kinases (EC 2.7.11.22)
Language	English
Publishing date	2002-05-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/jphysiol.2001.013376
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Book ; Online: LQ-LoRA

Guo, Han / Greengard, Philip / Xing, Eric P. / Kim, Yoon

Low-rank Plus Quantized Matrix Decomposition for Efficient Language Model Finetuning

2023

Abstract: We propose a simple approach for memory-efficient adaptation of pretrained language models. Our approach uses an iterative algorithm to decompose each pretrained matrix into a high-precision low-rank component and a memory-efficient quantized component. ... ...

Abstract	We propose a simple approach for memory-efficient adaptation of pretrained language models. Our approach uses an iterative algorithm to decompose each pretrained matrix into a high-precision low-rank component and a memory-efficient quantized component. During finetuning, the quantized component remains fixed and only the low-rank component is updated. We present an integer linear programming formulation of the quantization component which enables dynamic configuration of quantization parameters (e.g., bit-width, block size) for each matrix given an overall target memory budget. We further explore a data-aware version of the algorithm which uses an approximation of the Fisher information matrix to weight the reconstruction objective during matrix decomposition. Experiments on finetuning RoBERTa and LLaMA-2 (7B and 70B) demonstrate that our low-rank plus quantized matrix decomposition approach (LQ-LoRA) outperforms strong QLoRA and GPTQ-LoRA baselines and enables aggressive quantization to sub-3 bits with only minor performance degradations. When finetuned on a language modeling calibration dataset, LQ-LoRA can also be used for model compression; in this setting our 2.75-bit LLaMA-2-70B model (which has 2.85 bits on average when including the low-rank components and requires 27GB of GPU memory) performs respectably compared to the 16-bit baseline.
Keywords	Computer Science - Computation and Language ; Computer Science - Machine Learning
Subject code	518
Publishing date	2023-11-20
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A conversation with Paul Greengard. Interview by Ushma S. Neill.

Greengard, Paul

The Journal of clinical investigation

2013 Volume 123, Issue 3, Page(s) 937–938

MeSH term(s)	England ; History, 20th Century ; History, 21st Century ; Netherlands ; Neurophysiology/history ; Nobel Prize ; United States
Language	English
Publishing date	2013-03-01
Publishing country	United States
Document type	Autobiography ; Biography ; Historical Article ; Interview ; Portrait
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI68877
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Article ; Online: A conversation with Paul Greengard. Interview by Eric J Nestler.

Greengard, Paul

Annual review of pharmacology and toxicology

2013 Volume 53, Page(s) 1–16

Abstract: Paul Greengard was born in New York City in 1925. After completing high school, he served three ... substrates in the regulation of synaptic transmission. In 1983, Greengard moved to The Rockefeller University ... Parkinson's disease, and depression. He is the author of more than 950 research articles and reviews. Greengard has ...

Abstract	Paul Greengard was born in New York City in 1925. After completing high school, he served three years in the US Navy during World War II and then completed his bachelor's degree at Hamilton College where he majored in physics and mathematics. He obtained a PhD in biophysics from Johns Hopkins University in 1953 and pursued postdoctoral training with Wilhelm Feldberg at the National Institute for Medical Research in England. After eight years as head of biochemistry at Geigy, and sabbaticals at Albert Einstein College of Medicine and Vanderbilt University, he joined the Yale University faculty as a full professor of pharmacology in 1968. While he was at Yale, Greengard's laboratory performed groundbreaking research, which demonstrated a role for cyclic nucleotides, protein kinases and protein phosphatases, and their protein substrates in the regulation of synaptic transmission. In 1983, Greengard moved to The Rockefeller University, where he has since served as the Vincent Astor Professor and Head of the Laboratory of Molecular and Cellular Neuroscience. Greengard's paradigm-shifting research has continued at Rockefeller and has informed our understanding and possible treatment of a host of brain disorders, including schizophrenia, Alzheimer's disease, Parkinson's disease, and depression. He is the author of more than 950 research articles and reviews. Greengard has received numerous awards and honors, including the Nobel Prize in Physiology or Medicine in 2000, the Metropolitan Life Foundation Award for Medical Research, The National Academy of Sciences Award in Neuroscience, the Ralph W. Gerard Prize in Neuroscience for the Society for Neuroscience, and the Karolinska Institutet's Bicentennial Gold Medal. He is a member of the US National Academy of Sciences and the Institute of Medicine of the National Academies. The following interview was conducted on May 29, 2012.
MeSH term(s)	Animals ; Brain/physiology ; Cyclic AMP/physiology ; Dopamine and cAMP-Regulated Phosphoprotein 32/physiology ; Humans ; Neurons/physiology ; Neuropharmacology
Chemical Substances	Dopamine and cAMP-Regulated Phosphoprotein 32 ; PPP1R1B protein, human ; Cyclic AMP (E0399OZS9N)
Language	English
Publishing date	2013
Publishing country	United States
Document type	Interview
ZDB-ID	196587-6
ISSN	1545-4304 ; 0362-1642
ISSN (online)	1545-4304
ISSN	0362-1642
DOI	10.1146/annurev-pharmtox-062712-160347
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Article ; Online: A fast spectral method for electrostatics in doubly periodic slit channels.

Maxian, Ondrej / Peláez, Raúl P / Greengard, Leslie / Donev, Aleksandar

The Journal of chemical physics

2021 Volume 154, Issue 20, Page(s) 204107

Abstract: We develop a fast method for computing the electrostatic energy and forces for a collection of charges in doubly periodic slabs with jumps in the dielectric permittivity at the slab boundaries. Our method achieves spectral accuracy by using Ewald ... ...

Abstract	We develop a fast method for computing the electrostatic energy and forces for a collection of charges in doubly periodic slabs with jumps in the dielectric permittivity at the slab boundaries. Our method achieves spectral accuracy by using Ewald splitting to replace the original Poisson equation for nearly singular sources with a smooth far-field Poisson equation, combined with a localized near-field correction. Unlike existing spectral Ewald methods, which make use of the Fourier transform in the aperiodic direction, we recast the problem as a two-point boundary value problem in the aperiodic direction for each transverse Fourier mode for which exact analytic boundary conditions are available. We solve each of these boundary value problems using a fast, well-conditioned Chebyshev method. In the presence of dielectric jumps, combining Ewald splitting with the classical method of images results in smoothed charge distributions, which overlap the dielectric boundaries themselves. We show how to preserve the spectral accuracy in this case through the use of a harmonic correction, which involves solving a simple Laplace equation with smooth boundary data. We implement our method on graphical processing units and combine our doubly periodic Poisson solver with Brownian dynamics to study the equilibrium structure of double layers in binary electrolytes confined by dielectric boundaries. Consistent with prior studies, we find strong charge depletion near the interfaces due to repulsive interactions with image charges, which points to the need for incorporating polarization effects in understanding confined electrolytes, both theoretically and computationally.
Language	English
Publishing date	2021-06-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	3113-6
ISSN	1089-7690 ; 0021-9606
ISSN (online)	1089-7690
ISSN	0021-9606
DOI	10.1063/5.0044677
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Article ; Online: Ependymal cells-CSF flow regulates stress-induced depression.

Seo, Ji-Seon / Mantas, Ioannis / Svenningsson, Per / Greengard, Paul

Molecular psychiatry

2021 Volume 26, Issue 12, Page(s) 7308–7315

Abstract: Major depressive disorder (MDD) is a severe, common mood disorder. While reduced cerebrospinal fluid (CSF) flow adversely affects brain metabolism and fluid balance in the aging population and during development, only indirect evidence links aberrant CSF ...

Abstract	Major depressive disorder (MDD) is a severe, common mood disorder. While reduced cerebrospinal fluid (CSF) flow adversely affects brain metabolism and fluid balance in the aging population and during development, only indirect evidence links aberrant CSF circulation with many diseases including neurological, neurodegenerative, and psychiatric disorders, such as anxiety and depression. Here we show a very high concentration of p11 as a key molecular determinant for depression in ependymal cells, which is significantly decreased in patients with MDD, and in two mouse models of depression induced by chronic stress, such as restraint and social isolation. The loss of p11 in ependymal cells causes disoriented ependymal planar cell polarity (PCP), reduced CSF flow, and depression-like and anxiety-like behaviors. p11 intrinsically controls PCP core genes, which mediates CSF flow. Viral expression of p11 in ependymal cells specifically rescues the pathophysiological and behavioral deficits caused by loss of p11. Taken together, our results identify a new role and a key molecular determinant for ependymal cell-driven CSF flow in mood disorders and suggest a novel strategy for development of treatments for stress-associated neurological, neurodegenerative, and psychiatric disorders.
MeSH term(s)	Aged ; Animals ; Anxiety Disorders ; Depression/metabolism ; Depressive Disorder, Major ; Disease Models, Animal ; Humans ; Mice ; Neuroglia
Language	English
Publishing date	2021-07-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-021-01202-1
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Article: Prognostic Factors for Development of Subsequent Metastases in Localized Osteosarcoma: A Systematic Review and Identification of Literature Gaps.

Basile, Patrick / Greengard, Emily / Weigel, Brenda / Spector, Logan

Sarcoma

2020 Volume 2020, Page(s) 7431549

Abstract: Aim: To investigate prognostic factors in pediatric and young adult patients with localized osteosarcoma that could predict the development of subsequent pulmonary metastases and lead to an ability to risk-stratify therapy. We performed a systematic ... ...

Abstract	Aim: To investigate prognostic factors in pediatric and young adult patients with localized osteosarcoma that could predict the development of subsequent pulmonary metastases and lead to an ability to risk-stratify therapy. We performed a systematic review of the literature published since January 1990 to establish common evidence-based prognostic factors. Methods: PubMed and Embase searches (Jan 1990-Aug 2018) were performed. Two reviewers independently selected papers for patients with localized osteosarcoma with subsequent metastatic development and then reviewed for quality of methods and prognostic factors. Results: Database searches yielded 216 unique results. After screening, 27 full-text articles were studied in depth, with 9 items fulfilling predetermined inclusion and exclusion criteria. Age, tumor location, tumor size/volume, and histologic response carried independent prognostic value in the majority of the studies. Conclusions: Several prognostic factors seemed to be consistent amongst the studies, but the heterogeneity and smaller sizes of the study populations made pooling of results difficult. Standardization of larger patient populations and consistent definitions/cutoffs for prognostic factors are needed to further assess for consistent prognostic factors and potential predictive models to be developed.
Language	English
Publishing date	2020-03-18
Publishing country	Egypt
Document type	Journal Article ; Review
ZDB-ID	1338527-6
ISSN	1357-714X
ISSN	1357-714X
DOI	10.1155/2020/7431549
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Book ; Online: Federated Learning as Variational Inference

Guo, Han / Greengard, Philip / Wang, Hongyi / Gelman, Andrew / Kim, Yoon / Xing, Eric P.

A Scalable Expectation Propagation Approach

2023

Abstract: The canonical formulation of federated learning treats it as a distributed optimization problem where the model parameters are optimized against a global loss function that decomposes across client loss functions. A recent alternative formulation instead ...

Abstract	The canonical formulation of federated learning treats it as a distributed optimization problem where the model parameters are optimized against a global loss function that decomposes across client loss functions. A recent alternative formulation instead treats federated learning as a distributed inference problem, where the goal is to infer a global posterior from partitioned client data (Al-Shedivat et al., 2021). This paper extends the inference view and describes a variational inference formulation of federated learning where the goal is to find a global variational posterior that well-approximates the true posterior. This naturally motivates an expectation propagation approach to federated learning (FedEP), where approximations to the global posterior are iteratively refined through probabilistic message-passing between the central server and the clients. We conduct an extensive empirical study across various algorithmic considerations and describe practical strategies for scaling up expectation propagation to the modern federated setting. We apply FedEP on standard federated learning benchmarks and find that it outperforms strong baselines in terms of both convergence speed and accuracy.
Keywords	Computer Science - Machine Learning
Subject code	006
Publishing date	2023-02-08
Publishing country	us
Document type	Book ; Online
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Article ; Online: Molecularly Targeted Therapy for Neuroblastoma

Emily G. Greengard

Children, Vol 5, Iss 10, p

2018 Volume 142

Abstract: Neuroblastoma is the most common extra-cranial solid tumor encountered in childhood and accounts for 15% of pediatric cancer-related deaths. Although there has been significant improvement in the outcomes for patients with high-risk disease, the therapy ... ...

Abstract	Neuroblastoma is the most common extra-cranial solid tumor encountered in childhood and accounts for 15% of pediatric cancer-related deaths. Although there has been significant improvement in the outcomes for patients with high-risk disease, the therapy needed to achieve a cure is quite toxic and for those that do experience a disease recurrence, the prognosis is very dismal. Given this, there is a tremendous need for novel therapies for children with high-risk neuroblastoma and the molecular discoveries over recent years provide hope for developing new, less toxic, and potentially more efficacious treatments. Here I discuss many of the molecular aberrations identified thus far in neuroblastoma, as well as the agents in development to target these changes. The progress made in both the preclinical arena and in early phase drug development provide much promise for the future of precision medicine in neuroblastoma.
Keywords	neuroblastoma ; molecular guided therapy ; targeted agents ; precision medicine ; Pediatrics ; RJ1-570
Subject code	610
Language	English
Publishing date	2018-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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