Publications by authors named "Alex Thomas"

77 Publications

A metabolic CRISPR-Cas9 screen in Chinese hamster ovary cells identifies glutamine-sensitive genes.

Metab Eng 2021 Apr 1;66:114-122. Epub 2021 Apr 1.

The Novo Nordisk Foundation Center for Biosustainability at the University of California, San Diego, USA; Department of Pediatrics, University of California, San Diego, USA; Department of Bioengineering, University of California, San Diego, USA; National Biologics Facility, Technical University of Denmark, Denmark. Electronic address:

Media and feed optimization have fueled many-fold improvements in mammalian biopharmaceutical production, but genome editing offers an emerging avenue for further enhancing cell metabolism and bioproduction. However, the complexity of metabolism, involving thousands of genes, makes it unclear which engineering strategies will result in desired traits. Here we present a comprehensive pooled CRISPR screen for CHO cell metabolism, including ~16,000 gRNAs against ~2500 metabolic enzymes and regulators. Using this screen, we identified a glutamine response network in CHO cells. Glutamine is particularly important since it is often over-fed to drive increased TCA cycle flux, but toxic ammonia may accumulate. With the screen we found one orphan glutamine-responsive gene with no clear connection to our network. Knockout of this novel and poorly characterized lipase, Abhd11, substantially increased growth in glutamine-free media by altering the regulation of the TCA cycle. Thus, the screen provides an invaluable targeted platform to comprehensively study genes involved in any metabolic trait, and elucidate novel regulators of metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymben.2021.03.017DOI Listing
April 2021

F-fluorodeoxyglucose PET/CT findings in a systemic inflammatory response syndrome after COVID-19 vaccine.

Lancet 2021 03 8;397(10279):e9. Epub 2021 Mar 8.

Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis MO, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(21)00464-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972305PMC
March 2021

Single position circumferential fusion improves operative efficiency, reduces complications and length of stay compared with traditional circumferential fusion.

Spine J 2021 May 13;21(5):810-820. Epub 2020 Nov 13.

Atlantic Neurosurgical and Spine Specialists, Wilmington, 2208 S 17th St, NC 28401, USA.

Background Context: Anterior lumbar interbody fusion (ALIF) and lateral lumbar interbody fusion (LLIF) with percutaneous posterior screw fixation are two techniques used to address degenerative lumbar pathologies. Traditionally, these anterior-posterior (AP) surgeries involve repositioning the patient from the supine or lateral decubitus position to prone for posterior fixation. To reduce operative time (OpTime) and subsequent complications of prolonged anesthesia, single-position lumbar surgery (SPLS) is a novel, minimally invasive alternative performed entirely from the lateral decubitus position.

Purpose: Assess the perioperative safety and efficacy of single position AP lumbar fusion surgery (SPLS).

Study Design: Multicenter retrospective cohort study.

Patient Sample: Three hundred and ninety patients undergoing AP surgery were included, of which 237 underwent SPLS and 153 were in the Flip group.

Outcome Measures: Outcome measures included levels fused, percentage of cases including L5-S1 fusion, fluoroscopy radiation dosage, OpTime, estimated blood loss (EBL), length of stay (LOS), and perioperative complications. Radiographic analysis included lumbar lordosis (LL), pelvic incidence, pelvic tilt, and segmental LL.

Methods: Patients undergoing primary ALIF and/or LLIF surgery with bilateral percutaneous pedicle screw fixation between L2-S1 were included over a 4-year period. Patients were classified as either traditional repositioned "Flip" surgery or SPLS. Outcome measures included levels fused, percentage of cases including L5-S1 fusion, fluoroscopy radiation dosage, OpTime, EBL, LOS, perioperative complications. Radiographic analysis included LL, pelvic incidence, pelvic tilt, and segmental LL. All measures were compared using independent samples t-tests and chi-squared analyses as appropriate with significance set at p < .05. Propensity matching was completed where demographic differences were found.

Results: Three hundred and ninety patients undergoing AP surgery were included, of which 237 underwent SPLS and 153 were in the Flip group. Age, gender, BMI, and CCI were similar between groups. Levels fused (1.47 SPLS vs 1.52 Flip, p = .468) and percent cases including L5-S1 (31% SPLS, 35% Flip, p = .405) were similar between cohorts. SPLS significantly reduced OpTime (103 min vs 306 min, p < .001), EBL (97 vs 313 mL, p < .001), LOS (1.71 vs 4.12 days, p < .001), and fluoroscopy radiation dosage (32 vs 88 mGy, p < .001) compared to Flip. Perioperative complications were similar between cohorts with the exception of postoperative ileus, which was significantly lower in the SPLS group (0% vs 5%, p < .001). There was no significant difference in wound, vascular injury, neurological complications, or Venous Thrombotic Event. There was no significant difference found in 90-day return to operating room (OR).

Conclusions: SPLS improves operative efficiency in addition to reducing blood loss, LOS and ileus in this large cohort study, while maintaining safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.spinee.2020.11.002DOI Listing
May 2021

Rate of failure of indirect decompression in lateral single-position surgery: clinical results.

Neurosurg Focus 2020 09;49(3):E5

3HVC Hospital and Columna Institute, Belo Horizonte, Brazil.

Objective: Lateral single-position surgery (LSPS) of the lumbar spine generally involves anterior lumbar interbody fusion (ALIF) performed in the lateral position (LALIF) at L5-S1 with or without lateral lumbar interbody fusion (LLIF) at L4-5 and above, followed by bilateral pedicle screw fixation (PSF) without repositioning the patient. One obstacle to more widespread adoption of LSPS is the perceived need for direct decompression of the neural elements, which typically requires flipping the patient to the prone position. The purpose of this study was to examine the rate of failure of indirect decompression in a cohort of patients undergoing LSPS from L4 to S1.

Methods: A multicenter, post hoc analysis was undertaken from prospectively collected data of patients at 3 institutions who underwent LALIF at L5-S1 with or without LLIF at L4-5 with bilateral PSF in the lateral decubitus position between March 2018 and March 2020. Inclusion criteria were symptoms of radiculopathy or neurogenic claudication, central or foraminal stenosis (regardless of degree or etiology), and indication for interbody fusion at L5-S1 or L4-S1. Patients with back pain only; those who were younger than 18 years; those with tumor, trauma, or suspicion of infection; those needing revision surgery; and patients who required greater than 2 levels of fusion were excluded. Baseline patient demographic information and surgical data were collected and analyzed. The number of patients in whom indirect decompression failed was recorded and each individual case of failure was analyzed.

Results: A total of 178 consecutive patients underwent LSPS during the time period (105 patients underwent LALIF at L5-S1 and 73 patients underwent LALIF at L5-S1 with LLIF at L4-5). The mean follow-up duration was 10.9 ± 6.5 months. Bilateral PSF was placed with the patient in the lateral decubitus position in 149 patients, and there were 29 stand-alone cases. The mean case time was 101.9 ± 41.5 minutes: 79.3 minutes for single-level cases and 134.5 minutes for 2-level cases. Three patients (1.7%) required reoperation for failure of indirect decompression.

Conclusions: The rate of failure of indirect decompression in LSPS from L4 to S1 is exceedingly low. This low risk of failure should be weighed against the risks associated with direct decompression as well as the risks of the extra operative time needed to perform this decompression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3171/2020.6.FOCUS20375DOI Listing
September 2020

Use and outcomes of wearable cardioverter-defibrillators in a large integrated academic health system.

Am Heart J 2020 08;226:232-234

Yale School of Medicine, Section of Cardiovascular Medicine, New Haven, CT. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ahj.2020.04.007DOI Listing
August 2020

Team clinic: Expansion of a multidisciplinary care model for adolescents with type 1 diabetes.

Contemp Clin Trials 2020 08 4;95:106079. Epub 2020 Jul 4.

Center for Endocrinology, Diabetes, & Metabolism, Children's Hospital Los Angeles, United States of America. Electronic address:

Background: Adolescent and young adults (AYA) with Type 1 Diabetes (T1D) experience more difficulty with glycemic control than patients in all other age groups. The shared medical appointment (SMA) model has been effective in multiple healthcare populations, but the feasibility and effectiveness of SMA in AYA patients with T1D is unclear.

Methods: This research leverages the team's multidisciplinary expertise to develop an engaging intervention toolkit and test the implementation of the Team Clinic care model for the treatment of T1D among middle school adolescents in a large urban children's hospital serving an economically, racially and ethnically diverse population. In Phase 1, the team will manualize the Team Clinic care model into an engaging, age-appropriate educational and intervention toolkit. In Phase 2, the team will conduct a randomized clinical trial to test the feasibility and usability of the toolkit from the provider perspective (team member satisfaction; clinical efficiency; compliance with American Diabetes Association, American Association of Diabetes Educators, and California Children's Services standards; and payor-level cost data) and the preliminary efficacy of the intervention toolkit on patient- and family-level outcomes (attendance, acceptability/satisfaction with care, patient-level cost data, diabetes outcomes, diabetes family conflict, diabetes distress, and depression).

Discussion: AYA patients with T1D often receive care in clinics and institutions with limited resources and time. This research tests the feasibility and efficacy of an innovative and potentially cost-effective SMA model to address the unique needs of underserved populations, while meeting national and state clinical standards. Trial registration The study is registered with ClinicalTrials.gov (Protocol Record: NCT04190368).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cct.2020.106079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098333PMC
August 2020

Web Exclusive. Annals Graphic Medicine - True Tales From the Outbreak: Telemediocrity.

Authors:
Alex Thomas

Ann Intern Med 2020 Jun 16;172(11):W140-W141. Epub 2020 Apr 16.

Chicago, Illinois (A.T.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7326/G20-0033DOI Listing
June 2020

Annals Graphic Medicine - True Tales From the Outbreak: Life in the Hot Zone.

Authors:
Alex Thomas

Ann Intern Med 2020 May 31;172(9):W119-W120. Epub 2020 Mar 31.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7326/G20-0022DOI Listing
May 2020

Clades of huge phages from across Earth's ecosystems.

Nature 2020 02 12;578(7795):425-431. Epub 2020 Feb 12.

Earth and Planetary Science, University of California Berkeley, Berkeley, CA, USA.

Bacteriophages typically have small genomes and depend on their bacterial hosts for replication. Here we sequenced DNA from diverse ecosystems and found hundreds of phage genomes with lengths of more than 200 kilobases (kb), including a genome of 735 kb, which is-to our knowledge-the largest phage genome to be described to date. Thirty-five genomes were manually curated to completion (circular and no gaps). Expanded genetic repertoires include diverse and previously undescribed CRISPR-Cas systems, transfer RNAs (tRNAs), tRNA synthetases, tRNA-modification enzymes, translation-initiation and elongation factors, and ribosomal proteins. The CRISPR-Cas systems of phages have the capacity to silence host transcription factors and translational genes, potentially as part of a larger interaction network that intercepts translation to redirect biosynthesis to phage-encoded functions. In addition, some phages may repurpose bacterial CRISPR-Cas systems to eliminate competing phages. We phylogenetically define the major clades of huge phages from human and other animal microbiomes, as well as from oceans, lakes, sediments, soils and the built environment. We conclude that the large gene inventories of huge phages reflect a conserved biological strategy, and that the phages are distributed across a broad bacterial host range and across Earth's ecosystems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2007-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162821PMC
February 2020

Should donors who have used marijuana be considered candidates for living kidney donation?

Clin Kidney J 2019 Jun 15;12(3):437-442. Epub 2018 Nov 15.

Department of Urology, Loma Linda University Health, Loma Linda, CA, USA.

Background: The use of marijuana in the USA has been steadily increasing over the last 10 years. This study is the first to investigate the effect of marijuana use by live kidney donors upon outcomes in both donors and recipients.

Methods: Living kidney donor transplants performed between January 2000 and May 2016 in a single academic institution were retrospectively reviewed. Donor and recipient groups were each divided into two groups by donor marijuana usage. Outcomes in donor and recipient groups were compared using -test, Chi-square and mixed linear analysis (P < 0.05 considered significant).

Results: This was 294 living renal donor medical records were reviewed including 31 marijuana-using donors (MUD) and 263 non-MUDs (NMUD). It was 230 living kidney recipient records were reviewed including 27 marijuana kidney recipients (MKRs) and 203 non-MKRs (NMKR). There was no difference in donor or recipient perioperative characteristics or postoperative outcomes based upon donor marijuana use (P > 0.05 for all comparisons). There was no difference in renal function between NMUD and MUD groups and no long-term difference in kidney allograft function between NMKR and MKR groups.

Conclusions: Considering individuals with a history of marijuana use for living kidney donation could increase the donor pool and yield acceptable outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ckj/sfy107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543962PMC
June 2019

Impact of extremely low-frequency magnetic fields on human postural control.

Exp Brain Res 2019 Mar 5;237(3):611-623. Epub 2018 Dec 5.

Lawson Health Research Institute, St. Joseph Hospital, London, ON, Canada.

Studies have found that extremely low-frequency (ELF, < 300 Hz) magnetic fields (MF) can modulate standing balance; however, the acute balance effects of high flux densities in this frequency range have not been systematically investigated yet. This study explores acute human standing balance responses of 22 participants exposed to magnetic induction at 50 and 100 mTrms (MF), and to 1.5 mA alternating currents (AC). The center of pressure displacement (COP) was collected and analyzed to investigate postural modulation. The path length, the area, the velocity, the power spectrum in low (< 0.5 Hz) and medium (0.5-2 Hz) bands have computed and showed the expected effect of the positive control direct current (DC) electric stimulation but failed to show any significant effect of the time-varying stimulations (AC and MF). However, we showed a significant biased stabilization effect on postural data from the custom experimental apparatus employed in this work, which might have neutralized the hypothesized results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00221-018-5442-9DOI Listing
March 2019

Are Comic Books Appropriate Health Education Formats to Offer Adult Patients?

AMA J Ethics 2018 Feb 1;20(1):134-140. Epub 2018 Feb 1.

A pediatric allergist and immunologist based in Chicago and a co-founder of Booster Shot Media.

Physicians who recommend patient education comics should consider that some patients might question the appropriateness of this format, especially in the US, where a dominant cultural view of comics is that they are juvenile and intended to be funny. In this case, Dr. S might have approached communication with Mrs. T differently, even without knowing her attitude toward comics as a format for delivering health information. Dr. S could acknowledge that though some people might not expect useful medical information in a comic format, it has unique aspects and new research on patient education comics shows that even adults are finding this medium to be effective, educational, and engaging. Offering comics to patients, however, does potentially require patient educators to invest additional time to review and assess their accuracy and relevance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/journalofethics.2018.20.2.ecas1-1802DOI Listing
February 2018

Metaphors matter: from biobank to a library of medical information.

Genet Med 2018 08 21;20(8):802-805. Epub 2017 Dec 21.

Stanford Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, California, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2017.204DOI Listing
August 2018

Coastal ocean and shelf-sea biogeochemical cycling of trace elements and isotopes: lessons learned from GEOTRACES.

Philos Trans A Math Phys Eng Sci 2016 Nov;374(2081)

Physics Department-ICTA, Universitat Autònoma de Barcelona, Barcelona 08193, Spain.

Continental shelves and shelf seas play a central role in the global carbon cycle. However, their importance with respect to trace element and isotope (TEI) inputs to ocean basins is less well understood. Here, we present major findings on shelf TEI biogeochemistry from the GEOTRACES programme as well as a proof of concept for a new method to estimate shelf TEI fluxes. The case studies focus on advances in our understanding of TEI cycling in the Arctic, transformations within a major river estuary (Amazon), shelf sediment micronutrient fluxes and basin-scale estimates of submarine groundwater discharge. The proposed shelf flux tracer is 228-radium ( = 5.75 yr), which is continuously supplied to the shelf from coastal aquifers, sediment porewater exchange and rivers. Model-derived shelf Ra fluxes are combined with TEI/ Ra ratios to quantify ocean TEI fluxes from the western North Atlantic margin. The results from this new approach agree well with previous estimates for shelf Co, Fe, Mn and Zn inputs and exceed published estimates of atmospheric deposition by factors of approximately 3-23. Lastly, recommendations are made for additional GEOTRACES process studies and coastal margin-focused section cruises that will help refine the model and provide better insight on the mechanisms driving shelf-derived TEI fluxes to the ocean.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1098/rsta.2016.0076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069537PMC
November 2016

AgRP knockdown blocks long-term appetitive, but not consummatory, feeding behaviors in Siberian hamsters.

Physiol Behav 2018 06 12;190:61-70. Epub 2017 Oct 12.

Department of Biology, Georgia State University, Atlanta, GA 30302, USA; Center for Obesity Reversal, Georgia State University, Atlanta, GA 30302, USA; Neuroscience Institute, Georgia State University, Atlanta, GA, 30302, USA.

Arcuate hypothalamus-derived agouti-related protein (AgRP) and neuropeptide Y (NPY) are critical for maintaining energy homeostasis. Fasting markedly upregulates AgRP/NPY expression and circulating ghrelin, and exogenous ghrelin treatment robustly increases acute food foraging and food intake, and chronic food hoarding behaviors in Siberian hamsters. We previously demonstrated that 3rd ventricular AgRP injection robustly stimulates acute and chronic food hoarding, largely independent of food foraging and intake. By contrast, 3rd ventricular NPY injection increases food foraging, food intake, and food hoarding, but this effect is transient and gone by 24h post-injection. Because of this discrepancy in AgRP/NPY-induced ingestive behaviors, we tested whether selective knockdown of AgRP blocks fasting and ghrelin-induced increases in food hoarding. AgRP gene knockdown by a novel DICER small interfering RNA (AgRP-DsiRNA) blocked food-deprivation induced increases in AgRP expression, but had no effect on NPY expression. AgRP-DsiRNA attenuated acute (1day), and significantly decreased chronic (4-6days), food deprivation-induced increases in food hoarding. In addition, AgRP-DsiRNA treatment blocked exogenous ghrelin-induced increases in food hoarding through day 3, but had no effect on basal food foraging, food intake, or food hoarding prior to ghrelin treatment. Lastly, chronic AgRP knockdown had no effect on body mass, fat mass, or lean mass in either food deprived or ad libitum fed hamsters. These data collectively suggest that the prolonged increase in food hoarding behavior following energetic challenges, and food deprivation especially, is primarily regulated by downstream AgRP signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.physbeh.2017.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897226PMC
June 2018

Mechanisms for AgRP neuron-mediated regulation of appetitive behaviors in rodents.

Physiol Behav 2018 06 12;190:34-42. Epub 2017 Oct 12.

Department of Biology, Georgia State University, Atlanta, GA 30302, USA; Center for Obesity Reversal, Georgia State University, Atlanta, GA 30302, USA; Neuroscience Institute, Georgia State University, Atlanta, GA 30302, USA. Electronic address:

The obesity epidemic is a major health and economic burden facing both developed and developing countries worldwide. Interrogation of the central and peripheral mechanisms regulating ingestive behaviors have primarily focused on food intake, and in the process uncovered a detailed neuroanatomical framework controlling this behavior. However, these studies have largely ignored the behaviors that bring animals, including humans, in contact with food. It is therefore useful to dichotomize ingestive behaviors as appetitive (motivation to find and store food) and consummatory (consumption of food once found), and utilize an animal model that naturally displays these behaviors. Recent advances in genetics have facilitated the identification of several neuronal populations critical for regulating ingestive behaviors in mice, and novel functions of these neurons and neuropeptides in regulating appetitive behaviors in Siberian hamsters, a natural model of food foraging and food hoarding, have been identified. To this end, hypothalamic agouti-related protein/neuropeptide Y expressing neurons (AgRP neurons) have emerged as a critical regulator of ingestive behaviors. Recent studies by Dr. Timothy Bartness and others have identified several discrete mechanisms through which peripheral endocrine signals regulate AgRP neurons to control food foraging, food hoarding, and food intake. We review here recent advances in our understanding of the neuroendocrine control of ingestive behaviors in Siberian hamsters and other laboratory rodents, and identify novel mechanisms through which AgRP neurons mediate appetitive and consummatory behaviors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.physbeh.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897189PMC
June 2018

MIS Single-position Lateral and Oblique Lateral Lumbar Interbody Fusion and Bilateral Pedicle Screw Fixation: Feasibility and Perioperative Results.

Spine (Phila Pa 1976) 2018 03;43(6):440-446

Atlantic Neurosurgical and Spine Specialists, Wilmington, NC.

Study Design: Retrospective review of prospectively collected data of the first 72 consecutive patients treated with single-position one- or two-level lateral (LLIF) or oblique lateral interbody fusion (OLLIF) with bilateral percutaneous pedicle screw and rod fixation by a single spine surgeon.

Objective: To evaluate the clinical feasibility, accuracy, and efficiency of a single-position technique for LLIF and OLLIF with bilateral pedicle screw and rod fixation.

Summary Of Background Data: Minimally-invasive lateral interbody approaches are performed in the lateral decubitus position. Subsequent repositioning prone for bilateral pedicle screw and rod fixation requires significant time and resources and does not facilitate increased lumbar lordosis.

Methods: The first 72 consecutive patients (300 screws) treated with single-position LLIF or OLLIF and bilateral pedicle screws by a single surgeon between December 2013 and August 2016 were included in the study. Screw accuracy and fusion were graded using computed tomography and several timing parameters were recorded including retractor, fluoroscopy, and screw placement time. Complications including reoperation, infection, and postoperative radicular pain and weakness were recorded.

Results: Average screw placement time was 5.9 min/screw (standard deviation, SD: 1.5 min; range: 3-9.5 min). Average total operative time (interbody cage and pedicle screw placement) was 87.9 minutes (SD: 25.1 min; range: 49-195 min). Average fluoroscopy time was 15.0 s/screw (SD: 4.7 s; range: 6-25 s). The pedicle screw breach rate was 5.1% with 10/13 breaches measured as < 2 mm in magnitude. Fusion rate at 6-months postoperative was 87.5%. Two (2.8%) patients underwent reoperation for malpositioned pedicle screws with subsequent resolution of symptoms.

Conclusion: The single-position, all-lateral technique was found to be feasible with accuracy, fluoroscopy usage, and complication rates comparable with the published literature. This technique eliminates the time and staffing associated with intraoperative repositioning and may lead to significant improvements in operative efficiency and cost savings.

Level Of Evidence: 4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BRS.0000000000002330DOI Listing
March 2018

Human exposure to power frequency magnetic fields up to 7.6 mT: An integrated EEG/fMRI study.

Bioelectromagnetics 2017 Sep 19;38(6):425-435. Epub 2017 Jun 19.

Human Threshold Research and Bioelectromagnetics Group, Imaging Program, Lawson Health Research Institute, London, Canada.

We assessed the effects of power-line frequency (60 Hz in North America) magnetic fields (MF) in humans using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Twenty-five participants were enrolled in a pseudo-double-blind experiment involving "real" or "sham" exposure to sinusoidal 60 Hz MF exposures delivered using the gradient coil of an MRI scanner following two conditions: (i) 10 s exposures at 3 mT (10 repetitions); (ii) 2 s exposures at 7.6 mT (100 repetitions). Occipital EEG spectral power was computed in the alpha range (8-12 Hz, reportedly the most sensitive to MF exposure in the literature) with/without exposure. Brain functional activation was studied using fMRI blood oxygen level-dependent (BOLD, inversely correlated with EEG alpha power) maps. No significant effects were detected on occipital EEG alpha power during or post-exposure for any exposure condition. Consistent with EEG results, no effects were observed on fMRI BOLD maps in any brain region. Our results suggest that acute exposure (2-10 s) to 60 Hz MF from 3 to 7.6 mT (30,000 to 76,000 times higher than average public exposure levels for 60 Hz MF) does not induce detectable changes in EEG or BOLD signals. Combined with previous findings in which effects were observed on the BOLD signal after 1 h exposure to 3 mT, 60 Hz MF, this suggests that MF exposure in the low mT range (<10 mT) might require prolonged durations of exposure to induce detectable effects. Bioelectromagnetics. 38:425-435, 2017. © 2017 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bem.22064DOI Listing
September 2017

Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.

Nat Methods 2017 Jun 20;14(6):573-576. Epub 2017 Mar 20.

Moores UCSD Cancer Center, La Jolla, California, USA.

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nmeth.4225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449203PMC
June 2017

Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism.

Sci Rep 2017 01 25;7:41241. Epub 2017 Jan 25.

Department of Bioengineering, University of California, San Diego, La Jolla CA 92093-0412, USA.

Malignant transformation is often accompanied by significant metabolic changes. To identify drivers underlying these changes, we calculated metabolic flux states for the NCI60 cell line collection and correlated the variance between metabolic states of these lines with their other properties. The analysis revealed a remarkably consistent structure underlying high flux metabolism. The three primary uptake pathways, glucose, glutamine and serine, are each characterized by three features: (1) metabolite uptake sufficient for the stoichiometric requirement to sustain observed growth, (2) overflow metabolism, which scales with excess nutrient uptake over the basal growth requirement, and (3) redox production, which also scales with nutrient uptake but greatly exceeds the requirement for growth. We discovered that resistance to chemotherapeutic drugs in these lines broadly correlates with the amount of glucose uptake. These results support an interpretation of the Warburg effect and glutamine addiction as features of a growth state that provides resistance to metabolic stress through excess redox and energy production. Furthermore, overflow metabolism observed may indicate that mitochondrial catabolic capacity is a key constraint setting an upper limit on the rate of cofactor production possible. These results provide a greater context within which the metabolic alterations in cancer can be understood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep41241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264163PMC
January 2017

A Consensus Genome-scale Reconstruction of Chinese Hamster Ovary Cell Metabolism.

Cell Syst 2016 11;3(5):434-443.e8

Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, 1190 Vienna, Austria; Austrian Centre of Industrial Biotechnology, 1190 Vienna, Austria.

Chinese hamster ovary (CHO) cells dominate biotherapeutic protein production and are widely used in mammalian cell line engineering research. To elucidate metabolic bottlenecks in protein production and to guide cell engineering and bioprocess optimization, we reconstructed the metabolic pathways in CHO and associated them with >1,700 genes in the Cricetulus griseus genome. The genome-scale metabolic model based on this reconstruction, iCHO1766, and cell-line-specific models for CHO-K1, CHO-S, and CHO-DG44 cells provide the biochemical basis of growth and recombinant protein production. The models accurately predict growth phenotypes and known auxotrophies in CHO cells. With the models, we quantify the protein synthesis capacity of CHO cells and demonstrate that common bioprocess treatments, such as histone deacetylase inhibitors, inefficiently increase product yield. However, our simulations show that the metabolic resources in CHO are more than three times more efficiently utilized for growth or recombinant protein synthesis following targeted efforts to engineer the CHO secretory pathway. This model will further accelerate CHO cell engineering and help optimize bioprocesses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cels.2016.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132346PMC
November 2016

Genomes OnLine Database (GOLD) v.6: data updates and feature enhancements.

Nucleic Acids Res 2017 01 27;45(D1):D446-D456. Epub 2016 Oct 27.

Prokaryotic Super Program, DOE Joint Genome Institute, Walnut Creek, 94598 CA, USA

The Genomes Online Database (GOLD) (https://gold.jgi.doe.gov) is a manually curated data management system that catalogs sequencing projects with associated metadata from around the world. In the current version of GOLD (v.6), all projects are organized based on a four level classification system in the form of a Study, Organism (for isolates) or Biosample (for environmental samples), Sequencing Project and Analysis Project. Currently, GOLD provides information for 26 117 Studies, 239 100 Organisms, 15 887 Biosamples, 97 212 Sequencing Projects and 78 579 Analysis Projects. These are integrated with over 312 metadata fields from which 58 are controlled vocabularies with 2067 terms. The web interface facilitates submission of a diverse range of Sequencing Projects (such as isolate genome, single-cell genome, metagenome, metatranscriptome) and complex Analysis Projects (such as genome from metagenome, or combined assembly from multiple Sequencing Projects). GOLD provides a seamless interface with the Integrated Microbial Genomes (IMG) system and supports and promotes the Genomic Standards Consortium (GSC) Minimum Information standards. This paper describes the data updates and additional features added during the last two years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkw992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210664PMC
January 2017

The Feasibility of Utilizing a Comic for Education in the Emergency Department Setting.

Health Commun 2017 05 19;32(5):529-532. Epub 2016 Aug 19.

c Booster Shot Media.

The objective of this study was to determine the feasibility of a comic education module in the Emergency Department setting. A convenience sample of 50 injured children and their caregivers were enrolled. The comic was found to be likeable, easy to read, and provided important information to both children and their caregivers. Total time to read the comic was three minutes (SD 1.4, range 1.4-7.1). Most children (60%) read the comic independently, including all children over age 14 years. At 72-hour phone follow-up, 86% of caregivers had accurate recall of all three comic teaching points. This innovative comic educational module is feasible for use for children ages 4-18 years in the Emergency Department. Though this comic was intended to educate children, caregivers recalled all three teaching points 72 hours after discharge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10410236.2016.1211076DOI Listing
May 2017

Uncovering Earth's virome.

Nature 2016 08 17;536(7617):425-30. Epub 2016 Aug 17.

Viruses are the most abundant biological entities on Earth, but challenges in detecting, isolating, and classifying unknown viruses have prevented exhaustive surveys of the global virome. Here we analysed over 5 Tb of metagenomic sequence data from 3,042 geographically diverse samples to assess the global distribution, phylogenetic diversity, and host specificity of viruses. We discovered over 125,000 partial DNA viral genomes, including the largest phage yet identified, and increased the number of known viral genes by 16-fold. Half of the predicted partial viral genomes were clustered into genetically distinct groups, most of which included genes unrelated to those in known viruses. Using CRISPR spacers and transfer RNA matches to link viral groups to microbial host(s), we doubled the number of microbial phyla known to be infected by viruses, and identified viruses that can infect organisms from different phyla. Analysis of viral distribution across diverse ecosystems revealed strong habitat-type specificity for the vast majority of viruses, but also identified some cosmopolitan groups. Our results highlight an extensive global viral diversity and provide detailed insight into viral habitat distribution and host–virus interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature19094DOI Listing
August 2016

Access and Use: Improving Digital Multimedia Consumer Health Information.

Authors:
Alex Thomas

Stud Health Technol Inform 2016 ;227:120-5

Business Technology and Information Management Branch, Department of Health and Human Services, Victorian Government.

This project enabled novel organisational insight into the comparative utility of a portfolio of consumer health information content, by measuring patterns of attrition (abandonment) in content use. The project used as a case study the event activity log of a fully automated digital information kiosk, located in a community health facility. Direct measurements of the duration of content use were derived from the user interface activity recorded in the kiosk log, thus avoiding issues in using other approaches to collecting this type of data, such as sampling and observer bias. The distribution patterns of 1,383 durations of observed abandonments of use for twenty-eight discrete modules of health information content were visualised using Kaplan-Meir survival plots. Clear patterns of abandonment of content use were exhibited. The method of analysis is cost-effective, scalable and provides deep insight into the utility of health promotion content. The impact on the content producers, platform operators and service users is to improve organisational learning and thus increase the confidence in stakeholders that the service is continuously delivering high quality health and wellbeing benefits.
View Article and Find Full Text PDF

Download full-text PDF

Source
February 2018

Recon 2.2: from reconstruction to model of human metabolism.

Metabolomics 2016;12:109. Epub 2016 Jun 7.

Manchester Centre for Synthetic Biology of Fine and Speciality Chemicals (SYNBIOCHEM), Manchester Institute of Biotechnology, The University of Manchester, Manchester, M1 7DN UK ; School of Computer Science, The University of Manchester, Manchester, M13 9PL UK ; Center for Quantitative Medicine, UConn Health, 263 Farmington Avenue, Farmington, CT 06030-6033 USA.

Introduction: The human genome-scale metabolic reconstruction details all known metabolic reactions occurring in humans, and thereby holds substantial promise for studying complex diseases and phenotypes. Capturing the whole human metabolic reconstruction is an on-going task and since the last community effort generated a consensus reconstruction, several updates have been developed.

Objectives: We report a new consensus version, Recon 2.2, which integrates various alternative versions with significant additional updates. In addition to re-establishing a consensus reconstruction, further key objectives included providing more comprehensive annotation of metabolites and genes, ensuring full mass and charge balance in all reactions, and developing a model that correctly predicts ATP production on a range of carbon sources.

Methods: Recon 2.2 has been developed through a combination of manual curation and automated error checking. Specific and significant manual updates include a respecification of fatty acid metabolism, oxidative phosphorylation and a coupling of the electron transport chain to ATP synthase activity. All metabolites have definitive chemical formulae and charges specified, and these are used to ensure full mass and charge reaction balancing through an automated linear programming approach. Additionally, improved integration with transcriptomics and proteomics data has been facilitated with the updated curation of relationships between genes, proteins and reactions.

Results: Recon 2.2 now represents the most predictive model of human metabolism to date as demonstrated here. Extensive manual curation has increased the reconstruction size to 5324 metabolites, 7785 reactions and 1675 associated genes, which now are mapped to a single standard. The focus upon mass and charge balancing of all reactions, along with better representation of energy generation, has produced a flux model that correctly predicts ATP yield on different carbon sources.

Conclusion: Through these updates we have achieved the most complete and best annotated consensus human metabolic reconstruction available, thereby increasing the ability of this resource to provide novel insights into normal and disease states in human. The model is freely available from the Biomodels database (http://identifiers.org/biomodels.db/MODEL1603150001).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11306-016-1051-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896983PMC
June 2016

Molecular and Cellular Mechanisms of Rapid-Acting Antidepressants Ketamine and Scopolamine.

Curr Neuropharmacol 2017 ;15(1):11-20

Department of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT, 34 Park Street, New Haven, CT 06519, USA.

Major depressive disorder (MDD) is a prevalent neuropsychiatric disease that causes profound social and economic burdens. The impact of MDD is compounded by the limited therapeutic efficacy and delay of weeks to months of currently available medications. These issues highlight the need for more efficacious and faster-acting treatments to alleviate the burdens of MDD. Recent breakthroughs demonstrate that certain drugs, including ketamine and scopolamine, produce rapid and long-lasting antidepressant effects in MDD patients. Moreover, preclinical work has shown that the antidepressant actions of ketamine and scopolamine in rodent models are caused by an increase of extracellular glutamate, elevated BDNF, activation of the mammalian target of rapamycin complex 1 (mTORC1) cascade, and increased number and function of spine synapses in the prefrontal cortex (PFC). Here we review studies showing that both ketamine and scopolamine elicit rapid antidepressant effects through converging molecular and cellular mechanisms in the PFC. In addition, we discuss evidence that selective antagonists of NMDA and muscarinic acetylcholine (mACh) receptor subtypes (i.e., NR2B and M1-AChR) in the PFC produce comparable antidepressant responses. Furthermore, we discuss evidence that ketamine and scopolamine antagonize inhibitory interneurons in the PFC leading to disinhibition of pyramidal neurons and increased extracellular glutamate that promotes the rapid antidepressant responses to these agents. Collectively, these studies indicate that specific NMDA and mACh receptor subtypes on GABAergic interneurons are promising targets for novel rapid-acting antidepressant therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5327447PMC
http://dx.doi.org/10.2174/1570159x14666160309114549DOI Listing
February 2017

The Significance of Tinospora crispa in Treatment of Diabetes Mellitus.

Phytother Res 2016 Mar 7;30(3):357-66. Epub 2016 Jan 7.

CARe Keralam Ltd, KINFRA Small Industries Park, KINFRA Park P.O., Koratty, 680 309, Kerala, India.

Tinospora crispa is a medicinal plant belonging to the botanical family Menispermiaceae. The plant is widely distributed in Southeast Asia and the northeastern region of India. A related species Tinospora cordifolia is used in Ayurveda for treating a large spectrum of diseases. Traditional healers of Thailand, Malaysia, Guyana, Bangladesh and the southern Indian province of Kerala use this plant in the treatment of diabetes. Many diterpenes, triterpenes, phytosteroids, alkaloids and their glycosides have been isolated from T. crispa. Cell culture and animal studies suggest that the herb stimulates secretion of insulin from β-cells. It also causes dose-dependent and time-dependent enhancement of glucose uptake in muscles. However, in view of the reported hepatotoxicity, this herb may be used with caution. This article reviews the animal studies and human clinical trials carried out using this herb. Areas of future research are also identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ptr.5559DOI Listing
March 2016

Systems biology definition of the core proteome of metabolism and expression is consistent with high-throughput data.

Proc Natl Acad Sci U S A 2015 Aug 10;112(34):10810-5. Epub 2015 Aug 10.

Department of Bioengineering, University of California at San Diego, La Jolla, CA 92093; Novo Nordisk Foundation Center for Biosustainability, 2970 Hørsholm, Denmark;

Finding the minimal set of gene functions needed to sustain life is of both fundamental and practical importance. Minimal gene lists have been proposed by using comparative genomics-based core proteome definitions. A definition of a core proteome that is supported by empirical data, is understood at the systems-level, and provides a basis for computing essential cell functions is lacking. Here, we use a systems biology-based genome-scale model of metabolism and expression to define a functional core proteome consisting of 356 gene products, accounting for 44% of the Escherichia coli proteome by mass based on proteomics data. This systems biology core proteome includes 212 genes not found in previous comparative genomics-based core proteome definitions, accounts for 65% of known essential genes in E. coli, and has 78% gene function overlap with minimal genomes (Buchnera aphidicola and Mycoplasma genitalium). Based on transcriptomics data across environmental and genetic backgrounds, the systems biology core proteome is significantly enriched in nondifferentially expressed genes and depleted in differentially expressed genes. Compared with the noncore, core gene expression levels are also similar across genetic backgrounds (two times higher Spearman rank correlation) and exhibit significantly more complex transcriptional and posttranscriptional regulatory features (40% more transcription start sites per gene, 22% longer 5'UTR). Thus, genome-scale systems biology approaches rigorously identify a functional core proteome needed to support growth. This framework, validated by using high-throughput datasets, facilitates a mechanistic understanding of systems-level core proteome function through in silico models; it de facto defines a paleome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1501384112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553782PMC
August 2015

Effects of a 60 Hz Magnetic Field Exposure Up to 3000 μT on Human Brain Activation as Measured by Functional Magnetic Resonance Imaging.

PLoS One 2015 27;10(7):e0132024. Epub 2015 Jul 27.

Human Threshold Research Group, Lawson Health Research Institute, London, Ontario, Canada; Department of Medical Biophysics, Western University, London, Ontario, Canada; Department of Medical Imaging, Western University, London, Ontario, Canada.

Several aspects of the human nervous system and associated motor and cognitive processes have been reported to be modulated by extremely low-frequency (ELF, < 300 Hz) time-varying Magnetic Fields (MF). Due do their worldwide prevalence; power-line frequencies (60 Hz in North America) are of particular interest. Despite intense research efforts over the last few decades, the potential effects of 60 Hz MF still need to be elucidated, and the underlying mechanisms to be understood. In this study, we have used functional Magnetic Resonance Imaging (fMRI) to characterize potential changes in functional brain activation following human exposure to a 60 Hz MF through motor and cognitive tasks. First, pilot results acquired in a first set of subjects (N=9) were used to demonstrate the technical feasibility of using fMRI to detect subtle changes in functional brain activation with 60 Hz MF exposure at 1800 μT. Second, a full study involving a larger cohort of subjects tested brain activation during 1) a finger tapping task (N=20), and 2) a mental rotation task (N=21); before and after a one-hour, 60 Hz, 3000 μT MF exposure. The results indicate significant changes in task-induced functional brain activation as a consequence of MF exposure. However, no impact on task performance was found. These results illustrate the potential of using fMRI to identify MF-induced changes in functional brain activation, suggesting that a one-hour 60 Hz, 3000 μT MF exposure can modulate activity in specific brain regions after the end of the exposure period (i.e., residual effects). We discuss the possibility that MF exposure at 60 Hz, 3000 μT may be capable of modulating cortical excitability via a modulation of synaptic plasticity processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132024PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516358PMC
May 2016