Fast non-negative deconvolution for spike train inference from population calcium imaging

Calcium imaging for observing spiking activity from large populations of neurons are quickly gaining popularity. While the raw data are fluorescence movies, the underlying spike trains are of interest. This work presents a fast non-negative deconvolution filter to infer the approximately most likely spike train for each neuron, given the fluorescence observations. This algorithm outperforms optimal linear deconvolution (Wiener filtering) on both simulated and biological data. The performance gains come from restricting the inferred spike trains to be positive (using an interior-point method), unlike the Wiener filter. The algorithm is fast enough that even when imaging over 100 neurons, inference can be performed on the set of all observed traces faster than real-time. Performing optimal spatial filtering on the images further refines the estimates. Importantly, all the parameters required to perform the inference can be estimated using only the fluorescence data, obviating the need to perform joint electrophysiological and imaging calibration experiments.Comment: 22 pages, 10 figure

A Functional Difficulty and Functional Pain Instrument for Hip and Knee Osteoarthritis

Introduction: The objectives of this study were to develop a functional outcome instrument for hip and knee osteoarthritis research (OA-FUNCTION-CAT) using item response theory (IRT) and computer adaptive test (CAT) methods and to assess its psychometric performance compared to the current standard in the field. Methods: We conducted an extensive literature review, focus groups, and cognitive testing to guide the construction of an item bank consisting of 125 functional activities commonly affected by hip and knee osteoarthritis. We recruited a convenience sample of 328 adults with confirmed hip and/or knee osteoarthritis. Subjects reported their degree of functional difficulty and functional pain in performing each activity in the item bank and completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Confirmatory factor analyses were conducted to assess scale uni-dimensionality, and IRT methods were used to calibrate the items and examine the fit of the data. We assessed the performance of OA-FUNCTION-CATs of different lengths relative to the full item bank and WOMAC using CAT simulation analyses. Results: Confirmatory factor analyses revealed distinct functional difficulty and functional pain domains. Descriptive statistics for scores from 5-, 10-, and 15-item CATs were similar to those for the full item bank. The 10-item OA-FUNCTION-CAT scales demonstrated a high degree of accuracy compared with the item bank (r = 0.96 and 0.89, respectively). Compared to the WOMAC, both scales covered a broader score range and demonstrated a higher degree of precision at the ceiling and reliability across the range of scores. Conclusions: The OA-FUNCTION-CAT provided superior reliability throughout the score range and improved breadth and precision at the ceiling compared with the WOMAC. Further research is needed to assess whether these improvements carry over into superior ability to measure change

MicroRNA132 Modulates Short-Term Synaptic Plasticity but Not Basal Release Probability in Hippocampal Neurons

MicroRNAs play important regulatory roles in a broad range of cellular processes including neuronal morphology and long-term synaptic plasticity. MicroRNA-132 (miR132) is a CREB-regulated miRNA that is induced by neuronal activity and neurotrophins, and plays a role in regulating neuronal morphology and cellular excitability. Little is known about the effects of miR132 expression on synaptic function. Here we show that overexpression of miR132 increases the paired-pulse ratio and decreases synaptic depression in cultured mouse hippocampal neurons without affecting the initial probability of neurotransmitter release, the calcium sensitivity of release, the amplitude of excitatory postsynaptic currents or the size of the readily releasable pool of synaptic vesicles. These findings are the first to demonstrate that microRNAs can regulate short-term plasticity in neurons

A two-neuron system for adaptive goal-directed decision-making in Lymnaea

During goal-directed decision-making, animals must integrate information from the external environment and their internal state to maximize resource localization while minimizing energy expenditure. How this complex problem is solved by the nervous system remains poorly understood. Here, using a combined behavioural and neurophysiological approach, we demonstrate that the mollusc Lymnaea performs a sophisticated form of decision-making during food-searching behaviour, using a core system consisting of just two neuron types. The first reports the presence of food and the second encodes motivational state acting as a gain controller for adaptive behaviour in the absence of food. Using an in vitro analogue of the decision-making process, we show that the system employs an energy management strategy, switching between a low- and high-use mode depending on the outcome of the decision. Our study reveals a parsimonious mechanism that drives a complex decision-making process via regulation of levels of tonic inhibition and phasic excitation

Structural and Functional Deficits in a Neuronal Calcium Sensor-1 Mutant Identified in a Case of Autistic Spectrum Disorder

Neuronal calcium sensor-1 (NCS-1) is a Ca2+ sensor protein that has been implicated in the regulation of various aspects of neuronal development and neurotransmission. It exerts its effects through interactions with a range of target proteins one of which is interleukin receptor accessory protein like-1 (IL1RAPL1) protein. Mutations in IL1RAPL1 have recently been associated with autism spectrum disorders and a missense mutation (R102Q) on NCS-1 has been found in one individual with autism. We have examined the effect of this mutation on the structure and function of NCS-1. From use of NMR spectroscopy, it appeared that the R102Q affected the structure of the protein particularly with an increase in the extent of conformational exchange in the C-terminus of the protein. Despite this change NCS-1(R102Q) did not show changes in its affinity for Ca2+ or binding to IL1RAPL1 and its intracellular localisation was unaffected. Assessment of NCS-1 dynamics indicated that it could rapidly cycle between cytosolic and membrane pools and that the cycling onto the plasma membrane was specifically changed in NCS-1(R102Q) with the loss of a Ca2+ -dependent component. From these data we speculate that impairment of the normal cycling of NCS-1 by the R102Q mutation could have subtle effects on neuronal signalling and physiology in the developing and adult brain

Type 3 Fimbriae and Biofilm Formation Are Regulated by the Transcriptional Regulators MrkHI in Klebsiella pneumoniae▿

Klebsiella pneumoniae is an opportunistic pathogen which frequently causes hospital-acquired urinary and respiratory tract infections. K. pneumoniae may establish these infections in vivo following adherence, using the type 3 fimbriae, to indwelling devices coated with extracellular matrix components. Using a colony immunoblot screen, we identified transposon insertion mutants which were deficient for type 3 fimbrial surface production. One of these mutants possessed a transposon insertion within a gene, designated mrkI, encoding a putative transcriptional regulator. A site-directed mutant of this gene was constructed and shown to be deficient for fimbrial surface expression under aerobic conditions. MrkI mutants have a significantly decreased ability to form biofilms on both abiotic and extracellular matrix-coated surfaces. This gene was found to be cotranscribed with a gene predicted to encode a PilZ domain-containing protein, designated MrkH. This protein was found to bind cyclic-di-GMP (c-di-GMP) and regulate type 3 fimbrial expression

Evidencing the intersection of environmental, socioeconomic, behavioural and demographic drivers of antibacterial resistance in East Africa

Background: Risk factors for antibiotic-resistant infections are multi-scalar and interdependent, but few studies investigate them in an integrated way. We investigated how location, the environment, socioeconomics, behaviours, attitudes, and demographics are jointly associated with multi-drug resistant urinary tract infection (MDR UTI). Methods: Between 2018-2020, the Holistic Approach to Unravelling Antibacterial Resistance (HATUA) Consortium recruited outpatients with UTI symptoms in healthcare facilities in Kenya, Tanzania, and Uganda. We collected urine samples and questionnaires from patients and households. Our primary outcome was MDR UTI, defined as resistance to 3 or more categories of antibiotics. We used linked individual-level data on 67 variables capturing geographic, environmental, socioeconomic, demographic, attitudinal, and behavioural characteristics. We employed bivariate analyses and Bayesian profile regression to investigate the joint association of risk factors with MDR UTI. Findings: Out of 2332 patients with microbiologically-confirmed UTI, we analysed 1610 with linked microbiological, social, and environmental data. Most were female (1369 [85·0%]), younger than 45 years (1206 [74·9%]), and nearly half had MDR UTI (766 [47.6%]). Profile regression generated 10 high-risk and 7 low-risk MDR UTI clusters. High-risk MDR clusters contained patients that were on average older, with lower education, more chronic illness, and lived in resource-deprived households. They were also more likely to have contact with animals, and human/animal waste. Interpretation: Risk factors for antibiotic resistance are interrelated through multidimensional poverty. We need studies which explore how these factors interact longitudinally to shape inequalities, and to design appropriate interventions