bluuebunny/crossref_metadata_2025 huggingface dataset:
Model mimicry limits conclusions about neural tuning and can mistakenly imply unlikely priors
Authors: Wolff Michael J. , Rademaker Rosanne L.
Published: February 2024

In a recent issue of Nature Communications, Harrison, Bays, and Rideaux1use electroencephalography (EEG) to infer population tuning properties from human visual cortex, and deliver a major update to existing knowledge about the most elemental building block of visual perception – orientation tuning. Using EEG together with simulations in an approach they refer to as “generative forward modeling”, the authors adjudicate between two competing population tuning schemes for orientation tuning in visual cortex. They claim that a redistribution of orientation tuning curves can explain their observed pattern of EEG results, and that this tuning scheme embeds a prior of natural image statistics that exhibits a previously undiscovered anisotropy between vertical and horizontal orientations. If correct, this approach could become widely used to find unique neural coding solutions to population response data (e.g., from EEG) and to yield a “true” population tuning scheme deemed generalizable to other instances. However, here we identify major flaws that invalidate the promise of this approach, which we argue should not be used at all. First, we will examine the premise of Harrison and colleagues1, to subsequently explain why “generative forward modeling” cannot circumvent model mimicry pitfalls and can deliver many possible solutions of unknowable correctness. Finally, we show a tentative alternative explanation for the data.

Conflict of interest

The authors declare no conflict of interest
Cardiovascular and Locomotor Effects of Binary Mixtures of Common “Bath Salts” Constituents: Studies with Methylone, MDPV, and Caffeine in Rats
Authors: Seaman Robert W. , Galindo David G. , Stinson Benjamin T. , Sulima Agnieszka , Rice Kenner C. , Javors Martin A. , Ginsburg Brett C. , Collins Gregory T.
Published: February 2024

Background and Purpose

The use of “Bath Salts” drug preparations has been associated with high rates of toxicity and death. Preparations often contain mixtures of drugs including multiple synthetic cathinones or synthetic cathinones and caffeine; however, little is known about whether interactions among “Bath Salts” constituents contribute to the adverse effects often reported in users.

Experimental Approach

This study used adult male Sprague-Dawley rats to characterize the cardiovascular effects, locomotor effects, and pharmacokinetics of methylone, MDPV, and caffeine, administered alone and as binary mixtures. Dose-addition analyses were used to determine the effect levels predicted for a strictly additive interaction for each dose pair.

Key Results

Methylone, MDPV, and caffeine increased heart rate and locomotion, with methylone producing the largest increase in heart rate, MDPV producing the largest increase in locomotor activity, and caffeine being the least effective in stimulating heart rate and locomotor activity. MDPV and caffeine increased mean arterial pressure, with caffeine being more effective than MDPV. The nature of the interactions between methylone and MDPV tended toward sub-additivity for all endpoints, whereas interactions between MDPV or methylone and caffeine tended to be additive or sub-additive for cardiovascular endpoints, and additive or supra-additive for increases in locomotion. No pharmacokinetic interactions were observed between individual constituents, but methylone displayed non-linear pharmacokinetics at the largest dose evaluated.

Conclusion and Implications

These findings demonstrate that the composition of “Bath Salts” preparations can impact both cardiovascular and locomotor effects and suggest that such interactions among constituent drugs could contribute to the “Bath Salts” toxidrome reported by human users.

What is already known

“Bath Salts” preparations are associated with a sympathomimetic toxidrome in human users.

What this study adds

Characterization of both pharmacokinetic and pharmacodynamic interactions between common “Bath Salts” constituents with regard to cardiovascular and locomotor effects.

Clinical Significance

The vast majority of drug overdose deaths involve more than one substance. Though these studies focused on combinations of stimulant drugs, they provide direct evidence that the toxidrome resulting from multi-drug overdoses can be significantly different than would be expected for a single drug.
The T-cell niche tunes immune function through modulation of the cytoskeleton and TCR-antigen forces
Authors: Kellner Anna V. , Hunter Rae , Do Priscilla , Eggert Joel , Jaffe Maya , Geitgey Delaney K. , Lee Miyoung , Hamilton Jamie A. G. , Ross Anthony J. , Ank Raira S. , Bender Rachel L. , Ma Rong , Porter Christopher C. , Dreaden Erik C. , Au-Yeung Byron B. , Haynes Karmella A. , Henry Curtis J. , Salaita Khalid
Published: February 2024

Obesity is a major public health crisis given its rampant growth and association with an increased risk for cancer. Interestingly, patients with obesity tend to have an increased tumor burden and decreased T-cell function. It remains unclear how obesity compromises T-cell mediated immunity. To address this question, we modeled the adipocyte niche using the secretome released from adipocytes as well as the niche of stromal cells and investigated how these factors modulated T-cell function. We found that the secretomes altered antigen-specific T-cell receptor (TCR) triggering and activation. RNA-sequencing analysis identified thousands of gene targets modulated by the secretome including those associated with cytoskeletal regulation and actin polymerization. We next used molecular force probes to show that T-cells exposed to the adipocyte niche display dampened force transmission to the TCR-antigen complex and conversely, stromal cell secreted factors lead to significantly enhanced TCR forces. These results were then validated in diet-induced obese mice. Importantly, secretome-mediated TCR force modulation mirrored the changes in T-cell functional responses in human T-cells using the FDA-approved immunotherapy, blinatumomab. Thus, this work shows that the adipocyte niche contributes to T-cell dysfunction through cytoskeletal modulation and reduces TCR triggering by dampening TCR forces consistent with the mechanosensor model of T-cell activation.
Selective degradation of multimeric proteins via chemically induced proximity to TRIM21
Authors: Lu Panrui , Cheng Yalong , Xue Lei , Ren Xintong , Chen Chenglong , Li Jiao , Wu Qingcui , Sun Shan , Hou Junjie , Jia Wei , Li Chao , Qi Xiangbing , Huang Niu , Han Ting
Published: February 2024

Targeted protein degradation (TPD) has emerged as an effective strategy to eliminate disease-causing proteins by inducing their interactions with the protein degradation machinery. First-generation TPD agents exploit a limited set of broadly expressed E3 ubiquitin ligases with constitutive activity, forbidding their application to proteins requiring higher levels of targeting selectivity. Here, by phenotype-based screening, we discovered that the antipsychotic drug acepromazine possesses interferon-enhanced cytotoxicity towards cancer cell lines expressing high levels of aldo-keto reductases 1C. These enzymes convert acepromazine into its stereo-selective metabolite (S)-hydroxyl-acepromazine, which recruits the interferon-induced E3 ubiquitin ligase TRIM21 to the vicinity of the nuclear pore complex, resulting in the degradation of nuclear pore proteins. Co-crystal structures of acepromazine and derivatives in complex with the PRYSPRY domain of TRIM21 revealed a ligandable pocket, which was exploited for designing heterobifunctional degraders. The resulting chemicals selectively degrade multimeric proteins— such as those in biomolecular condensates—without affecting monomeric proteins, consistent with the requirement of substrate-induced clustering for TRIM21 activation. As aberrant protein assemblies have been causally linked to diseases such as neurodegeneration, autoimmunity, and cancer, our findings highlight the potential of TRIM21-based multimer-selective degraders as a strategy to tackle the direct causes of these diseases.
Older individuals do not show task specific variations in EEG band power and finger force coordination
Authors: Eswari Balasubramanian , Balasubramanian Sivakumar , SKM Varadhan
Published: February 2024

Background

Controlling and coordinating finger force is crucial for performing everyday tasks and maintaining functional independence. Aging naturally weakens neural, muscular, and musculoskeletal systems, leading to compromised hand motor function. This decline reduces cortical activity, finger force control and coordination in older adults.

Objective

To examine the relationship between EEG band power and finger force coordination in older individuals and compare the results with young adults.

Methods

Twenty healthy young adults aged 20–30 (26.96±2.68) and fourteen older adults aged 58–72 (62.57±3.58) participated in this study. Participants held the instrumented handle gently for five seconds then lifted and held it for an additional five seconds in the two conditions: fixed (thumb platform secured) and free condition (thumb platform may slide on slider).

Results

In the older individuals there was no difference observed in the finger force synergy indices, and EEG beta band power between the two task conditions. However, in the young group synergy indices and EEG beta band power were less in free condition compared to fixed condition. Additionally, in the fixed condition, older adults showed a reduced synergy indices and reduced EEG beta band power than the young adults.

Conclusion

Older participants showed consistent synergy indices and beta band power across conditions, unlike young adults who adjusted strategies based on tasks. Young adults exhibited task-dependent finger force synergy indices contrasting with older individuals. These results suggest that the EEG beta band power may serve as a marker for finger force coordination rather than indicating the magnitude of force.
Negative relationship between inter-regional interaction and regional power: a resting fMRI study
Authors: Lee Tien-Wen , Tramontano Gerald
Published: February 2024

Background

Regional neural response and network property used to be treated separately. However, evidence has suggested an intimate relationship between the regional and inter-regional profiles. This research aimed to investigate the influence of functional connectivity on regional spontaneous activity.

Methods

Thirty-six and sixty datasets of structural magnetic resonance imaging (sMRI) and resting state functional MRI (rsfMRI) were selected from the NKI and CAN-BIND database, respectively. The cerebral cortex in rsfMRI was parcellated by MOSI (modular analysis and similarity measurements), which enables multi-resolution exploration. For each parcellated cluster, the mean amplitude of low-frequency fluctuation (ALFF) and its average functional connectivity strength with the remaining cortical analogs were computed. Correlation analyses were exploited to examine their relationship. Supplementary analysis was applied to CAN-BIND EEG data (1 to 30 Hz).

Results

Negative correlation coefficients between inter-regional interaction and regional power were noticed in both MRI datasets. One-sample t-tests revealed robust statistics across different analytic resolutions yielded by MOSI, with individualPvalues at the level 10^-4 to 10^-5. The results suggested that the more intense crosstalk a neural node is embedded in, the less regional power it manifests, and vice versa. The negative relationship was replicated in EEG analysis but limited to delta (1 to 4 Hz) and theta (4 to 8 Hz) frequencies.

Conclusions

We postulate that inhibitory coupling is the mechanism that bridges the local and inter-regional properties, which is more prominent in the lower spectra. The interpretation warrants particular caution since noise may also contribute to the observation.
Screening of associated bacteria ofAlexandrium catenellaon affecting PSTs production and influence mechanism
Authors: Zou Shanmei , Yu Xinke , Sun Tiantian , Wei Lina , Wu Xuemin
Published: February 2024

Alexandriumcauses serious food safety and human death due to paralytic shellfish toxins (PSTs) production. The associated bacteria can affect PSTs production ofAlexandrium. However, the influencing mechanism is still unclear. Here we firstly screened functional associated bacteria for affecting PSTs production ofAlexandrium catenellain Yangtze Estuary and further studied their influence on physiological process and molecular regulation ofA. catenella. Thirteen bacteria strains for affecting PSTs production ofA. catenellawere selected. TheA. catenellastrains co-cultured with different functional associated bacteria all produced more PSTs than axenic strain with antibiotic treatment. Compared with axenicA. catenella, the non-axenicA. catenellaproduced more algal cells, soluble sugar, soluble protein and neutral lipid. By RNA-seq, it was found that non-axenicA. catenellaproduced more upregulated functional genes than axenicA. catenella. The biosynthesis of cofactors and spliceosome were the dominant different pathways between axenic and non-axenicA. catenellastrains. The sxtA expression was closely related with Arginine and proline metabolism, Arginine biosynthesis, Fatty acid biosynthesis, TCA cycle and Glutathione metabolism, which were all downregulated in axenicA. catenella. Meantime, the non-axenicA. catenellaunder nitrogen deprivation produced less PSTs and functional genes than non-axenic strain under common culture condition, indicating the nitrogen significance for PSTs production. The detailed signal molecular released by associated bacteria for regulating PSTs ofA. catenellaneeds to be further studied.
A systematic analysis of the joint effects of ganglion cells, lagged LGN cells, and intercortical inhibition on spatiotemporal processing and direction selectivity
Authors: Larisch Reńe , Hamker Fred H.
Published: February 2024

Simple cells in the visual cortex process spatial as well as temporal information of the visual stream and enable the perception of motion information. Previous work suggests that the direction selectivity of V1 simple cells is associated with a temporal offset in the thalamocortical input stream through lagged and non-lagged cells of the lateral geniculate nucleus (LGN), but alternatively, it may also result from intercortical inhibition. While there exists a large corpus of models for spatiotemporal receptive fields, the majority of them built-in the spatiotemporal dynamics by utilizing a combination of spatial and temporal functions and thus, do not explain the emergence of spatiotemporal dynamics on basis of network dynamics emerging in the retina and the LGN. In order to better comprehend the emergence of spatiotemporal processing and direction selectivity, we used a spiking neural network to implement the visual pathway from the retina to the primary visual cortex. By varying different functional parts in our network, we demonstrate how the direction selectivity of simple cells emerges through the interplay between two components: tuned intercortical inhibition and a temporal offset in the feedforward path through lagged LGN cells. We observe that direction-selective simple cells are linked to a particular spiking pattern in a local excitatory-inhibitory circuit: If the stimulus moves in the non-preferred direction of a simple cell, inhibitory neurons with a different spatial position or tuning spike earlier, preventing the simple cell to spike. However, in the preferred direction, these inhibitory cells spike later, enabling the simple cell to spike.
Selfish herd effects in aggregated caterpillars and their interaction with warning signals
Authors: Kersh-Mellor Rami , Montgomery Stephen H. , McLellan Callum F.
Published: February 2024

Larval Lepidoptera gain survival advantages by aggregating, especially when combined with aposematic warning signals, yet reductions in predation risk may not be experienced equally across all group members. Hamilton’s selfish herd theory predicts that larvae which surround themselves with their group mates should be at lower risk of predation, and those on the periphery of aggregations experience the greatest risk, yet this has rarely been tested. Here, we expose aggregations of artificial ‘caterpillar’ targets to predation from free-flying, wild birds to test for marginal predation when all prey are equally accessible, and for an interaction between warning colouration and marginal predation. We find that targets nearer the centre of the aggregation survived better than peripheral targets and nearby targets isolated from the group. However, there was no difference in survival between peripheral and isolated targets. We also find that grouped targets survived better than isolated targets when both are aposematic, but not when they are non-signalling. Our data suggest that avian predators preferentially target peripheral larvae from aggregations, and that prey warning signals enhance predator avoidance of groups.
Utilising affordable smartphones and open-source time-lapse photography for monitoring pollinators
Authors: Ștefan Valentin , Workman Aspen , Cobain Jared C. , Rakosy Demetra , Knight Tiffany M.
Published: February 2024

Monitoring plant-pollinator interactions is crucial for understanding factors that influence these relationships across space and time. While traditional methods in pollination ecology are time-consuming and resource-intensive, the growing availability of photographic technology, coupled with advancements in artificial intelligence classification, offers the potential for non-destructive and automated techniques. However, it is important that the photographs are of high enough quality to enable insects to be identified at lower taxonomic levels, preferably genus or species levels. This study assessed the feasibility of using smartphones to automatically capture images of insects visiting flowers and evaluated whether the captured images offered sufficient resolution for precise insect identification. Smartphones were positioned above target flowers from various plant species to capture time-lapse images of any flower visitor in urban green areas around Leipzig and Halle, Germany. We present the proportions of insect identifications achieved at different taxonomic levels, such as order, family, genus, and species, and discuss whether limitations stem from the automated approach (e.g., inability to observe distinguishing features in images despite high image quality) or low image quality. Practical recommendations are provided to address these challenges. Our results indicate that for bee families, nearly three quarters of all cases could be identified to genus level. Flies were more difficult, due to the small size of many individuals and the more challenging features needed for identification (e.g., in the wing veins). Overall, we suggest that smartphones are an effective tool when optimised by researchers. As technology continues to advance, smartphones are becoming increasingly accessible, affordable, and user-friendly, rendering them an appealing option for pollinator monitoring.
Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation
Authors: Iannuzzo Alberto , Delafontaine Selket , Masri Rana El , Tacine Rachida , Prencipe Giusi , Nishitani-Isa Masahiko , van Wijck Rogier T.A. , Bhuyan Farzana , de Jesus Rasheed Adriana A. , Coppola Simona , van Daele Paul L.A. , Insalaco Antonella , Goldbach-Mansky Raphaela , Yasumi Takahiro , Tartaglia Marco , Meyts Isabelle , Delon Jérôme
Published: February 2024

Most autoinflammatory diseases are caused by mutations in innate immunity genes. Recently, four variants in the RHO GTPase CDC42 were discovered in patients affected by syndromes generally characterized by neonatal-onset of cytopenia and auto-inflammation, including hemophagocytic lymphohistiocytosis and rash in the most severe form (NOCARH syndrome). However, the mechanisms responsible for these phenotypes remain largely elusive. Here, we show that the recurrent p.R186C CDC42 variant, which is trapped in the Golgi apparatus, elicits a block in both anterograde and retrograde transports, and endoplasmic reticulum stress. Consequently, it favors STING accumulation in the Golgi in a COPI-dependent manner. This is also observed for the other Golgi-trapped p.*192C*24 CDC42 variant, but not for the p.Y64C and p.C188Y variants that do not accumulate in the Golgi. We demonstrate that the two Golgi-trapped CDC42 variants are the only ones that exhibit overactivation of the STING pathway. Consistent with these results, patients carrying Golgi-trapped CDC42 mutants present very high levels of circulating IFNα at the onset of their disease. Thus, we report new mechanistic insights on the impact of the Golgi-trapped CDC42 variants. This increase in STING activation provides a rationale for combination treatments for these severe cases.
The role of hidden hearing loss in tinnitus: insights from early markers of peripheral hearing damage
Authors: Devolder Pauline , Keppler Hannah , Keshishzadeh Sarineh , Taghon Baziel , Dhooge Ingeborg , Verhulst Sarah
Published: February 2024

Since the presence of tinnitus is not always associated with audiometric hearing loss, it has been hypothesized that hidden hearing loss may act as a potential trigger for increased central gain along the neural pathway leading to tinnitus perception. In recent years, the study of hidden hearing loss has improved with the discovery of cochlear synaptopathy and several objective diagnostic markers. This study investigated three potential markers of peripheral hidden hearing loss in subjects with tinnitus: extended high-frequency audiometric thresholds, the auditory brainstem response, and the envelope following response. In addition, speech intelligibility was measured as a functional outcome measurement of hidden hearing loss. To account for age-related hidden hearing loss, participants were grouped according to age, presence of tinnitus, and audiometric thresholds. Group comparisons were conducted to differentiate between age- and tinnitus-related effects of hidden hearing loss. All three markers revealed age-related differences, whereas no differences were observed between the tinnitus and non-tinnitus groups. However, the older tinnitus group showed improved performance on low-pass filtered speech in noise tests compared to the older non-tinnitus group. These low-pass speech in noise scores were significantly correlated with tinnitus distress, as indicated using questionnaires, and could be related to the presence of hyperacusis. Based on our observations, cochlear synaptopathy does not appear to be the underlying cause of tinnitus. The improvement in low-pass speech-in-noise could be explained by enhanced temporal fine structure encoding or hyperacusis. Therefore, we recommend that future tinnitus research takes into account age-related factors, explores low-frequency encoding, and thoroughly assesses hyperacusis.
MXRA8 promotes adipose tissue whitening to drive obesity
Authors: Jia Wentong , Giwa Rocky , Moley John R. , Smith Gordon I. , Petersen Max C. , Field Rachael L , Abousaway Omar , Kim Arthur S. , Coffey Sarah R. , Varnum Stella , Wright Jasmine M. , Zhang Xinya , Krysa Samantha , Lodhi Irfan J. , Abumrad Nada A. , Klein Samuel , Diamond Michael S. , Brestoff Jonathan R.
Published: February 2024

Matrix-remodeling associated 8 (MXRA8), also known as Dual immunoglobulin domain cell adhesion molecule (DICAM), is a type 1 transmembrane protein that reportedly binds the αVβ3integrin1and regulates the differentiation of osteoclasts2and chondrocytes3, tumor growth4, T cell trafficking5, and angiogenesis6. MXRA8 is also an essential entry receptor for chikungunya virus and other related arthritogenic alphaviruses.7-9We compared MXRA8 expression in 51 tissues in the Human Protein Atlas and found it is most highly expressed in white adipose tissue (WAT), however the function of MXRA8 in WAT is unknown. Here, we found that MXRA8 expression in WAT is increased in people with obesity and that this response is also observed in a mouse model of high fat-diet (HFD)-induced obesity. Single-nucleus RNA sequencing and high-dimensional spectral flow cytometry analyses revealed that MXRA8 is expressed predominantly by adipocyte progenitor (AP) cells and mature adipocytes. MXRA8 mutant primary adipocytes from inguinal (i)WAT exhibited increased expression of Uncoupling protein 1 (UCP1), a thermogenic protein expressed by beige and brown adipocytes that limits obesity pathogenesis.10-12Indeed, MXRA8 mutant mice fed a HFD had preserved UCP1+beige and brown adipocytes and were protected from HFD-induced obesity in a UCP1-dependent manner. Collectively, these findings indicate that MXRA8 promotes whitening of beige and brown adipose tissues to drive obesity pathogenesis and identify MXRA8 as a possible therapeutic target to treat obesity and associated metabolic diseases.
FoxO factors are essential for maintaining organ homeostasis by acting as stress sensors in airway epithelial cells
Authors: Uliczka Karin , Bossen Judith , Zissler Ulrich M. , Fink Christine , Niu Xiao , Pieper Mario , Prange Ruben D. , Vock Christina , Wagner Christina , Knop Mirjam , Abdelsadik Ahmed , Franzenburg Sören , Bruchhaus Iris , Wegmann Michael , Schmidt-Weber Carsten B. , König Peter , Pfefferle Petra , Heine Holger , Roeder Thomas
Published: February 2024

Airway epithelia have the challenging task of maintaining functional and structural homeostasis, even when exposed to various stress factors. Transcription factors of the FoxO family can fulfill this complex task, as they act as integration hubs that translate extrinsic and intrinsic information into a physiologically appropriate response. We could show that FoxO factors inDrosophila, mouse, and human airway epithelial cells (AECs) respond to stressors like hypoxia, temperature, or oxidative stress by nuclear translocation. A complex activation pattern is revealed in human cell culture systems, which differs between individual hFOXO factors and cell types. Studies withDrosophilashowed that hypoxia was the only stressor that induced a dfoxo-dependent, local immune response activation. SinceDrosophilahas only one ortholog of FoxO, it was possible to show that the absence of dfoxo in the airways strongly increases the stress sensitivity of the airways. This stress sensitivity finds its counterpart in mouse models of chronic and acute asthma, with reduced mFoxO expression in the lung, particularly mFoxO1 and mFoxO3A. Finally, it is also reflected in asthma patients who show reduced hFOXO transcripts in their sputum samples. We conclude that active FoxO signaling in AECs is necessary to respond appropriately to stressors. Impaired FoxO signaling limits this ability and thus promotes disease development.
Individualized functional connectivity markers associated with motor and mood symptoms of Parkinson’s disease
Authors: Dahmani Louisa , Bai Yan , Zhang Wei , Ren Jianxun , Li Shiyi , Hu Qingyu , Fu Xiaoxuan , Ma Jianjun , Wei Wei , Wang Meiyun , Liu Hesheng , Wang Danhong
Published: February 2024

Parkinson’s disease (PD) is a complex neurological disorder characterized by many motor and non-motor symptoms. While most studies focus on the motor symptoms of the disease, it is important to identify markers that underlie different facets of the disease. In this case-control study, we sought to discover reliable, individualized functional connectivity markers associated with both motor and mood symptoms of PD. Using functional MRI, we extensively sampled 166 patients with PD (64 women, 102 men; mean age=61.8 years, SD=7.81) and 51 healthy control participants (32 women, 19 men; mean age=55.68 years, SD=7.62). We found that a model consisting of 44 functional connections predicted both motor (UPDRS-III: Pearsonr=0.21, FDR-adjustedp=0.006) and mood symptoms (HAMD: Pearsonr=0.23, FDR-adjustedp=0.006; HAMA: Pearsonr=0.21, FDR-adjustedp=0.006). Two sets of connections contributed differentially to these predictions. Between-network connections, mainly connecting the sensorimotor and visual large-scale functional networks, substantially contributed to the prediction of motor measures, while within-network connections in the insula and sensorimotor network contributed more so to mood prediction. The middle to posterior insula region played a particularly important role in predicting depression and anxiety scores. We successfully replicated and generalized our findings in two independent PD datasets. Taken together, our findings indicate that sensorimotor and visual network markers are indicative of PD brain pathology, and that distinct subsets of markers are associated with motor and mood symptoms of PD.
Open-Source Platform for Kinematic Analysis of Mouse Forelimb Movement
Authors: Berezhnoi Daniil , Chehade Hiba Douja , Chu Hong-Yuan
Published: February 2024

We present an open-source behavioral platform and software solution for studying fine motor skills in mice performing reach-to-grasp task. The behavioral platform uses readily available and 3D-printed components and was designed to be affordable and universally reproducible. The protocol describes how to assemble the box, train mice to perform the task and process the video with the custom software pipeline to analyze forepaw kinematics. All the schematics, 3D models, code and assembly instructions are provided in the open GitHub repository.

Graphical abstract
Modeling nearshore-offshore water exchange in Lake Ontario
Authors: Hlevca Bogdan , Howell Todd , Valipour Reza , Madani Mohammad
Published: February 2024

The water quality and resources of Lake Ontario’s nearshore ecosystem undergo heightened stress, particularly along the northwest shoreline. Hydrodynamic processes linking the distinct nearshore and offshore trophic structures play a crucial role in transporting nutrient-loaded water along and across the shore. Despite the pivotal connection between algae growth and the development of nuisance proportions, the scales over which these processes operate remain poorly understood. This study delves into the exchange dynamics between nearshore and offshore areas of Lake Ontario throughout 2018, employing a validated three-dimensional numerical model. A virtual passive age tracer is utilized to discern horizontal mixing time scales between nearshore regions of the lake (water depth < 30 m) and offshore locations. The dispersal pattern, as revealed by a passive tracer released from eight points around the model lake’s perimeter, indicates more extensive diffusion in late summer when lake-wide stratification is established, compared to the mixed period. Coastal upwelling events, leading to intrusions of hypolimnetic waters, significantly contribute to net cross-shore transport, with the most pronounced effects observed in May and June when the offshore thermocline is shallow. In the northern part of the lake, dispersal predominantly occurs alongshore, mirroring the prevailing cyclonic (counterclockwise) coastal circulation during the stratified season. This pattern is a consequence of a 45% increase in upwelling events compared to three decades ago. In the northwestern and southern sectors of the lake, elevated cross-shore mixing is attributed to geomorphology-induced cross-basin currents.
Physicochemical Principles Driving Small Molecule Binding to RNA
Authors: Allen Timothy E. H. , McDonagh James L. , Broncel Malgorzata , Bryant Carson J. , Incarnato Danny , Vasudevan Anil , Khan Rabia T.
Published: February 2024

The possibility of using RNA-targeting small molecules to treat diseases is gaining traction as the next frontier of drug discovery and development. The chemical characteristics of small molecules that bind to RNA are still relatively poorly understood, particularly in comparison to protein-targeting small molecules. To fill this gap, we have generated an unprecedented amount of RNA-small molecule binding data, and used it to derive physicochemical rules of thumb that could be used to define areas of chemical space enriched for RNA binders - the Small molecules Targeting RNA (STaR) rules of thumb. These rules have been applied to publicly available RNA-small molecule datasets and found to be largely generalizable. Furthermore, a number of patented RNA-targeting compounds and FDA-approved compounds also pass these rules, as well as key RNA binding approved drug case studies including Risdiplam. We anticipate this work will significantly accelerate the exploration of the RNA-targeted chemical space, towards unlocking RNA’s potential as a small molecule drug target.

Graphical Abstract
TopEC: Improved classification of enzyme function by a localized 3D protein descriptor and 3D Graph Neural Networks
Authors: van der Weg Karel , Merdivan Erinc , Piraud Marie , Gohlke Holger
Published: February 2024

Accurately annotating molecular function to enzymes remains challenging. Computational methods can aid in this and allow for high-throughput annotation. Tools available for inferring enzyme function from general sequence, fold, or evolutionary information are generally successful. However, they can lead to misclassification if for certain sequences a deviation in local structural features influences the function. Here, we present TopEC, a 3D graph neural network based on a localized 3D descriptor to learn chemical reactions of enzymes from (predicted) enzyme structures and predict Enzyme Commission (EC) classes. Using the message passing frameworks from SchNet and DimeNet++, we include distance and angle information to improve the predictive performance compared to regular 2D graph neural networks. We obtained significantly improved EC classification prediction (F-score: 0.72) without fold bias at residue and atomic resolutions and trained networks that can classify both experimental and computationally generated enzyme structures for a vast functional space (> 800 ECs). Our model is robust to uncertainties in binding site locations and similar functions in distinct binding sites. By investigating the importance of each graph node to the predictive performance, we see that TopEC networks learn from an interplay between biochemical features and local shape-dependent features.
Dynamic formation of a posterior-to-anterior peak-alpha-frequency gradient driven by two distinct processes
Authors: Smith Max Kailler , Grabowekcy Marcia , Suzuki Satoru
Published: February 2024

Peak-alpha frequency varies across individuals and mental states, but it also forms a negative gradient from posterior to anterior regions in association with increases in cortical thickness and connectivity reflecting the cortical hierarchy in temporal integration. Tracking the spatial standard deviation of peak-alpha frequency in scalp EEG, we observed that the posterior-to-anterior gradient dynamically formed and dissolved. Periods of high spatial standard deviation yielded robustly negative posterior-to-anterior gradients—the gradient state—while periods of low spatial standard deviation yielded globally converged peak-alpha frequency—the uniform state. Our analyses suggest that the fluctuations between the gradient and uniform states are associated with two separate variables: (1) coordinated variations in peak-alpha frequency in anterior regions and (2) coordinated variations in peak-alpha power in central regions driven by posterior regions. These variables each accounted for ∼25% of the state fluctuations, were uncorrelated with each other, and together accounted for ∼50% of the state fluctuations. These results reflect general mechanisms as they replicated while participants engaged in a variety of behavioral tasks with their eyes closed (breath focus, vigilance, working memory, mental arithmetic, and generative thinking). Overall, our results suggest that the spatial pattern of peak-alpha frequency dynamically fluctuates between the gradient state, potentially facilitating information influx and temporal integration toward anterior regions, and the uniform state, potentially facilitating global communication, with the state fluctuations controlled by at least two distinct mechanisms, an anterior mechanism that directly adjusts peak-alpha frequencies and a posterior mechanism that indirectly adjusts them by influencing synchronization.
Notch controls early temporal factor expression to control timing of Mushroom body neuroblast apoptosis
Authors: Branham Kendall R. , Sood Chhavi , Doyle Susan E. , Pahl Matt C. , Siegrist Sarah E.
Published: February 2024

The neurogenic period, where neural stem cells (NSCs) proliferate to produce molecularly distinct progeny in the developing brain, is a critical time of growth in many organisms. Proper brain development is crucial for survival and requires strict regulation of NSC divisions along a set developmental timeline. InDrosophilaNSCs known as neuroblasts (NBs), cell intrinsic programs integrate with extrinsic cues to control periods of rapid growth through temporal patterning genes. Without regulation, NSCs can under proliferate leading to diseases like microcephaly and autism spectrum disorders, or over proliferate leading to macrocephaly and tumors. We know programs to control timing of proliferation and elimination of NSCs exist, but many elements of temporal cassettes are still unclear. What genes may be upstream to regulate known temporal programs to control when certain progeny are produced have not been fully identified, leaving a gap in our understanding. To address these questions, we carried out a large-scale RNAi screen aimed at identifying genes required for NSC elimination. We identified Notch and its ligand, Delta. When Notch pathway activity is reduced in NSCs, we found premature elimination of an important subset of neuroblasts called the mushroom body neuroblasts (MBNBs). These MBNBs produce the neurons responsible for formation of the evolutionarily conserved structure called the mushroom body (MB), which is involved in olfactory based learning and memory. MBNBs with reduced Notch pathway activity also experienced defects in MB structure. Furthermore, we determined that temporal patterning is disrupted primarily through loss of early temporal factor expression. In this work, we find that cell signaling pathways that involve the receptor Notch and its ligand. Delta function to regulate NB proliferation inDrosophila melanogasterby regulating early temporal factor expression.
Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity
Authors: Yu Hong , Nishio Hiroshi , Barbi Joseph , Mitchell-Flack Marisa , Vignali Paolo D. A. , Zheng Ying , Lebid Andriana , Chang Kwang-Yu , Fu Juan , Higgins Makenzie , Huang Ching-Tai , Zhang Xuehong , Li Zhiguang , Blosser Lee , Tam Ada , Drake Charles G. , Pardoll Drew M.
Published: February 2024

The adaptive T cell response is accompanied by continuous rewiring of the T cell’s electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.
Comparative transcriptomic analyses reveal differences in the responses of diploid and triploid eastern oysters to environmental stress during a summer mortality event
Authors: Vaidya Rujuta V. , Bodenstein Sarah , Rasulova Dildorakhon , La Peyre Jerome F. , Kelly Morgan W.
Published: February 2024

Triploid oysters are commonly used as the basis for production in the aquaculture of eastern oysters along the U.S East and Gulf of Mexico coasts. While they are valued for their rapid growth, incidents of triploid mortality during summer months have been well documented in eastern oysters, especially at low salinity sites. We compared global transcriptomic responses of diploid and triploid oysters bred from the same three maternal lines and outplanted to a high (annual mean salinity = 19.4 ± 6.7) and low (annual mean salinity = 9.3 ± 5.0) salinity site at the onset of mortality event in summer of 2021 to test for effect of parental contribution on triploid performance. We compared transcriptomic responses of same diploid and triploid oysters to test for ploidy specific differences in gene expression in response to high and low salinity sites and tested for instances of aneuploidy in experimental triploid oyster lines. Maternal parentage did not affect triploid mortality, but a strong effect of hatchery conditions (cohort) was observed. We detected a higher number of DEGs in response to outplant sites (salinity) and cohorts, indicating stronger influence of these two factors on triploid mortality. At the low salinity site where triploid oysters experienced high mortality, we observed downregulation of transcripts related to calcium signaling (Calmodulin-a, Histidine-rich calcium binding protein (HRC), and cadherin EGF LAG seven-pass G-type receptor 1(CELSR1)), ciliary activity (axonemal and cytoplasmic dyneins), and cell cycle check points (CDK1, HAUS augmin-like complex subunit 3, and MAPKKK, MCM7, SMCs, RTEL1). These transcripts suggest dampening of the salinity stress response and problems during cell division as key contributors to elevated summer mortality in triploid oysters. No instances of aneuploidy were detected in our triploid oyster lines.
Assessing quadriceps strength in patellofemoral pain patients: A study on the reliability and validity of a low-cost load-cell for clinical practice
Authors: Deysel Germari , van Aswegen Mariaan , Kramer Mark
Published: February 2024

Background

Patellofemoral pain (PFP) is a common knee complaint affecting diverse populations both acutely and chronically. Quadriceps muscle weakness is one possible aetiology, but current devices for measuring muscle strength (isokinetic dynamometer and hand-held dynamometers) are frequently too expensive for practitioners, especially in under-resourced settings. There is a need to evaluate a low-cost device to manage rehabilitation of people with PFP.

Methods

Isometric quadriceps strength of participants aged 18-35 years (total [n = 33], control group [n = 17] and PFP group [n = 16]) were evaluated on an isokinetic dynamometer and a low-cost load cell at baseline and after an 8-week non-standardised intervention for validity scores.

Results

The load cell showed high absolute and relative reliability (intraclass correlation coefficient = 0.89-0.99; typical error of measurement = 3.9-10.4%). Clinically meaningful difference scores (12.2-45 Nm) were greater than the typical error of measurement, implying sufficient sensitivity of the load cell to measure true changes in isometric quadricep strength. Strong to very strong correlations were evident between the load cell and isokinetic dynamometer torque measurements (r = 0.88-0.90, SEE = 0.05-0.07 Nm), but slope values (β = 0.65-0.77) indicated that torque from the load cell was typically lower than that obtained from the isokinetic dynamometer. An average systematic bias of 16.3-28.8 Nm was evident in favour of the isokinetic dynamometer, with no statistically significant between-group differences being noted between the baseline and follow-up testing.

Conclusion

The load cell is a reliable instrument, sensitive enough to detect clinically meaningful differences in quadriceps strength in healthy individuals and those with PFP. The load cell lacks validity and cannot replace isokinetic dynamometry. Given the low cost and excellent reliability, the load cell can be a valuable tool to assess quadriceps muscle deficits and track rehabilitation progress in people with PFP.
White Matter Microstructure Alterations in Early Psychosis and Schizophrenia
Authors: Pavan Tommaso , Alemán-Gómez Yasser , Jenni Raoul , Steullet Pascal , Schilliger Zoé , Dwir Daniella , Cleusix Martine , Alameda Luis , Do Kim Q. , Conus Philippe , Klauser Paul , Hagmann Patric , Jelescu Ileana
Published: February 2024

Studies on schizophrenia feature diffusion magnetic resonance imaging (dMRI) to investigate white matter (WM) anomalies. The heterogeneity in the possible interpretations of typical Diffusion Tensor Imaging (DTI) metrics highlights the importance of increasing their specificity. Here, we characterize WM pathology in early psychosis (EP) and schizophrenia (SZ) with increased specificity using advanced dMRI: Diffusion Kurtosis Imaging and the biophysical model White Matter Tract Integrity – Watson (WMTI-W). This enables us to better characterize WM abnormalities, while preserving good sensitivity to group differences, and relate them to the current literature (ENIGMA-schizophrenia), patient’s clinical characteristics and symptomatology. dMRI-derived microstructure features were extracted from all of WM and from individual regions of interest in 275 individuals. 93 subjects diagnosed with EP and 47 with SZ were compared respectively to 135 age-range matched healthy controls (HC). WM DTI diffusivities were higher, while kurtosis was lower in EP vs HC and in SZ vs HC. Differences were more widespread in EP than SZ. The regional alterations found in our cohort matched the DTI patterns found in ENIGMA-schizophrenia. WMTI-W model parameters indicate that the WM alterations in patients come primarily from the extra-axonal compartment, consistent with abnormal myelin integrity in the disease pathology. The direct link between WM alterations and symptomatology is, however, limited.
An Empirical Study on KDIGO-Defined Acute Kidney Injury Prediction in the Intensive Care Unit
Authors: Lyu Xinrui , Fan Bowen , Hüser Matthias , Hartout Philip , Gumbsch Thomas , Faltys Martin , Merz Tobias M. , Rätsch Gunnar , Borgwardt Karsten
Published: February 2024

Motivation

Acute kidney injury (AKI) is a syndrome that affects a large fraction of all critically ill patients, and early diagnosis to receive adequate treatment is as imperative as it is challenging to make early. Consequently, machine learning approaches have been developed to predict AKI ahead of time. However, the prevalence of AKI is often underestimated in state-of-the-art approaches, as they rely on an AKI event annotation solely based on creatinine, ignoring urine output.

Methods

We construct and evaluate early warning systems for AKI in a multi-disciplinary ICU setting, using the complete KDIGO definition of AKI. We propose several variants of gradient-boosted decision trees (GBDT)-based models, including a novel time-stacking based approach. A state-of-the-art LSTM-based model previously proposed for AKI prediction is used as a comparison, which was not specifically evaluated in ICU settings yet.

Results

We find that optimal performance is achieved by using GBDT with the time-based stacking technique (AUPRC=65.7%, compared with the LSTM-based model’s AUPRC=62.6%), which is motivated by the high relevance of time since ICU admission for this task. Both models show mildly reduced performance in the limited training data setting, perform fairly across different subco-horts, and exhibit no issues in gender transfer.

Conclusion

Following the official KDIGO definition substantially increases the number of annotated AKI events. In our study GBDTs outperform LSTM models for AKI prediction. Generally, we find that both model types are robust in a variety of challenging settings arising for ICU data.