Mini-review: Induced pluripotent stem cells and the search for new cell-specific ALS therapeutic targets

Amongst the most important discoveries in ALS pathobiology are the works demonstrating that multiple cell types contribute to disease onset and progression. However, a significant limitation in ALS research is the inability to obtain tissues from ALS patient brain and spinal cord during the course of the disease. In vivo modeling has provided insights into the role of these cell subtypes in disease onset and progression. However, in vivo models also have shortcomings, including the reliance on a limited number of models based upon hereditary forms of the disease. Therefore, using human induced pluripotent stem cells (iPSC) reprogrammed from somatic cells of ALS patients, with both hereditary and sporadic forms of the disease, and differentiated into cell subtypes of both the central nervous system (CNS) and peripheral nervous system (PNS), have become powerful complementary tools for investigating basic mechanisms of disease as well as a platform for drug discovery. Motor neuron and other neuron subtypes, as well as non-neuronal cells have been differentiated from human iPSC and studied for their potential contributions to ALS pathobiology. As iPSC technologies have advanced, 3D modeling with multicellular systems organised in microfluidic chambers or organoids are the next step in validating the pathways and therapeutic targets already identified. Precision medicine approaches with iPSC using either traditional strategies of screening drugs that target a known pathogenic mechanism as well as “blind-to-target” drug screenings that allow for patient stratification based on drug response rather than clinical characteristics are now being employed

Variational finite-difference representation of the kinetic energy operator

A potential disadvantage of real-space-grid electronic structure methods is the lack of a variational principle and the concomitant increase of total energy with grid refinement. We show that the origin of this feature is the systematic underestimation of the kinetic energy by the finite difference representation of the Laplacian operator. We present an alternative representation that provides a rigorous upper bound estimate of the true kinetic energy and we illustrate its properties with a harmonic oscillator potential. For a more realistic application, we study the convergence of the total energy of bulk silicon using a real-space-grid density-functional code and employing both the conventional and the alternative representations of the kinetic energy operator.Comment: 3 pages, 3 figures, 1 table. To appear in Phys. Rev. B. Contribution for the 10th anniversary of the eprint serve

The use of live attenuated influenza vaccine (LAIV) in healthcare personnel (HCP): Guidance from the society for healthcare epidemiology of America (SHEA)

Because of the live viral backbone of live attenuated influenza vaccine (LAIV), questions have arisen regarding infection control precautions and restrictions surrounding its use in healthcare personnel (HCP). This document provides guidance from the Society for Healthcare Epidemiology of America regarding use of LAIV in HCP and the infection control precautions that are recommended with its use in this population. Infect Control Hosp Epidemiol 2012;33(10):981-98

MicroRNA profiling reveals marker of motor neuron disease in ALS models

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining thein vivomiRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease progresses, suggesting that it may be a clinically useful marker of disease status. Furthermore, rats treated with ALS therapy have restored expression of this MN RNA marker, making it an MN-specific and drug-responsive marker for ALS rodents.</jats:p

Time-dependent calculation of ionization in Potassium at mid-infrared wavelengths

We study the dynamics of the Potassium atom in the mid-infrared, high intensity, short laser pulse regime. We ascertain numerical convergence by comparing the results obtained by the direct expansion of the time-dependent Schroedinger equation onto B-Splines, to those obtained by the eigenbasis expansion method. We present ionization curves in the 12-, 13-, and 14-photon ionization range for Potassium. The ionization curve of a scaled system, namely Hydrogen starting from the 2s, is compared to the 12-photon results. In the 13-photon regime, a dynamic resonance is found and analyzed in some detail. The results for all wavelengths and intensities, including Hydrogen, display a clear plateau in the peak-heights of the low energy part of the Above Threshold Ionization (ATI) spectrum, which scales with the ponderomotive energy Up, and extends to 2.8 +- 0.5 Up.Comment: 15 two-column pages with 15 figures, 3 tables. Accepted for publication in Phys. Rev A. Improved figures, language and punctuation, and made minor corrections. We also added a comparison to the ADK theor

Mechanisms, models and biomarkers in amyotrophic lateral sclerosis

The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery

Posterior probability and fluctuation theorem in stochastic processes

A generalization of fluctuation theorems in stochastic processes is proposed. The new theorem is written in terms of posterior probabilities, which are introduced via the Bayes theorem. In usual fluctuation theorems, a forward path and its time reversal play an important role, so that a microscopically reversible condition is essential. In contrast, the microscopically reversible condition is not necessary in the new theorem. It is shown that the new theorem adequately recovers various theorems and relations previously known, such as the Gallavotti-Cohen-type fluctuation theorem, the Jarzynski equality, and the Hatano-Sasa relation, when adequate assumptions are employed.Comment: 4 page

Strategies to prevent Clostridium difficile infections in acute care hospitals: 2014 update

Previously published guidelines are available that provide comprehensive recommendations for detecting and preventing healthcare-associated infections (HAIs). The intent of this document is to highlight practical recommendations in a concise format designed to assist acute care hospitals in implementing and prioritizing their Clostridium difficile infection (CDI) prevention efforts. This document updates “Strategies to Prevent Clostridium difficile Infections in Acute Care Hospitals,” published in 2008. This expert guidance document is sponsored by the Society for Healthcare Epidemiology of America (SHEA) and is the product of a collaborative effort led by SHEA, the Infectious Diseases Society of America (IDSA), the American Hospital Association (AHA), the Association for Professionals in Infection Control and Epidemiology (APIC), and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise. The list of endorsing and supporting organizations is presented in the introduction to the 2014 updates

Many-electron tunneling in atoms

A theoretical derivation is given for the formula describing N-electron ionization of atom by a dc field and laser radiation in tunneling regime. Numerical examples are presented for noble gases atoms.Comment: 11 pages, 1 EPS figure, submitted to JETP (Jan 99

Human Glial-Restricted Progenitor Transplantation into Cervical Spinal Cord of the SOD1G93A Mouse Model of ALS

Cellular abnormalities are not limited to motor neurons in amyotrophic lateral sclerosis (ALS). There are numerous observations of astrocyte dysfunction in both humans with ALS and in SOD1G93A rodents, a widely studied ALS model. The present study therapeutically targeted astrocyte replacement in this model via transplantation of human Glial-Restricted Progenitors (hGRPs), lineage-restricted progenitors derived from human fetal neural tissue. Our previous findings demonstrated that transplantation of rodent-derived GRPs into cervical spinal cord ventral gray matter (in order to target therapy to diaphragmatic function) resulted in therapeutic efficacy in the SOD1G93A rat. Those findings demonstrated the feasibility and efficacy of transplantation-based astrocyte replacement for ALS, and also show that targeted multi-segmental cell delivery to cervical spinal cord is a promising therapeutic strategy, particularly because of its relevance to addressing respiratory compromise associated with ALS. The present study investigated the safety and in vivo survival, distribution, differentiation, and potential efficacy of hGRPs in the SOD1G93A mouse. hGRP transplants robustly survived and migrated in both gray and white matter and differentiated into astrocytes in SOD1G93A mice spinal cord, despite ongoing disease progression. However, cervical spinal cord transplants did not result in motor neuron protection or any therapeutic benefits on functional outcome measures. This study provides an in vivo characterization of this glial progenitor cell and provides a foundation for understanding their capacity for survival, integration within host tissues, differentiation into glial subtypes, migration, and lack of toxicity or tumor formation