Measurement error models with zero inflation and multiple sources of zeros, with applications to hard zeros.

We consider measurement error models for two variables observed repeatedly and subject to measurement error. One variable is continuous, while the other variable is a mixture of continuous and zero measurements. This second variable has two sources of zeros. The first source is episodic zeros, wherein some of the measurements for an individual may be zero and others positive. The second source is hard zeros, i.e., some individuals will always report zero. An example is the consumption of alcohol from alcoholic beverages: some individuals consume alcoholic beverages episodically, while others never consume alcoholic beverages. However, with a small number of repeat measurements from individuals, it is not possible to determine those who are episodic zeros and those who are hard zeros. We develop a new measurement error model for this problem, and use Bayesian methods to fit it. Simulations and data analyses are used to illustrate our methods. Extensions to parametric models and survival analysis are discussed briefly.

Implementation of mechanistic modeling and global sensitivity analysis (GSA) for design, optimization, and scale-up of a roller compaction process.

The pharmaceutical industry has been shifting towards the application of mechanistic modeling to improve process robustness, enable scale-up, and reduce time to market. Modeling approaches have been well-developed for processes such as roller compaction, a continuous dry granulation process. Several mechanistic models/approaches have been documented with limited application to high drug-loaded formulations. In this study, the Johanson model was employed to optimize roller compaction processing and guide its scale-up for a high drug loaded formulation. The model was calibrated using a pilot-scale Minipactor and was validated for a commercial-scale Macropactor. Global sensitivity analysis (GSA) was implemented to determine the impact of process parameter variations (roll force, gap, speed) on a quality attribute [solid fraction (SF)]. The throughput method, which estimates SF values of ribbons using granule production rate, was also studied. The model predicted SF values for all 14 Macropactor batches within ± 0.04 SF. The throughput method estimated SF with ± 0.06 SF for 7 out of 11 batches. GSA confirmed that roll force had the largest impact on SF. This case study represents a process modeling approach to build quality into the products/processes and expands the use of mechanistic modeling during drug product development.

Exploiting the Synergism of a Carbon-Catalyst Interface to Achieve Magneto-Electrocatalytic Overall Water Splitting at 2.197 V.

The desire to electrolyze water at low energy and high kinetics for achieving rapid H2 production forms the holy grail for the paradigm shift to a sustainable H2-driven economy. While alkaline electrolysis is preferred due to the use of earth-abundant catalysts, its sluggish kinetics and high overpotential are the persistent challenges. Addressing this, we demonstrate the coupling of an externally applied magnetic field (Hext) to a synergistically designed interface of nanostructured carbon floret with antiferromagnetic NiO nanoflakes that act in unison to achieve rapid hydrogen generation (6.3 N m3 h-1 W-1) that is comparable with existing technologies. Specifically, the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) overpotentials are simultaneously reduced by 10 and 7%, respectively, under the influence of a weak fridge magnet (Hext = 200 mT). Consequently, ∼11% improvement in the energy efficiency is observed with a 21% reduced cell voltage for overall water splitting. The stability of the system is demonstrated over a prolonged lifetime of ∼95 h. This performance enhancement with Hext for both HER and OER is explained in terms of improved kinetic facility for the reaction and lower resistance of charge transfer pathway. Moreover, the electrocatalyst is seen to retain the improved performance for prolonged usage (∼3 h) even after the removal of the Hext, and hence, it provides an energy-efficient hydrogen and oxygen generation pathway.

Time-dependent exfoliation study of MoS2 for its use as a cathode material in high-performance hybrid supercapacitors.

Quick and precise exfoliation of bulk molybdenum sulphide into few layers can bring a quantum leap in the electrochemical performance of this material. Such a cost-effective exfoliation route to obtain few layers of MoS2 nanosheets with a high mass yield of ∼75% is presented in this study. The electrochemical behaviours of three types of samples, namely pristine MoS2 and MoS2 exfoliated for 3 h and 5 h, were compared and the reasons leading to their performance modulation are explained. The performance could be tuned by changing the nature of the electrolytes, as shown using three different electrolytes, i.e. H2SO4, Na2SO4, and KOH. The electrochemical performance of a supercapacitor device fabricated using the 5 h-exfoliated sample showed many fold improvement. The strategy of combining with a 2D material-based anode is an interesting way forward for such devices. In addition, the anode material has to be carefully chosen so that high performance can be ensured. The usefulness of 2D flake-like WO3 as an anode was investigated first before establishing its worthiness in a hybrid device. The hybrid device was able to deliver an excellent energy density of 33.74 W h kg-1 with long-term cycling stability and coulombic efficiency, thus proving its applicability for high-performance energy-storage devices.

Organic Supercapacitors as the Next Generation Energy Storage Device: Emergence, Opportunity, and Challenges.

Harnessing new materials for developing high-energy storage devices set off research in the field of organic supercapacitors. Various attractive properties like high energy density, lower device weight, excellent cycling stability, and impressive pseudocapacitive nature make organic supercapacitors suitable candidates for high-end storage device applications. This review highlights the overall progress and future of organic supercapacitors. Sustainable energy production and storage depend on low cost, large supercapacitor packs with high energy density. Organic supercapacitors with high pseudocapacitance, lightweight form factor, and higher device potential are alternatives to other energy storage devices. There are many recent ongoing research works that focus on organic electrolytes along with the material aspect of organic supercapacitors. This review summarizes the current research status and the chemistry behind the storage mechanism in organic supercapacitors to overcome the challenges and achieve superior performance for future opportunities.

A locus coeruleus-dorsal CA1 dopaminergic circuit modulates memory linking.

Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on a temporary increase in excitability that drives the overlap between dorsal CA1 (dCA1) hippocampal ensembles that encode the linked memories. Here, we show that locus coeruleus (LC) cells projecting to dCA1 have a key permissive role in contextual memory linking, without affecting contextual memory formation, and that this effect is mediated by dopamine. Additionally, we found that LC-to-dCA1-projecting neurons modulate the excitability of dCA1 neurons and the extent of overlap between dCA1 memory ensembles as well as the stability of coactivity patterns within these ensembles. This discovery of a neuromodulatory system that specifically affects memory linking without affecting memory formation reveals a fundamental separation between the brain mechanisms modulating these two distinct processes.

Dimensions and mechanisms of memory organization.

Memory formation is dynamic in nature, and acquisition of new information is often influenced by previous experiences. Memories sharing certain attributes are known to interact so that retrieval of one increases the likelihood of retrieving the other, raising the possibility that related memories are organized into associative mnemonic structures of interconnected representations. Although the formation and retrieval of single memories have been studied extensively, very little is known about the brain mechanisms that organize and link related memories. Here we review studies that suggest the existence of mnemonic structures in humans and animal models. These studies suggest three main dimensions of experience that can serve to organize related memories: time, space, and perceptual/conceptual similarities. We propose potential molecular, cellular, and systems mechanisms that might support organization of memories according to these dimensions.

Hierarchical cage-frame type nanostructure of CeO2 for bio sensing applications: from glucose to protein detection.

Self-assembled hierarchical nanostructures are slowly superseding their conventional counterparts for use in biosensors. These morphologies show high surface area with tunable porosity and packing density. Modulating the interfacial interactions and subsequent particle assembly occurring at the water-and-oil interface in inverse miniemulsions, are amongst the best strategies to stabilize various type of hollow nanostructures. The paper presents a successful protocol to obtain CeO2 hollow structures based biosensors that are useful for glucose to protein sensing. The fabricated glucose sensor is able to deliver high sensitivity (0.495 µA cm-2 nM-1), low detection limit (6.46 nM) and wide linear range (0 nM to 600 nM). CeO2 based bioelectrode can also be considered as a suitable candidate for protein sensors. It can detect protein concentrations varying from 0 to 30 µM, which is similar or higher than most reports in the literature. The limit of detection (LOD) for protein was ∼0.04 µM. Therefore, the hollow CeO2 electrodes, with excellent reproducibility, stability and repeatability, open a new area of application for cage-frame type particles.

Author Correction: Time units for learning involving maintenance of system-wide cFos expression in neuronal assemblies.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Getting the full picture.

A combination of old and new techniques has revealed new details about the behavior of individual neurons across the sleep-wake-cycle.

Time units for learning involving maintenance of system-wide cFos expression in neuronal assemblies.

Repeated experiences may be integrated in succession during a learning process, or they may be combined as a whole within dedicated time windows to possibly promote quality control. Here we show that in Pavlovian, incremental and incidental learning, related information acquired within time windows of 5 h is combined to determine what mice learn. Trials required for learning had to occur within 5 h, when learning-related shared cues could produce association and interference. Upon acquisition, cFos expression was elevated during 5 h throughout specific system-wide neuronal assemblies. Time window function depended on network activity and cFos expression. Local cFos activity was required for distant assembly recruitment through network activity and distant BDNF. Activation of learning-related cFos assemblies was sufficient and necessary for time window function. Therefore, learning processes consist of dedicated 5 h time windows (time units for learning), involving maintenance of system-wide neuronal assemblies through network activity and cFos expression.

Author Correction: PV plasticity sustained through D1/5 dopamine signaling required for long-term memory consolidation.

In the version of this article initially published, the right panel in Fig. 2b was duplicated from the corresponding panel in Fig. 2c, and some data points in Fig. 3b were duplicated from Fig. 3a. None of the conclusions in the paper are affected. The errors have been corrected in the HTML and PDF versions of the article, and source data have been posted for the revised panels. The original and corrected figures are shown in the accompanying Author Correction.

Parvalbumin Interneuron Plasticity for Consolidation of Reinforced Learning.

Parvalbumin (PV) basket cells are widespread local interneurons that inhibit principal neurons and each other through perisomatic boutons. They enhance network function and regulate local ensemble activities, particularly in the γ range. Organized network activity is critically important for long-term memory consolidation during a late time window 11-15 h after acquisition. Here, we discuss the role of learning-related plasticity in PV neurons for long-term memory consolidation. The plasticity can lead to enhanced (high-PV) or reduced (low-PV) expression of PV/GAD67. High-PV plasticity is induced upon definite reinforced learning in early-born PV basket cells, whereas low-PV plasticity is induced upon provisional reinforced learning in late-born PV basket cells. The plasticity is first detectable 6 h after acquisition, at the end of a time window for memory specification through experience, and is critically important 11-15 h after acquisition for enhanced network activity and long-term memory consolidation. High- and low-PV plasticity appear to regulate activity in distinct local networks of principal neurons and PV basket cells. These findings suggest how flexibility and stability in learning and memory might be implemented through parallel circuits and networks.

Effect of Low Dose Oral Vitamin-D and Calcium Replacement in HIV Patients.

BACKGROUND: There is high prevalence of vitamin-D deficiency and abnormal bone mineral density (BMD) in HIV patients. Our aim is to find out the effect of replacement of low dose oral vitamin-D (800 International unit) with calcium (500mg) as a once daily regimen along with antiretroviral (ARV) on serum vitamin-D and parathyroid hormone (PTH) level and bone mineral density (BMD) changes on patients with HIV infection who have vitamin- D deficiency. METHODS: This is a non-randomised, open label study. We collected information about demography, viral load, CD-4 count, fracture risk factors. We measured serum 25(OH)D, parathyroid hormone (intact PTH), inorganic phosphate, corrected calcium, alkaline phosphatase (ALP) and BMD of hip and spine at baseline and after 12 months of routine follow up. Patients were treatment experienced and were divided into tenofovir containing, efavirenz containing, and protease Inhibitor (PI) containing regimens. RESULTS: The study included 87 treatment experienced HIV patients with mean age 42.8 (+/-7.8) years, 55 (63%) females, 73 (84%) black African ethnicity, CD4 count 451.7 (+/-184.6) cells/dL, plasma VL 1.6 log (+/-0.03) copies/mL, exposure to antiretroviral therapy 43.2 (+/-30.2) months and duration of illness 58.4 (+/- 24.1) months. Forty four patients agreed to take vitamin-D with calcium replacement and 43 patients did not agree to take the replacement. After 12 months of follow up patients on vitamin D and calcium replacement (n=44) had significant increase in vitamin-D level (15.4+/-6.2 vs. 55.9+/-22.6, p=0.0001), reduction in PTH (8.04 +/-7.5, vs. 4.7 +/-1.8, p=0.005), alkaline phosphatase (111.1 +/-79.1 vs. 90.2+/-42.2, p=0.038) and increase in corrected calcium (2.18 +/-0.09 vs. 2.19 +/-0.09 p=0.001). In patients not on vitamin-D replacement (n=43), there was increase in vitamin-D (16.9 +/-12.1 vs. 49.4 +/-29.2, p=0.001) and corrected calcium (2.12 +/-0.09 vs. 2.16 +/-0.08 p=0.0001) level, but PTH and ALP did not change. BMD of hip and spine did not show any significant change in either of the two groups. In multivariate analysis that included all significant variables, vitamin-D and calcium replacement independently was associated with increase in vitamin-D level (OR 1.07, CI 1.02, 1.12, p=0.005), decrease in PTH level (OR 0.53, CI 0.35, 0.82, p=0.004), but not with change in corrected calcium, alkaline phosphatase, BMD of hip or spine. CONCLUSION: After 12 months of follow up, replacement of low dose once daily oral vitamin-D with calcium in treatment experienced HIV patients with vitamin-D deficiency can increase vitamin-D level, reduce PTH level without any change in BMD of hip and spine.

PV plasticity sustained through D1/5 dopamine signaling required for long-term memory consolidation.

Long-term consolidation of memories depends on processes occurring many hours after acquisition. Whether this involves plasticity that is specifically required for long-term consolidation remains unclear. We found that learning-induced plasticity of local parvalbumin (PV) basket cells was specifically required for long-term, but not short/intermediate-term, memory consolidation in mice. PV plasticity, which involves changes in PV and GAD67 expression and connectivity onto PV neurons, was regulated by cAMP signaling in PV neurons. Following induction, PV plasticity depended on local D1/5 dopamine receptor signaling at 0-5 h to regulate its magnitude, and at 12-14 h for its continuance, ensuring memory consolidation. D1/5 dopamine receptor activation selectively induced DARPP-32 and ERK phosphorylation in PV neurons. At 12-14 h, PV plasticity was required for enhanced sharp-wave ripple densities and c-Fos expression in pyramidal neurons. Our results reveal general network mechanisms of long-term memory consolidation that requires plasticity of PV basket cells induced after acquisition and sustained subsequently through D1/5 receptor signaling.

Early- and late-born parvalbumin basket cell subpopulations exhibiting distinct regulation and roles in learning.

Brain networks can support learning by promoting acquisition of task-relevant information or by adhering to validated rules, but the mechanisms involved are poorly understood. Upon learning, local inhibitory parvalbumin (PV)-expressing Basket cell networks can switch to opposite configurations that either favor or interfere with further learning, but how this opposite plasticity is induced and relates to distinct learning requirements has remained unclear. Here, we show that PV Basket cells consist of hitherto unrecognized subpopulations, with distinct schedules of neurogenesis, input connectivities, output target neurons, and roles in learning. Plasticity of hippocampal early-born PV neurons was recruited in rule consolidation, whereas plasticity of late-born PV neurons was recruited in new information acquisition. This involved regulation of early-born neuron plasticity specifically through excitation, and of late-born neuron plasticity specifically through inhibition. Therefore, opposite learning requirements are implemented by distinct local networks involving PV Basket cell subpopulations specifically regulated through inhibition or excitation.

Data calibration and reduction allows to visualize behavioural profiles of psychosocial influences in mice towards clinical domains.

Psychosocial stress-particularly in combination with genetic vulnerability-is a critical environmental risk factor for psychiatric diseases in humans. Isolation rearing (IR) and social defeat (SD) paradigms model psychosocial risk factors in rodents, while enriched environment (EE) protects them from behavioural deficits. Studying the influence of various environmental conditions, e.g., on genetic mouse models can help to dissect the complex gene-environment relationships underlying human psychiatric diseases. Such studies may require analysing multiple mouse cohorts; however, the comparability of behavioural experiments is challenging and often compromised by practical limitations such as group sizes and influences of handling. Therefore, protocol standardization as well as appropriate statistical normalization is necessary to compare different experiments. In this study, we analysed two independent cohorts to compare the behavioural profiles of wild-type male mice subjected to IR and SD. In both cases, EE conditions served as a reference. Multivariate statistics was applied to merge the data from individual measures into broader categories (such as curiosity, anxiety and fear memory) by estimating their calibrated joint effect within a category. Plotting and overlaying these calibrated effect sizes in a single graph allowed intuitive comparison of IR and SD behavioural profiles. This approach allows analysing multiple behavioural tests at once, which is more relevant to psychiatric syndromes than focusing on single behavioural measures. Our method revealed that motivation and fear memory are impaired by both conditions, whereas ambulation and pain sensitivity are affected only by IR and curiosity is mainly diminished upon SD. Thus, IR could be a paradigm of choice in studies focusing on positive symptoms, while SD might be more relevant for negative and cognitive symptoms.

Synapse rearrangements upon learning: from divergent-sparse connectivity to dedicated sub-circuits.

Learning can involve formation of new synapses and loss of synapses, providing memory traces of learned skills. Recent findings suggest that these synapse rearrangements reflect assembly of task-related sub-circuits from initially broadly distributed and sparse connectivity in the brain. These local circuit remodeling processes involve rapid emergence of synapses upon learning, followed by protracted validation involving strengthening of some new synapses, and selective elimination of others. The timing of these consolidation processes can vary. Here, we review these findings, focusing on how molecular/cellular mechanisms of synapse assembly, strengthening, and elimination might interface with circuit/system mechanisms of learning and memory consolidation. An integrated understanding of these learning-related processes should provide a better basis to elucidate how experience, genetic background, and disease influence brain function.

Total sleep deprivation impairs the encoding of trace-conditioned memory in the rat.

Sleep may help consolidate the information of certain memories, though its benefits in the consolidation of trace-conditioned memory still remain elusive. We investigated the effect of sleep deprivation on trace learning in male wistar rats. Rats were trained for trace conditioning and the number of head entries into liquid dispenser was accounted as an outcome measure of trace-learning. For training and testing, 75 presentations of conditioned stimulus (CS) (light) and unconditioned stimulus (US) (juice) were offered in five sessions (15 presentations/session; with 5 min inter-session gap). The duration of CS and US stimuli were 15 and 20s respectively, with 5s trace delay between stimuli and 20s condition delay between each presentation. The animals were divided randomly into three groups soon after training, sleep deprived (SD) (n=8), non-SD (NSD) (n=8) and stress control (n=5) groups. The animals of NSD and control groups were left undisturbed, while SD animals were sleep deprived for 6h after training. The learning of trace-conditioned task was examined on following days. We observed that SD rats poked approximately 63% less than NSD and control groups (p<0.001) to obtain juice on testing day. Also, the NSD rats exhibited significant positive correlation in number of head entries during the training and testing days; while the SD rats showed no significant correlation. The results demonstrate that SD animals had difficulties to associate CS with US and suggest that sleep deprivation soon after training impairs the encoding of trace memory.