Miracle-dz/UniFAR-FTUs huggingface dataset:
Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly

Type I lissencephaly is a neuronal migration disorder caused by haploinsuffiency of the LIS1 gene and is characterized in humans by agyria, mislamination of brain structures, developmental delays, and epilepsy. Here, we investigate the impact of LIS1 mutation on the cellular migration, morphophysiology, microcircuitry and genomics of mouse hippocampal CA1 parvalbumin-containing inhibitory interneurons (PV+INTs). We find that WT PV+INTs consist of two physiological subtypes (80% fast-spiking (FS), 20% non-fast-spiking (NFS)) and four morphological subtypes (basket, axo-axonic, bistratified, radiatum-targeting). We also discover that cell-autonomous mutations within interneurons disrupts morphological development of PV+INTs and results in the emergence of a non-canonical “intermediate spiking (IS)” subset of PV+INTs. In the GlobalLis mutant, IS/NFS cells become the dominant PV+INT subtypes (56%) and the percentage of FS cells shrinks to 44%. We also find that IS/NFS cells are prone to entering depolarizing block, causing them to temporarily lose the ability to initiate action potentials and control network excitation, potentially promoting seizures. Finally, single-cell nuclear RNAsequencing of PV+INTs revealed several misregulated genes related to morphogenesis, cellular excitability, and synapse formation.
H-MAGMA, inheriting a shaky statistical foundation, yields excess false positives

The ‘snp-wise mean model’ of Multi-marker Analysis of GenoMic Annotation is often used to perform gene-level testing for association with disease and other phenotypes. This methodology, in turn, forms the foundation for H-MAGMA. Unfortunately, that foundation is unsound, with implications for H-MAGMA results published in Nature Neuroscience regarding genes associated with psychiatric disorders: e.g., only 125 of H-MAGMA’s 275 reported discoveries for autism replicate when the foundation’s flaws are corrected.
Multiplex LAMP for Simplified Monitoring Cryptosporidium and Giardia in Surface Water

A detailed investigation was conducted into the application of an isothermal nucleic acid amplification procedure, LAMP, in conjunction with components of conventional procedure to determine ability to simplify water processing for monitoring Cryptosporidium and Giardia in surface water samples. Based on previous work demonstrating a high degree of sensitivity and selectivity of the LAMP procedure for detecting target organism DNA at low concentration in environmental media without significant interferences, this project sought to determine if LAMP primers for both organisms could be combined and applied to detect the target organisms collected from surface water samples after only minimal processing. Implementation consisted of optimizing previously described LAMPs for the SAM-1 gene of Cryptosporidium and for the EF1-α gene of Giardia; establishing their limits of detection on both specific DNA and on small numbers of oocysts and cysts processed by freeze-thaw cycles. Based on positive results from preliminary testing, a multiplexed LAMP for both organisms was applied. The multiplex lamp was able to detect the DNA of Cryptosporidium and of Giardia from samples seeded with replicates of 1, 2, 3 and 4 oocysts and cysts, both in clean water and in surface water processed by filtration and centrifuging to pellet followed only by freeze-thaw cycles. Positive and specific amplification was observed with potential for quantification using 25 µL reactions including 8 µL template, in RT qLAMP format by LightCycler. The procedure is significantly simpler and less time consuming presenting realistically practical procedure for improvement of surface water monitoring of Cryptosporidium and Giardia, compared to the widely used USEPA Method 1623 Importance Pathogen identification by LAMP is well established as a sensitive and highly selective procedure, insensitive to interferences, permitting specific detection of target DNA in samples containing extraneous DNA. This combination of features was shown effective for identifying numbers of Cryptosporidium oocysts and Giardia cysts as few as 1 in unseparated particle assemblages subject only to freeze thaw cycles. Although LAMP has not been widely adopted for environmental monitoring, it has been previously demonstrated for Cryptosporidium and for Giardia in water and wastewater. Also, many clinical assays have demonstrated applicability to use where facilities and skills are limited. The simplified analysis sequence offers significant time and cost saving for routine monitoring of Cryptosporidium and Giardia in surface water samples.
Circuit reorganization in the Drosophila mushroom body calyx accompanies memory consolidation

The capacity of utilizing past experience to guide future action is a fundamental and conserved function of the nervous system. Associative memory formation initiated by the coincident detection of a conditioned stimulus (CS, e.g. odour) and an unconditioned stimulus (US, e.g. sugar reward) can lead to a short-lived memory trace (STM) within distinct circuits [1-5]. Memories can be consolidated into long-term memories (LTM) through processes that are not fully understood, but depend on de-novo protein synthesis [6, 7], require structural modifications within the involved neuronal circuits and might lead to the recruitment of additional ones [8-17]. Compared to modulation of existing connections, the reorganization of circuits affords the unique possibility of sampling for potential new partners [18-20]. Nonetheless, only few examples of rewiring associated with learning have been established thus far [14, 21-24]. Here, we report that memory consolidation is associated with the structural and functional reorganization of an identified circuit in the adult fly brain. The formation and retrieval of olfactory associative memories in Drosophila requires the mushroom body (MB) [25]. We identified the individual synapses of olfactory projection neurons (PNs) that deliver a conditioned odour to the MB and reconstructed the complexity of the microcircuit they form. Combining behavioural experiments with high-resolution microscopy and functional imaging, we demonstrated that the consolidation of appetitive olfactory memories closely correlates with an increase in the number of synaptic complexes formed by the PNs that deliver the conditioned stimulus and their postsynaptic partners. These structural changes result in additional functional synaptic connections.
Sodium leak channel as a therapeutic target for neuronal sensitization in neuropathic pain

Neuropathic pain affects up to 10% of the total population and no specific target is ideal for therapeutic need. The sodium leak channel (NALCN), a voltage-independent cation channel, mediates the background Na+ leak conductance and controls neuronal excitability and rhythmic behaviors. Here, we show that increases of NALCN expression and function in dorsal root ganglion (DRG) and dorsal spinal cord contribute to chronic constriction injury (CCI)-induced neuropathic pain in rodents. NALCN current and neuronal excitability in acutely isolated DRG neurons and spinal cord slices of rats were increased after CCI which were decreased to normal levels by NALCN-siRNA. Accordingly, pain-related symptoms were significantly alleviated by NALCN-siRNA-mediated NALCN knockdown and completely reversed by NALCN-shRNA-mediated NALCN knockdown in rats or by conditional NALCN knockout in mice. Our results indicate that increases in NALCN expression and function contribute to CCI-induced neuronal sensitization; therefore, NALCN may be a novel therapeutic target for neuropathic pain.
Coherence Shifts in Attribute Evaluations

In two experiments, people repeatedly judged individual options with respect to both overall value and attribute values. When required to choose between two snacks, each differing in two attributes (pleasure and nutrition), people’s assessments of value shifted from pre- to post-choice in the direction that spread the alternatives further apart so as to favor the winner, thereby increasing confidence in the choice. This shift was observed not only for ratings of overall value, but also for each of the two individual attributes. The magnitude of the coherence shift increased with choice difficulty as measured by the difference in initial ratings of overall value for the two options, as well as with a measure of attribute disparity (the degree to which individual attributes “disagree” with one another as to which option is superior). In Experiment 2, a task requiring comparison of value similarity generated the same qualitative pattern of value and confidence changes, even though the similarity judgments entirely preceded the actual choice task. These findings support the hypothesis that active comparison of values is the core component of the decision process during which perceived values are shifted so as to more sharply distinguish the items being compared.
TMS bursts can modulate local and networks oscillations during lower-limb movement

Introduction Lower-limb motor functions involve processing information via both motor and cognitive control networks. Measuring oscillations is a key element in communication within and between cortical networks during high order motor functions. Increased midfrontal theta oscillations are related to improved lower-limb motor performances in patients with movement disorders. Non-invasive neuromodulation approaches have not been explored extensively to understand the oscillatory mechanism of lower-limb motor functions. This study aims to examine the effects of repetitive transcranial magnetic stimulation (rTMS) on local and network EEG oscillations in healthy elderly subjects. Methods Eleven healthy elder subjects (67-73 years) were recruited via advertisements, and underwent both active and sham stimulation procedures in a random, counterbalanced design. TMS bursts (θ-TMS; 4 pulses/sec) were applied over the midfrontal lead (vertex) before a GO-Cue pedaling task, and signals were analyzed using time-frequency methods. Results TMS bursts increase the theta activity in the local (p=0.02), as well as the associated network during the lower-limb pedaling task (p = 0.02). Furthermore, after task-related TMS burst sessions, increased resting-state alpha activity was observed in the midfrontal region (p= 0.01). Conclusion Our study suggests the ability of midfrontal TMS bursts to directly modulate local and network oscillations in a frequency manner during lower-limb motor task. TMS burst-induced modulation may provide insights into the functional roles of oscillatory activity during lower-limb movement in normal and disease conditions.
Thalamic encoding of complex sensory patterns and its possible role in cognition

The function of the higher-order sensory thalamus remains unresolved. Here, POm nucleus was examined by in vivo extracellular recordings across a range of complex sensory patterns. We found that POm was highly sensitive to multiwhisker stimuli involving complex spatiotemporal interactions. The dynamical spatiotemporal structure of sensory patterns and the different complexity of their parts were accurately reflected in precise POm activity changes. Importantly, POm was also able to respond to ipsilateral stimulation and was implicated in the representation of bilateral tactile events by integrating simultaneous signals arising from both whisker pads. We found that POm nuclei are mutually connected through the cortex forming a functional POm-POm loop. We unravelled the nature and content of the messages travelling through this loop showing that they were ‘structured patterns of sustained activity’. These structured messages were transmitted preserving their integrated structure. The implication of different cortical areas was investigated revealing that S1 plays a protagonist role in this functional loop. Our results also demonstrated different laminar implication in the processing of sustained activity in this cortical area and its transmission between hemispheres. We propose a theoretical model in which these ‘structured patterns of sustained activity’ generated by POm may play important roles in perceptual, motor and cognitive functions. From a functional perspective, this proposal, supported by the results described here, provides a novel theoretical framework to understand the implication of the thalamus in cognition. In addition, a profound difference was found between VPM and POm functioning. The hypothesis of Complementary Components is proposed here to explain it. Highlights POm is implicated in the representation of complex sensory patterns. POm is implicated in the encoding of bilateral tactile events. POm nuclei are mutually connected through the cortex forming a functional POm-POm loop. ‘Structured patterns of sustained activity’ travelling through the loop
Perspectives on the design and performance of upper-limb wearable stimulation devices for stroke survivors with hemiplegia and spasticity

Background Vibrotactile stimulation may improve limb function after stroke; however, current studies are limited by the stationary and clinic-based apparatus used to apply this stimulation. A wearable device could provide vibrotactile stimulation in a mobile form factor, enabling further study of this technique. Objective The aim of this work is twofold: (1) Design and validate a wearable device for stroke survivors that provides vibrotactile stimulation to the upper limb, and (2) Understand features that influence stroke survivors’ interaction with an upper-limb wearable device. Methods A vibrotactile glove was designed to apply stimulation to the stroke-affected hand. This device, the vibrotactile stimulation (VTS) Glove, features small electronics, provides hours of stimulation, and has the appearance of a fingerless fitness glove. We performed two studies. In Study 1, sixteen stroke survivors were given the glove and asked to wear it for three hours daily for eight weeks. Usage time, indicating adherence, was calculated by onboard sensors. The device was evaluated using a log of damages and feedback from participants. Self-reported behaviors during glove use were also collected. In Study 2, eight stroke survivors evaluated new device prototypes in a three-round iterative design study. Interviews were used to collect participant feedback as they donned and doffed the prototypes. Task completion time and correctness were measured. Thematic content analysis was used to define actionable design revisions between each round of evaluation and identify key perspectives on design principles. Results The VTS Glove is lightweight, wireless, and durable. Based on Study 1, adherence appears feasible. Each participant recorded over 140 hours wearing the VTS Glove. Participants reported wearing the glove during activities such as church, social events, dining out, and using the computer. However, 69% of participants struggled to extend or insert their fingers to don the device. Our analysis in Study 2 identified six other relevant perspectives from survivors regarding the wearable devices: hand supination is difficult, grip varies without awareness, devices may lead to sweat, separate finger attachments require dexterity, social comfort is perceived as unimportant, and the affected hand is infrequently used. New device designs with revised features (VTS Phalanx, VTS Armband, and VTS Palm) could be donned in an average time of 48 seconds (vs. 5.05 minutes to don the VTS Glove).
Activity of the GHRH Antagonist MIA602 and its Underlying Mechanisms of Action in sarcoidosis

Growth hormone releasing hormone (GHRH) is a potent stimulator of GH secretion from the pituitary gland. Although GHRH is essential for the growth of immune cells, the regulatory effects of its antagonist in granulomatous disease remains unknown. Here, we report expression of GHRH receptor (R) in human tissue with sarcoidosis granuloma and demonstrate the anti-inflammatory effects of MIA602 (a GHRH antagonist) in two in vitro human granuloma models and an in vivo granuloma model. MIA602 decreases levels of IL2, IL12, and IL17A in in vitro granuloma model. We show further that the anti-inflammatory effect of MIA602 appears to be mediated by reduction in CD45++CD68+ cells in granulomatous tissue and upregulation in PD-1 expression in macrophages. In analysis of expression of proteins involved in the mitochondrial stage of apoptosis, we show that MIA602 increases the levels of caspase 3, BCL-xL/BAK dimer, and MCl-1/Bak dimer in granuloma. These findings indicate that MIA602 may not induce apoptosis. The clinical relevance of our findings further suggest that HGRH-R is potentially a target for treatment of granulomatous disease and MIA602 possibly a novel therapeutic agent for sarcoidosis.
Characterization of brain‐derived extracellular vesicle lipids in Alzheimer's disease

Lipid dyshomeostasis is associated with the most common form of dementia, Alzheimer’s disease (AD). Substantial progress has been made in identifying positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers for AD, but they have limited use as front-line, non-invasive diagnostic tools. Small extracellular vesicles (EVs) are released by all cell types and contain an enriched subset of their parental cell molecular composition, including lipids. EVs are released from the brain into the periphery, providing a potential source of tissue and disease specific lipid biomarkers. However, the EV lipidome of the central nervous system (CNS) is currently unknown and the potential of brain-derived EVs (BDEVs) to inform on lipid dyshomeostasis in AD remains unclear. The aim of this study was to reveal the lipid composition of BDEVs in human frontal cortex tissue, and to determine whether BDEVs in AD have altered lipid profiles compared to age-matched neurological controls (NC). Here, using semi-quantitative mass spectrometry, we describe the BDEV lipidome, covering 4 lipid categories, 17 lipid classes and 692 lipid molecules. Frontal cortex-derived BDEVs were enriched in glycerophosphoserine (PS) lipids, a characteristic of small EVs. Here we report that BDEVs are enriched in ether-containing PS lipids. A novel finding that further establishes ether lipids as a feature of EVs. While no significant changes were detected in the frontal cortex in AD, the lipid profile of the BDEVs from this tissue exhibited disease related differences. AD BDEVs had altered glycerophospholipid (GP) and sphingolipid (SP) levels, specifically increased plasmalogen glycerophosphoethanolamine (PE-P) and decreased polyunsaturated fatty acyl containing lipids (PUFAs), and altered amide-linked acyl chain content in sphingomyelin (SM) and ceramide (Cer) lipids relative to vesicles from neurological control subjects. The most prominent alteration being a two-fold decrease in lipid species containing docosahexaenoic acid (DHA). The in-depth lipidome analysis provided in this study highlights the advantage of EVs over more complex tissues for improved detection of dysregulated lipids that may serve as potential biomarkers in the periphery.
Interaction between neuronal encoding and population dynamics during categorization task switching in parietal cortex

Primates excel at categorization, a cognitive process for assigning stimuli into behaviorally relevant groups. Categories are encoded in multiple brain areas and tasks, yet it remains unclear how neural encoding and dynamics support cognitive tasks with different demands. We recorded from parietal cortex during flexible switching between categorization tasks with distinct cognitive and motor demands, and also studied recurrent neural networks (RNNs) trained on the same tasks. In the one-interval categorization task (OIC), monkeys rapidly reported their decisions with a saccade. In the delayed match-to-category (DMC) task, monkeys decided whether sequentially presented stimuli were categorical matches. Neuronal category encoding generalized across tasks, but categorical encoding was more binary-like in the DMC task and more graded in the OIC task. Furthermore, analysis of the trained RNNs supports the hypothesis that binary-like encoding in the DMC task arises through compression of graded feature encoding by population attractor dynamics underlying short-term working memory.
Impact of Grazing Processes on the Structure and Persistence of Thin Biological Layers

Abstract : My long term goal is to understand the functional roles of microzooplankton (20-200 microns) in the sea. It has been argued that on a timescale of days, the instantaneous grazing rate of zooplankton in toto is greater than the instantaneous rates of vertical and horizontal mixing by at least an order of magnitude, and is the same order of magnitude as the instantaneous rate of phytoplankton cell division. Hence, grazing is a critically important loss term in phytoplankton dynamics (Banse, 1992). Because microzooplankton are the major grazers of phytoplankton in pelagic food webs under most circumstances, their grazing impacts exert an important impact on phytoplankton losses in the sea. My specific interests are in the vital rate processes of feeding and reproduction (e.g., Gifford 1988; Gifford, et al. 1995) and in understanding their function as prey for higher organisms (e.g., Gifford and Dagg, 1988; 1989; Gifford 1993).
Global patterns of tree species richness in moist forests : energy-diversity theory does not account for variation in species richness.

Energy-diversity theory has gained currency as an explanation for global patterns of species richness. We examine the suggestion of Currie and Paquin (1987; Nature 329: 326-327) that variation in evapotranspiration - a function of moisture availability and temperature that is directly related to plant production - predicts tree species richness in global comparisons. We present contrary evidence: the number of tree species on 26 large (17-7401 kmz) areas of moist temperate forest show continental differences unrelated to geographical patterns in evapotranspiration. Tree species richness of 128 samples of ca 1ha within moist-forest biomes of the world reveal patterns of variation amone continents. and with latitude. that likewise cannot be attributed to eeoeraohi