Miracle-dz/UniFAR-FTUs huggingface dataset:
Information Theoretic Approaches to Deciphering the Neural Code with Functional Fluorescence Imaging

Abstract Information theoretic metrics have proven useful in quantifying the relationship between behaviorally relevant parameters and neuronal activity with relatively few assumptions. However, these metrics are typically applied to action potential (AP) recordings and were not designed for the slow timescales and variable amplitudes typical of functional fluorescence recordings (e.g., calcium imaging). The lack of research guidelines on how to apply and interpret these metrics with fluorescence traces means the neuroscience community has yet to realize the power of information theoretic metrics. Here, we used computational methods to create mock AP traces with known amounts of information. From these, we generated fluorescence traces and examined the ability of different information metrics to recover the known information values. We provide guidelines for how to use information metrics when applying them to functional fluorescence and demonstrate their appropriate application to GCaMP6f population recordings from mouse hippocampal neurons imaged during virtual navigation.
Real-time tracking of Tomato brown rugose fruit virus (ToBRFV) outbreaks in the Netherlands using Nextstrain

Tomato brown rugose fruit virus (ToBRFV) is a Tobamovirus that was first observed in 2014 and 2015 on tomato plants in Israel and Jordan causing discolorations and deformation of leaves and fruits. Apart from tomato, damage in pepper fruits has been reported. Since the first description, the virus has been found on all continents except Oceania and Antarctica. In October 2019, the Dutch National Plant Protection Organization received a tomato sample suspected to be infected with ToBRFV as part of an official specific survey of tomato fruit growers in the Netherlands carried out July to October 2019. During the survey 124 companies were visited and inspected for possible ToBRFV symptoms. Of the 47 samples tested, one sample tested positive with ELISA and test plants, which was verified using real-time RT-PCR and Illumina RNAseq data. A follow-up survey was initiated to determine the extent of ToBRFV presence in the Dutch tomato horticulture and identify possible linkages between ToBRFV genotypes, companies and epidemiological traits. We used Nextstrain to visualize these potential connections. Genomic diversity of ToBRFV isolates found in the Netherlands group in three main clusters which are hypothesized to represent three sources. No correlation was found between genotypes, companies and epidemiological traits such as rootstock and scion varieties, seed batches and nurseries, and the source(s) of the Dutch outbreak remain unknown. This paper describes a Nextstrain build containing ToBRFV genomes up to and including November 2019. The NPPO-NL has committed itself to maintain and improve the build. Sharing data with this interactive online tool will enable the regulatory plant virology field to better understand and communicate the diversity and spread of this new virus. Other organizations are stimulated to share data or materials for inclusion in the Nextstrain build, which can be accessed at //40.91. 255.14/ToBRFV/20191231.
Muscle fiber type differences in nitrate and nitrite storage and nitric oxide signaling in rats

Recent studies have emphasized the importance of the nitric oxide synthase (NOS)-independent, nitrate (NO3−) → nitrite (NO2−) → nitric oxide (NO) pathway in skeletal muscle. In particular, it has been hypothesized that this pathway is especially active in type II, or fast-twitch, muscle fibers, necessitating greater NO3− and NO2− storage. We therefore measured NO3− and NO2− concentrations in the predominantly fast-twitch vastus lateralis and predominantly slow-twitch soleus muscles of rats. Contrary to the above hypothesis, we found that NO3− and NO2− concentrations were 3.4-fold and 1.8-fold higher, respectively, in the soleus. On the other hand, NO signaling (i.e., cyclic guanosine monophosphate (cGMP) level) was comparable in the two muscles. Although the physiological significance of these observations remains to be determined, we speculate that NO production via the NO3− → NO2− → NO pathway is normally higher in slow-twitch muscles, thus helping compensate for their inherently lower NOS activity.
High-fat diet impacts the colon and its transcriptome in a sex-dependent manner that is modifiable by estrogens

Epidemiological studies highlight a strong association between obesity and colorectal cancer (CRC), especially in men. Estrogen, on the other hand, is associated with protection against both the metabolic syndrome and CRC. The colon is the first organ to respond to a high-fat diet (HFD), and estrogen receptor beta (ERβ) in the intestine appears to prevent CRC. How estrogen impacts the colon under HFD condition has, however, not been investigated. Estrogen can act through three different receptors (ERα, ERβ, GPER1) which all may impact metabolism. In an effort to dissect this, we fed mice a control diet or a high-fat diet (HFD) for 13 weeks and administered receptor-selective estrogenic ligands for the last three weeks. We recorded corresponding physiological impact on fat distribution, fasting glucose, colon crypt proliferation and immune cell infiltration, and the colon transcriptome response. We identify clear sex-differences at the transcriptome level, both at base line and after HFD and ligand treatments. An unexpected observation was the significant sex-differences and impact by HFD and estrogens on circadian clock gene expression, such as Npas2 and Arntl (Bmal1), in the colon. Both sexes also exhibited an increased infiltration of F4/80+ macrophages as a result of HFD. In males, but not females, this was accompanied by changes in colonic epithelial cell proliferation. ERα-selective PPT treatment had significant systemic effects, reducing body weight in both sexes, whereas ERβ-selective DPN treatment did not impact body weight, but reduced infiltration of F4/80+ macrophages in colon of both sexes and attenuated HFD-induced proliferation of male colon crypts. Both ERα and ERβ activation contributed to circadian clock gene regulations. We detail for the first time how HFD and estrogens modulate the colon transcriptome and physiology in a sex and ER-specific manner.
Recording site placement on planar silicon-based probes affects neural signal quality: edge sites enhance acute recording performance

Objective Multisite, silicon-based probes are widely used tools to record the electrical activity of neuronal populations. Several physical features of these devices (e.g. shank thickness, tip geometry) are designed to improve their recording performance. Here, our goal was to investigate whether the position of recording sites on the silicon shank might affect the quality of the recorded neural signal in acute experiments. Approach Neural recordings obtained with five different types of high-density, single-shank, planar silicon probes from anesthetized rats were analyzed. Wideband data were filtered (500 - 5000 Hz) to extract spiking activity, then various quantitative properties (e.g. amplitude distribution of the filtered potential, single unit yield) of the recorded cortical and thalamic activity were compared between sites located at different positions of the silicon shank, focusing particularly on edge and center sites. Main results Edge sites outperformed center sites: mean values of the examined properties of the spiking activity were in most cases higher for edge sites (~94%, 33/35) and a large fraction of these differences were also statistically significant (~45%, 15/33) with effect sizes ranging from small to large. Although the single unit yield was similar between site positions, the difference in signal quality was remarkable in the range corresponding to high-amplitude spikes. Furthermore, the advantage of edge sites slightly decreased for probes having a narrower shank. Significance The better signal quality on edge sites might be the result of the reduced shielding effect of the silicon shank providing a larger field of view for edge sites to detect spikes, or the less tissue damage caused near the edges of the shank. Our results might aid the design of novel neural implants in enhancing their recording performance by identifying more efficient recording site placements.
Behaviour of tsetse flies (Glossina) in host odour plumes in the field

ABSTRACT. In Zimbabwe, studies were made of the responses of Glossina pallidipes Austen and G.morsitans morsitans Westwood to artificial host odour using an incomplete ring of electrocuting nets. In a plume of synthetic host odour tsetse flew generally upwind, with 50–60% flying within 35o of due upwind. More than 80% of tsetse flew at < 50 cm above ground level. Upon losing contact with odour they executed a reverse turn within about 2 m, and upon regaining contact they turned upwind. There were no clear differences in the responses of G.m. morsitans and G.pallidipes. Using electrocuting nets lying horizontally on the ground it was found that tsetse landed in the vicinity of the odour source, the propensity to land being greater for G.pallidipes than for G.m, morsitans, greater for immature than mature flies, and greater for males than females.
Internal timing-related dopaminergic dynamics can be explained by reward-prediction errors

Dopaminergic neurons (DANs) exhibit complex dynamics across a variety of behavioral contexts, often in ways that seem task-specific and even incompatible with results across different paradigms. Dopaminergic signaling during timing tasks has been a prime example. In behavioral timing, dopaminergic dynamics predict the initiation of self-timed movement via a seconds-long ramp up of activity prior to movement onset, similar to ramping seen in visuospatial reward approach and multi-step, goal-directed behaviors. By contrast, in perceptual timing, DANs exhibit more complex dynamics whose direction of modulation seems to be the opposite of that observed in behavioral timing. Mikhael et al. (2022) recently proposed a formal model in which dopaminergic dynamics encode reward expectation in the form of an “ongoing” reward-prediction error (RPE) that arises from resolving uncertainty of one’s position in the value landscape (i.e., one’s spatial-temporal distance to reward delivery/omission). Here, we show that application of this framework recapitulates and reconciles the seemingly contradictory dopaminergic dynamics observed in behavioral vs perceptual timing. These results suggest a common neural mechanism that broadly underlies timing behavior: trial-by-trial variation in the rate of the internal “pacemaker,” manifested in DAN signals that reflect stretching or compression of the derivative of the subjective value function relative to veridical time. In this view, faster pacemaking is associated with relatively high amplitude dopaminergic signaling, whereas slower pacemaking is associated with relatively low levels of dopaminergic signaling, consistent with findings from pharmacological and lesion studies.
Varenicline rescues nicotine-induced decrease in motivation for sucrose reinforcement

Varenicline is one of the top medications used for smoking cessation and is often prescribed before termination of nicotine use. The effect of this combined nicotine and varenicline use on the reward system and motivation for primary reinforcement is underexplored. The goal of this study was to assess the effects of nicotine and varenicline on the consumption of sucrose. In Experiment 1, we first assessed the responding for sucrose after pretreatment with nicotine (0, 0.1, or 0.4 mg/kg) and varenicline (0.0, 0.1, 1.0 mg/kg) using a behavioral economics approach. The responding for sucrose was then assessed using a progressive ratio schedule of reinforcement after pretreatment with all possible combinations of nicotine and varenicline doses. In Experiment 2, rats were assessed for the consumption of sucrose in home cages after pretreatment with nicotine and varenicline. We found that a) nicotine decreased economic demand for sucrose, b) varenicline rescued nicotine-induced reduction in economic demand for sucrose, and c) history of varenicline treatment predicted responding for sucrose on a progressive ratio schedule of reinforcement where rats with a history of varenicline treatment responded significantly lower for sucrose across nicotine doses than rats that have not being exposed to varenicline. The results of Experiment 2 largely confirmed that nicotine decreases motivation for sucrose using a passive consumption protocol and that varenicline rescues this effect. Overall, these findings suggest that varenicline interacts with the effects of nicotine by restoring nicotine-induced reduction in motivation for appetitive rewards.
Functional and Structural Moment Arm Validation for Musculoskeletal Models: A Study of the Human Forearm and Hand

The development of realistic musculoskeletal models is a fundamental goal for the theoretical progress in sensorimotor control and its engineering applications, e.g., in the biomimetic control of artificial limbs. Yet, accurate models require extensive experimental measures to validate structural and functional parameters describing muscle state over the full physiological range of motion. However, available experimental measurements of, for example, muscle moment arms are sparse and often disparate. Validation of these models is not trivial because of the highly complex anatomy and behavior of human limbs. In this study, we developed a method to validate and scale kinematic muscle parameters using posture-dependent moment arm profiles, isometric force measurements, and a computational detection of assembly errors. We used a previously published model with 18 degrees of freedom (DOFs) and 32 musculotendon actuators with force generated from a Hill-type muscle model. The muscle path from origin to insertion with wrapping geometry was used to model the muscle lengths and moment arms. We simulated moment arm profiles across the full physiological range of motion and compared them to an assembled dataset of published and merged experimental profiles. The muscle paths were adjusted using custom metrics based on root-mean-square and correlation coefficient of the difference between simulated and experimental values. Since the available measurements were sparse and the examination of high-dimensional muscles is challenging, we developed analyses to identify common failures, i.e., moment arm functional flipping due to the sign reversal in simulated moments and the imbalance of force generation between antagonistic groups in postural extremes. The validated model was used to evaluate the expected errors in torque generation with the assumption of constant instead of the posture-dependent moment arms at the wrist flexion-extension DOF, which is the critical joint in our model with the largest number of crossing muscles. We found that there was a reduction of joint torques by about 35% in the extreme quartiles of the wrist DOF. The use of realistic musculoskeletal models is essential for the reconstruction of hand dynamics. These models may improve the understanding of muscle actions and help in the design and control of artificial limbs in future applications. New & Noteworthy Realistic models of human limbs are a development goal required for the understanding of motor control and its applications in biomedical fields. However, developing accurate models is restrained by the lack of accurate and reliable musculoskeletal measurements in humans. Here, we have overcome this challenge by using multi-stage validation of simulated structures using both experimental data and the identification of structural failures in the high-dimensional muscle paths. We demonstrate that the rigorous structural and functional validation method is essential for the understanding of force generation at the wrist.
Dopamine Release Neuroenergetics in Mouse Striatal Slices

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Dopamine (DA) neurons in the substantia nigra par compacta with axonal projections to the dorsal striatum (dSTR) degenerate in PD while in contrast, DA neurons in the ventral tegmental area with axonal projections to the ventral striatum including the nucleus accumbens (NAcc) shell, are largely spared. To understand the pathogenesis of PD, it is important to study the neuroenergetics of DA neurons. This study aims to uncover the relative contribution of glycolysis and oxidative phosphorylation (OxPhos) to evoked DA release in the striatum. We measured evoked DA release in mouse striatal brain slices by fast-scan cyclic voltammetry every 2 minutes. Blocking OxPhos caused a greater reduction in evoked DA release in the dSTR compared to the NAcc shell, and blocking glycolysis caused a greater reduction in evoked DA release in the NAcc shell than in the dSTR. Furthermore, when glycolysis was bypassed in favor of direct OxPhos, evoked DA release in the NAcc shell was decreased by ∼50% over 40 minutes whereas evoked DA release in the dSTR was largely unaffected. These results demonstrated that the dSTR relies primarily on OxPhos for energy production to maintain evoked DA release whereas the NAcc shell relies more on glycolysis. Using two-photon imaging, we consistently found that the oxidation level of the DA terminals was higher in the dSTR than in the NAcc shell. Together, these findings partially explain the specific vulnerability of DA terminals in the dSTR to degeneration in PD. Significant statement The neuroenergetics of dopaminergic neuron is important to understand Parkinson’s disease (PD), a neurodegenerative disorder associated with mitochondrial dysfunctions. However, the relative contributions of glycolysis and oxidative phosphorylation (OxPhos) to presynaptic energy demands in DA terminals are unclear. We addressed this question by measuring DA release in the dorsal striatum and nucleus accumbens (NAcc) shell of mouse brain using FSCV under reagents blocking different energy systems. We found that the NAcc shell relies on both glycolysis and OxPhos to maintain DA release while the dSTR relies heavily on OxPhos. We demonstrate the different neuroenergetics of DA terminals in these two brain areas, providing new fundamentally important insight into the specific vulnerability of DA terminals in the dSTR to degeneration in PD.
Direct and indirect regulation of Pom1 cell size pathway by the protein phosphatase 2C Ptc1

The fission yeast cells Schizosaccharomyces pombe divide at constant cell size regulated by environmental stimuli. An important pathway of cell size control involves the membrane-associated DYRK-family kinase Pom1, which forms decreasing concentration gradients from cell poles and inhibits mitotic inducers at mid-cell. Here, we identify the phosphatase 2C Ptc1 as negative regulator of Pom1. Ptc1 localizes to cell poles in a manner dependent on polarity and cell-wall integrity factors. We show that Ptc1 directly binds Pom1 and can dephosphorylate it in vitro but modulates Pom1 localization indirectly upon growth in low glucose conditions by influencing microtubule stability. Thus, Ptc1 phosphatase plays both direct and indirect roles in the Pom1 cell size control pathway.
Identifying rare, medically-relevant genetic variation in a diverse population: opportunities and pitfalls

Purpose To evaluate the effectiveness and specificity of population-based genomic screening in Alabama. Methods The Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5,369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory before return of results. Results Among 131 variants identified by the GSA that were evaluated by Sanger sequencing, 67 (51%) were false positives (FP). For 39 of the 67 FP variants, a benign/likely benign variant was present at or near the targeted P/LP variant. Importantly, African-Americans were significantly enriched for FP variants, likely due to a higher rate of non-targeted alternative alleles close to array-targeted P/LP variants. Conclusion In AGHI, we have implemented an array-based process to screen for highly penetrant genetic variants in actionable disease genes. We demonstrate the need for clinical validation of array-identified variants in direct-to-consumer or population testing, especially for diverse populations.
COEXISTENCE OF WHITE-FOOTED MICE (PEROMYSCUS LEUCOPUS) AND GOLDEN MICE (OCHROTOMYS NUTTALLI) IN A SOUTHEASTERN FOREST

Abstract Many studies have examined coexistence among similar small mammal species. Most investigations have tended to focus on interactions such as predation and competition, with less emphasis on use of habitat space, plant cover stratification, and food resource partitioning. We investigated 2 similar small mammal species, the white-footed mouse (Peromyscus leucopus) and the golden mouse (Ochrotomys nuttalli) to determine how differences in 3-dimensional habitat use, vegetative cover, and food resources allow for similar species to coexist. P. leucopus was removed from 4 of 8 experimental grids within a forested riparian peninsula to assess the effect of competitive removal on population dynamics of O. nuttalli. After removal of P. leucopus, the relative abundance of O. nuttalli in removal grids did not change significantly from abundance in control grids. However, differences in use of 3-dimensional habitat appeared to provide enough niche segregation to allow these 2 species to coexist in the same habitat. Abundant resources (acorn mast crop of Quercus nigra and heavy vegetative cover of Ligustrum sinense) also appeared to dampen competition between these 2 species.