Failure in a population: Tauopathy disrupts homeostatic set-points in emergent dynamics despite stability in the constituent neurons.

Homeostatic regulation of neuronal activity is essential for robust computation; set-points, such as firing rate, are actively stabilized to compensate for perturbations. The disruption of brain function central to neurodegenerative disease likely arises from impairments of computationally essential set-points. Here, we systematically investigated the effects of tau-mediated neurodegeneration on all known set-points in neuronal activity. We continuously tracked hippocampal neuronal activity across the lifetime of a mouse model of tauopathy. We were unable to detect effects of disease in measures of single-neuron firing activity. By contrast, as tauopathy progressed, there was disruption of network-level neuronal activity, quantified by measuring neuronal pairwise interactions and criticality, a homeostatically controlled, ideal computational regime. Deviations in criticality correlated with symptoms, predicted underlying anatomical pathology, occurred in a sleep-wake-dependent manner, and could be used to reliably classify an animal's genotype. This work illustrates how neurodegeneration may disrupt the computational capacity of neurobiological systems.

Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons.

The homeostatic regulation of neuronal activity is essential for robust computation; key set-points, such as firing rate, are actively stabilized to compensate for perturbations. From this perspective, the disruption of brain function central to neurodegenerative disease should reflect impairments of computationally essential set-points. Despite connecting neurodegeneration to functional outcomes, the impact of disease on set-points in neuronal activity is unknown. Here we present a comprehensive, theory-driven investigation of the effects of tau-mediated neurodegeneration on homeostatic set-points in neuronal activity. In a mouse model of tauopathy, we examine 27,000 hours of hippocampal recordings during free behavior throughout disease progression. Contrary to our initial hypothesis that tauopathy would impact set-points in spike rate and variance, we found that cell-level set-points are resilient to even the latest stages of disease. Instead, we find that tauopathy disrupts neuronal activity at the network-level, which we quantify using both pairwise measures of neuron interactions as well as measurement of the network's nearness to criticality, an ideal computational regime that is known to be a homeostatic set-point. We find that shifts in network criticality 1) track with symptoms, 2) predict underlying anatomical and molecular pathology, 3) occur in a sleep/wake dependent manner, and 4) can be used to reliably classify an animal's genotype. Our data suggest that the critical set-point is intact, but that homeostatic machinery is progressively incapable of stabilizing hippocampal networks, particularly during waking. This work illustrates how neurodegenerative processes can impact the computational capacity of neurobiological systems, and suggest an important connection between molecular pathology, circuit function, and animal behavior.

Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models.

Alcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options for AUD are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing and alcohol intake is positively correlated with release of the eCB ligand 2-Arachidonoylglycerol (2-AG) within reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical models ranging from a voluntary free-access model to aversion resistant-drinking and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. Lastly, DAGL inhibition also prevented ethanol-induced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent an effective approach to reduce alcohol consumption across the spectrum of AUD severity.

Human Mitochondrial Control Region and mtGenome: Design and Forensic Validation of NGS Multiplexes, Sequencing and Analytical Software.

Forensic mitochondrial DNA (mtDNA) analysis conducted using next-generation sequencing (NGS), also known as massively parallel sequencing (MPS), as compared to Sanger-type sequencing brings modern advantages, such as deep coverage per base (herein referred to as read depth per base pair (bp)), simultaneous sequencing of multiple samples (libraries) and increased operational efficiencies. This report describes the design and developmental validation, according to forensic quality assurance standards, of end-to-end workflows for two multiplexes, comprised of ForenSeq mtDNA control region and mtDNA whole-genome kits the MiSeq FGxTM instrument and ForenSeq universal analysis software (UAS) 2.0/2.1. Polymerase chain reaction (PCR) enrichment and a tiled amplicon approach target small, overlapping amplicons (60-150 bp and 60-209 bp for the control region and mtGenome, respectively). The system provides convenient access to data files that can be used outside of the UAS if desired. Studies assessed a range of environmental and situational variables, including but not limited to buccal samples, rootless hairs, dental and skeletal remains, concordance of control region typing between the two multiplexes and as compared to orthogonal data, assorted sensitivity studies, two-person DNA mixtures and PCR-based performance testing. Limitations of the system and implementation considerations are discussed. Data indicated that the two mtDNA multiplexes, MiSeq FGx and ForenSeq software, meet or exceed forensic DNA quality assurance (QA) guidelines with robust, reproducible performance on samples of various quantities and qualities.

Correction: Effects of providing manuscript editing through a combination of in-house and external editing services in an academic hospital.

[This corrects the article DOI: 10.1371/journal.pone.0219567.].

Effects of providing manuscript editing through a combination of in-house and external editing services in an academic hospital.

BACKGROUND: English editing services are effective for improving manuscript quality as well as providing learning opportunities for non-native English-speaking authors. Herein, we describe the effects of a combined system of in-house and external editing services for handling large volumes of editing requests and providing personalized editing service in academic hospitals. METHODS: We established the Scientific Publications Team (SPT), an in-house editing team in Asan Medical Center in Seoul, Korea. The SPT is composed of two professional editors who manage editing requests sent to external companies while also providing one-on-one in-house editing services. We gathered author satisfaction data from 936 surveys between July 2017 and December 2018 and analyzed the number of editing requests and research publications by segmented regression analysis of interrupted time series data. RESULTS: The SPT processed 3931 editing requests in 2017-2018, which was a marked increase compared with prior to its establishment (P = 0.0097). The authors were generally satisfied with the quality of editing services from both in-house and external editors. Upon conducting regular quality control, overall author satisfaction with one external company gradually increased over the course of one year (P for trend = 0.086). Author satisfaction survey results revealed that overall satisfaction of editing service was most strongly correlated with how well the edits conformed to the authors' intentions (R = 0.796), and was only weakly correlated with quick turnaround time (R = 0.355). We also observed a significant increase in the trend of the number of research publications (P = 0.0007) at one year after the establishment of the SPT. CONCLUSION: Providing a combination of in-house and external editing services resulted in high author satisfaction and subsequent hospital-wide increases in manuscript writing and publication. Our model system may be adapted in academic hospitals to better address the editing needs of non-native English-speaking researchers.

C. elegans Development and Activity Test detects mammalian developmental neurotoxins.

Due to the high cost and long duration of traditional testing methods for developmental neurotoxicity (DNT), only a small fraction of chemicals that humans are exposed to have been assessed for DNT activity. In order to ensure public safety, human-predictive methods for DNT detection that are faster and less resource intensive are urgently required. Using Caenorhabditis elegans, a novel worm Development and Activity test (wDAT) has been designed that uses a relatively inexpensive small-animal activity tracker and takes less than 4 days to complete. The wDAT was able to detect both developmental delay and hyperactivity for arsenic, lead, and mercury, heavy metals that are known human developmental neurotoxins and have been associated with hyperactivity in children. Lithium was also tested as a control developmental toxin that is not considered a mammalian neurotoxin. With the wDAT, lithium induced developmental delay but not hyperactivity. This initial assessment of a new assay for DNT detection indicates that the wDAT has potential for detecting at least some types of mammalian developmental neurotoxins. A planned 20-compound validation study will clarify the utility of the wDAT for predicitive toxicology.

In vitro percutaneous penetration of silver nanoparticles in pig and human skin.

In this study, the effects of surface charge, dose, and cosmetic vehicle on the penetration of silver nanoparticles (AgNPs) into pig and human skin were compared. AgNPs (20 nm) with varying surface-charges (polyethylene glycol (PEG; neutral), citrate (CIT; negative), and branched polyethylenimine (bPEI; positive) were dosed onto skin in in vitro diffusion cells using an aqueous solution and an oil-in-water emulsion formulation. Samples were analyzed by inductively coupled plasma mass spectroscopy (ICP-MS) and transmission electron microscope (TEM) to assess AgNP skin penetration. The results showed that neutral and positive AgNPs penetrate human skin when applied in a high dose aqueous solution and less with the emulsion vehicle. A mass balance percutaneous penetration study in human skin found the majority of AgNPs were washed from the skin or remained mostly in the stratum corneum (3.4% of the applied dose for AgbPEI and 1.7% for AgPEG). Very little silver was found in the epidermis (1.2% AgbPEI and 0.3% AgPEG) and dermis (0.1% AgbPEI and none detected for AgPEG). These results indicate low dermal penetration of AgNPs that is not greatly affected by surface coating charge. The results will facilitate dermal exposure assessments by better understanding how nanoparticle properties affect skin absorption of nanoparticles found in personal care products.

Automated Overnight Closed-Loop Control Using a Proportional-Integral-Derivative Algorithm with Insulin Feedback in Children and Adolescents with Type 1 Diabetes at Diabetes Camp.

OBJECTIVE: This study determined the feasibility and efficacy of an automated proportional-integral-derivative with insulin feedback (PID-IFB) controller in overnight closed-loop (OCL) control of children and adolescents with type 1 diabetes over multiple days in a diabetes camp setting. RESEARCH DESIGN AND METHODS: The Medtronic (Northridge, CA) Android™ (Google, Mountain View, CA)-based PID-IFB system consists of the Medtronic Minimed Revel™ 2.0 pump and Enlite™ sensor, a control algorithm residing on an Android phone, a translator, and remote monitoring capabilities. An inpatient study was completed for 16 participants to determine feasibility. For the camp study, subjects with type 1 diabetes were randomized to either OCL or sensor-augmented pump therapy (control conditions) per night for up to 6 nights at diabetes camp. RESULTS: During the camp study, 21 subjects completed 50 OCL nights and 52 control nights. Based on intention to treat, the median time spent in range, from 70 to 150 mg/dL, was greater during OCL at 66.4% (n = 55) versus 50.6% (n = 52) during the control period (P = 0.004). A per-protocol analysis allowed for assessment of algorithm performance with the median percentage time in range, 70-150 mg/dL, being 75.5% (n = 37) for OCL versus 47.6% (n = 32) for the control period (P < 0.001). There was less time spent in the hypoglycemic ranges <60 mg/dL and <70 mg/dL during OCL compared with the control period (P = 0.003 and P < 0.001, respectively). CONCLUSIONS: The PID-IFB controller is effective in improving time spent in range as well as reducing nocturnal hypoglycemia during the overnight period in children and adolescents with type 1 diabetes in a diabetes camp setting.

The use of an automated, portable glucose control system for overnight glucose control in adolescents and young adults with type 1 diabetes.

OBJECTIVE: A key milestone in progress towards providing an efficacious and safe closed-loop artificial pancreas system for outpatient use is the development of fully automated, portable devices with fault detection capabilities to ensure patient safety. The ability to remotely monitor the operation of the closed-loop system would facilitate future physician-supervised home studies. RESEARCH DESIGN AND METHODS: This study was designed to investigate the efficacy and safety of a fully automated, portable, closed-loop system. The Medtronic Portable Glucose Control System (PGCS) consists of two subcutaneous glucose sensors, a control algorithm based on proportional-integral-derivative with insulin feedback operating from a BlackBerry Storm smartphone platform, Bluetooth radiofrequency translator, and an off-the-shelf Medtronic Paradigm Veo insulin pump. Participants with type 1 diabetes using insulin pump therapy underwent two consecutive nights of in-clinic, overnight, closed-loop control after a baseline open-loop assessment. RESULTS: Eight participants attended for 16 overnight studies. The PGCS maintained mean overnight plasma glucose levels of 6.4 ± 1.7 mmol/L (115 ± 31 mg/dL). The proportion of time with venous plasma glucose <3.9, between 3.9 and 8 (70 and 144 mg/dL), and >8 mmol/L was 7, 78, and 15%, respectively. The proportion of time the sensor glucose values were maintained between 3.9 and 8 mmol/L was greater for closed-loop than open-loop (84.5 vs. 46.7%; P < 0.0001), and time spent <3.3 mmol/L was also reduced (0.9 vs. 3%; P < 0.0001). CONCLUSIONS: These results suggest that the PGCS, an automated closed-loop device, is safe and effective in achieving overnight glucose control in patients with type 1 diabetes.

Quality and sensory acceptability of a chilled functional apple ready-dessert.

An apple and dairy based ready-dessert with an added prebiotic was stored and chill temperatures and number of quality attributes were monitored during chill (4 °C) storage for 30 days. All ready-desserts were thermally processed by sous vide (P (90) > 10 min). The stability of the dairy component in ready-desserts was monitored by measuring volatile free fatty acids. Changes in these components were more evident in prebiotic-enriched samples compared to controls. However, no significant differences were observed over storage in control and prebiotic-enriched ready-desserts. This was supported by sensory analysis that showed no significant changes over storage in control or prebiotic-enriched samples. Of the other quality parameters, the addition of prebiotic inclusions resulted in lower L and b values and dry matter (p < 0.05), while increasing (p < 0.05) soluble solids content compared to control samples. Fluctuations in some of the quality parameters were also observed over storage. Rheological characteristics, i.e. flow behaviour (n), consistency index (K), storage (G'), loss (G″) and complex (G*) moduli were unaffected by prebiotic inclusion. However, storage affected the rheological characteristics of ready-desserts. A decrease (p < 0.05) in flow behaviour (n) led to concomitant increases in consistency index (K) and complex modulus (G*) values in control samples.

Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback.

OBJECTIVE: To test three theories of hypercortisolemia in depression-hypothalamic overdrive, impaired glucocorticoid feedback, or autonomous cortisol production. METHOD: We applied an overnight low-cortisol feedback strategy by administering metyrapone to hypercortisolemic depressed in-patients and control subjects. RESULTS: Under metyrapone, the increases of plasma adrenocorticotropic hormone (ACTH) concentrations and of basal and pulsatile ACTH secretion were not exaggerated in hypercortisolemic depressed patients compared with control subjects. ACTH approximate entropy (ApEn) did not differ at baseline or under metyrapone. Thus, neither hypothalamic overdrive nor irregular ACTH secretion was seen. We did not detect impaired cortisol feedback: the ACTH response was not reduced, and ApEn measures that are sensitive to feedback changes were comparable in both groups. Metyrapone disrupted cortisol secretory regularity in depressed and control subjects. On the baseline day, basal cortisol secretion was significantly increased and was highly irregular (high ApEn), and ACTH-cortisol cross-ApEn was markedly elevated in high-cortisol patients. CONCLUSION: Classical feed-forward overdrive and impaired feedback theories of hypercortisolemia in depression were not supported. Depressive hypercortisolemia may result from alternative pathophysiological mechanisms involving irregular basal hypersecretion of cortisol, associated with adrenal enlargement, possibly through splanchnic sympathetic activation of the adrenal cortex.

Assessment of the USCENTCOM Medical Distribution Structure.

This study examined whether there might be a medical supply and distribution structure for U.S. Central Command (USCENTCOM) that would maintain or improve performance while reducing costs. The authors evaluated the likely performance and cost implications of the range of possibilities, considering both the medical and nonmedical logistics structures, for providing medical supplies to support medical activities in USCENTCOM. They found that three options would preserve or improve performance while either lowering or not increasing costs. Additionally, they considered how the value of these solutions would likely change with future shifts in USCENTCOM operations.

Continuous glucose monitoring considerations for the development of a closed-loop artificial pancreas system.

BACKGROUND: Commercialization of a closed-loop artificial pancreas system that employs continuous subcutaneous insulin infusion and interstitial fluid glucose sensing has been encumbered by state-of-the-art technology. Continuous glucose monitoring (CGM) devices with improved accuracy could significantly advance development efforts. However, the current accuracy of CGM devices might be adequate for closed-loop control. METHODS: The influence that known CGM limitations have on closed-loop control was investigated by integrating sources of sensor inaccuracy with the University of Virginia Padova Diabetes simulator. Non-glucose interference, physiological time lag and sensor error measurements, selected from 83 Enlite™ glucose sensor recordings with the Guardian® REAL-Time system, were used to modulate simulated plasma glucose signals. The effect of sensor accuracy on closed-loop controller performance was evaluated in silico, and contrasted with closed-loop clinical studies during the nocturnal control period. RESULTS: Based on n = 2472 reference points, a mean sensor error of 14% with physiological time lags of 3.28 ± 4.62 min (max 13.2 min) was calculated for simulation. Sensor bias reduced time in target for both simulation and clinical experiments. In simulation, additive error increased time <70 mg/dl and >180 mg/dl by 0.2% and 5.6%, respectively. In-clinic, the greatest low blood glucose index values (max = 5.9) corresponded to sensor performance. CONCLUSION: Sensors have sufficient accuracy for closed-loop control, however, algorithms are necessary to effectively calibrate and detect erroneous calibrations and failing sensors. Clinical closed-loop data suggest that control with a higher target of 140 mg/dl during the nocturnal period could significantly reduce the risk for hypoglycemia.

Closed-loop insulin delivery utilizing pole placement to compensate for delays in subcutaneous insulin delivery.

BACKGROUND: We have previously used insulin feedback (IFB) as a component of a closed-loop algorithm emulating the ß cell. This was based on the observation that insulin secretion is inhibited by insulin concentration. We show here that the effect of IFB is to make a closed-loop system behave as if delays in the insulin pharmacokinetic (PK)/pharmacodynamic (PD) response are reduced. We examine whether the mechanism can be used to compensate for delays in the subcutaneous PK/PD insulin response. METHOD: Closed-loop insulin delivery was performed in seven diabetic dogs using a proportional-integral-derivative model of the ß cell modified by model-predicted IFB. The level of IFB was set using pole placement. Meal responses were obtained on three occasions: without IFB (NONE), reference IFB (REF), and 2xREF, with experiments performed in random order. The ability of the insulin model to predict insulin concentration was evaluated by correlation with the measured profile and results reported as R(2). The ability of IFB to improve the meal response was evaluated by comparing peak and nadir postprandial glucose and area under the curve (AUC; repeated measures analysis of variance with post hoc test for linear trend). RESULTS: Insulin concentration was well predicted by the model (median R(2) = 0.87, 0.79, and 0.90 for NONE, REF, and 2xREF, respectively). Peak postprandial glucose (294 ± 15, 243 ± 21, and 247 ± 16 mg/dl) and AUC (518.2 ± 36.13, 353.5 ± 45.04, and 280.3 ± 39.37 mg/dl · min) decreased with increasing IFB (p < .05, linear trend). Nadir glucose was not affected by IFB (76 ± 5.4, 68 ± 7.3, and 72 ± 4.3 mg/dl; p = .63). CONCLUSIONS: Insulin feedback provides an effective mechanism to compensate for delay in the insulin PK/PD profile.

The pathway to the closed-loop artificial pancreas: research and commercial perspectives.

BACKGROUND: Over the past decades, insulin pumps (CSII) and continuous glucose monitoring (CGM) systems have been combined in sensor augmented pump therapy. In addition, artificial pancreas (AP) research has progressed to clinical studies, using combinations of commercially available devices. OBJECTIVE: Sensor augmented pump therapy has been evaluated in a number of clinical trials. These studies have been designed to show glycemic outcomes. The low glucose suspend (LGS) feature of the Medtronic Paradigm Veo (Medtronic MiniMed, Northridge, CA) pump allows CGM to suspend insulin delivery if preset hypoglycemic thresholds are achieved. Evaluation of the AP has been conducted to show effect on time in target, and has involved a variety of algorithms, pumps and CGM systems. RESULTS: Multiple studies have shown that more time is spent in the target range for glucose levels and that there is less hypoglycemia with sensor augmented pump, LGS and early AP platforms. CONCLUSIONS: Current research shows that progress has been made in the iterative steps required to develop the AP.

The effect of hot-boning and reduced added phosphate on the processing and sensory properties of cured beef prepared from two forequarter muscles.

The functionality of pre-rigor beef was investigated in terms of the effects of phosphate reduction and curing of hot-boned meat on the processing and sensory properties of relatively low-value muscles, M. infraspinatus (IS) and M. pectoralis profundus (PP), from the forequarter. Muscles were excised within 90 min post-mortem (HB) or, from chilled carcasses, 24 h post-mortem (CB), and were injected to 115% of green weight with brine containing phosphate and were vacuum tumbled continuously for 2 h. Hot-boning gave lower total yield of cooked meat for both muscles. Hot-boned PP joints had slightly higher (P<0.05) cook loss than cold-boned. Reduction of added phosphate (from sodium tri-polyphosphate) from 0.3% to 0.15% of cured meat had detrimental effects on colour; joints containing the conventional 0.3% were lighter (P<0.001) and redder for both muscles. Hot-boning gave PP joints which were rated less tender by sensory panels, corresponding with higher (P<0.001) hardness TPA values, higher (P<0.05) Warner-Bratzler shear force (WBSF) values and shorter (P<0.05) sarcomere lengths. Effects of phosphate level and boning method were less in IS joints. In these, hot-boning gave products that were rated by sensory panel as slightly more tender but there was no effect on TPA or WBSF values. Furthermore, total yields from hot-boned products did not reflect the expected increase in functionality and reducing added phosphate during processing had a detrimental effect in binding and forming of joints.