bluuebunny/crossref_metadata_2025 huggingface dataset:
Stem cell-specific ecdysone signaling regulates the development and function of aDrosophilasleep homeostat
Authors: Wani Adil R , Chowdhury Budhaditya , Luong Jenny , Chaya Gonzalo Morales , Patel Krishna , Isaacman-Beck Jesse , Shafer Orie , Kayser Matthew S. , Syed Mubarak Hussain
Published: October 2023

Complex behaviors arise from neural circuits that are assembled from diverse cell types. Sleep is a conserved and essential behavior, yet little is known regarding how the nervous system generates neuron types of the sleep-wake circuit. Here, we focus on the specification ofDrosophilasleep-promoting neurons—long-field tangential input neurons that project to the dorsal layers of the fan-shaped body neuropil in the central complex (CX). We use lineage analysis and genetic birth dating to identify two bilateral Type II neural stem cells that generate these dorsal fan-shaped body (dFB) neurons. We show that adult dFB neurons express Ecdysone-induced protein E93, and loss of Ecdysone signaling or E93 in Type II NSCs results in the misspecification of the adult dFB neurons. Finally, we show that E93 knockdown in Type II NSCs affects adult sleep behavior. Our results provide insight into how extrinsic hormonal signaling acts on NSCs to generate neuronal diversity required for adult sleep behavior. These findings suggest that some adult sleep disorders might derive from defects in stem cell-specific temporal neurodevelopmental programs.
TRIM72 restricts lyssavirus infection by inducing K48-linked ubiquitination and proteasome degradation of the matrix protein
Authors: Sui Baokun , Zheng Jiaxin , Fu Zhenfang , Zhao Ling , Zhou Ming
Published: September 2023

The tripartite motif (TRIM) protein family is the largest subfamily of E3 ubiquitin ligases, playing a crucial role in the antiviral process. In this study, we found that TRIM72, a member of the TRIM protein family, was increased in neuronal cells and mouse brains following rabies lyssavirus (RABV) infection. Over-expression of TRIM72 significantly reduced the viral titer of RABV in neuronal cells and mitigated the pathogenicity of RABV in mice. Furthermore, we found that TRIM72 over-expression effectively prevents the release of RABV. In terms of the mechanism, TRIM72 promotes the K48-linked ubiquitination of RABV Matrix protein (M), leading to the degradation of M through the proteasome pathway. TRIM72 directly interacts with M and the interaction sites were identified and confirmed through TRIM72-M interaction model construction and mutation analysis. Further investigation revealed that the degradation of M induced by TRIM72 was attributed to TRIM72’s promotion of ubiquitination at site K195 in M. Importantly, the K195 site was found to be partially conserved among lyssavirus’s M proteins, and TRIM72 over-expression induced the degradation of these lyssavirus M proteins. In summary, our study has uncovered a TRIM family protein, TRIM72, that can restrict lyssavirus replication by degrading M, and we have identified a novel ubiquitination site (K195) in lyssavirus M.

Author Summary

Rabies, caused by lyssaviruses, most often by rabies virus, the most lethal zoonotic disease, is responsible for approximately 59000 human deaths globally each year. Lyssavirus M protein displays an essential role in lyssavirus assembly and budding. Here, we found that TRIM family protein TRIM72 directly interacts with lyssavirus M thereby promoting the K48-linked ubiquitination of M, leading to the degradation of M through the proteasome pathway, restricting lyssavirus release. Moreover, we identified a novel important ubiquitination site (K195) in lyssavirus M. Prior to our study, there had been no reports of a direct interaction between TRIM72 and viral proteins, an antiviral function of TRIM72 was proved in our study. It is possible that TRIM72 interacts and ubiquitinates other viral proteins from various viruses, which warrants further investigation. This research contributes to our understanding of how TRIM72 and other TRIM proteins play a role in defending against viral invasions and may inspire further research in this field.
A locomotion-based assay to measure prepulse inhibition in zebrafish larvae
Authors: Read Emily , Hindges Robert
Published: September 2023

Sensory gating, assessed using a prepulse inhibition assay (PPI), is a promising endophenotype of neuropsychiatric disorders that can be measured in larval zebrafish models. However, current PPI assays require high-speed cameras to capture rapid c-bend startle behaviours. In this study, we designed and employed a PPI paradigm that uses locomotion as read-out of startle responses. PPI percentage was measured at a maximum of 86% and this was reduced to 42% upon administration of an NMDA receptor antagonist, MK-801. This work provides the foundation for simpler and more accessible PPI assays using larval zebrafish to model key endophenotypes of neurodevelopmental disorders.
Neural Evidence of Functional Compensation for Fluid Intelligence in Healthy Ageing
Authors: Knights Ethan , Henson Richard N. , Morcom Alexa M. , Mitchell Daniel J. , Tsvetanov Kamen A.
Published: September 2023

Functional compensation is a common notion in the neuroscience of healthy ageing, whereby older adults are proposed to recruit additional brain activity to compensate for reduced cognitive function. However, whether this additional brain activity in older participants actually helps their cognitive performance remains debated. We examined brain activity and cognitive performance in a human lifespan sample (N=223) while they performed a problem-solving task (based on Cattell’s test of fluid intelligence) during functional magnetic resonance imaging (fMRI). Whole-brain univariate analysis revealed that activity in bilateral cuneal cortex for hard vs. easy problems increased both with age and with performance, even when adjusting for an estimate of age-related differences in cerebrovascular reactivity. Multivariate Bayesian decoding further demonstrated that age increased the likelihood that activation patterns in this cuneal region provided non-redundant information about the two task conditions, beyond that of the multiple-demand network generally activated in this task. This constitutes some of the strongest evidence yet for functional compensation in healthy ageing, at least in this brain region during visual problem-solving.
Extensive co-regulation of neighbouring genes complicates the use of eQTLs in target gene prioritisation
Authors: Tambets Ralf , Kolde Anastassia , Kolberg Peep , Love Michael I , Alasoo Kaur
Published: September 2023

Identifying causal genes underlying genome-wide association studies (GWAS) is a fundamental problem in human genetics. Although colocalisation with gene expression quantitative trait loci (eQTLs) is often used to prioritise GWAS target genes, systematic benchmarking has been limited due to unavailability of large ground truth datasets. Here, we re-analysed plasma protein QTL data from 3,301 individuals of the INTERVAL cohort together with 131 eQTL Catalogue datasets. Focusing on variants located within or close to the affected protein identified 793 proteins with at least onecis-pQTL where we could assume that the most likely causal gene was the gene coding for the protein. We then benchmarked the ability ofcis-eQTLs to recover these causal genes by comparing three Bayesian colocalisation methods (coloc.susie, coloc.abf and CLPP) and five Mendelian randomisation (MR) approaches (three varieties of inverse-variance weighted MR, MR-RAPS, and MRLocus). We found that assigning fine-mapped pQTLs to their closest protein coding genes outperformed all colocalisation methods regarding both precision (71.9%) and recall (76.9%). Furthermore, the colocalisation method with the highest recall (coloc.susie - 46.3%) also had the lowest precision (45.1%). Combining evidence from multiple conditionally distinct colocalising QTLs with MR increased precision to 81%, but this was accompanied by a large reduction in recall to 7.1%. Furthermore, the choice of the MR method greatly affected performance, with the standard inverse-variance weighted MR often producing many false positives. Our results highlight that linking GWAS variants to target genes remains challenging with eQTL evidence alone, and prioritising novel targets requires triangulation of evidence from multiple sources.
Cell type-specific gene expression dynamics during human brain maturation
Authors: Steyn Christina , Mishi Ruvimbo , Fillmore Stephanie , Verhoog Matthijs B. , More Jessica , Rohlwink Ursula K. , Melvill Roger , Butler James , Enslin Johannes M. N. , Jacobs Muazzam , Sauka-Spengler Tatjana , Greco Maria , Quiñones Sadi , Dulla Chris G. , Raimondo Joseph V. , Figaji Anthony , Hockman Dorit
Published: September 2023

The human brain undergoes protracted post-natal maturation, guided by dynamic changes in gene expression. Most studies exploring these processes have used bulk tissue analyses, which mask cell type-specific gene expression dynamics. Here, using single nucleus (sn)RNA-seq on temporal lobe tissue, including samples of African ancestry, we build a joint paediatric and adult atlas of 75 cell subtypes, which we verify with spatial transcriptomics. We explore the differences between paediatric and adult cell types, revealing the genes and pathways that change during brain maturation. Our results highlight excitatory neuron subtypes, including theLTKandFREMsubtypes, that show elevated expression of genes associated with cognition and synaptic plasticity in paediatric tissue. The new resources we present here improve our understanding of the brain during its development and contribute to global efforts to build an inclusive brain cell map.
A Sodium-dependent Trehalose Transporter Contributes to Anhydrobiosis in Insect Cell Line, Pv11
Authors: Mizutani Kosuke , Yoshida Yuki , Nakanishi Eita , Miyata Yugo , Tokumoto Shoko , Fuse Hiroto , Gusev Oleg , Kikuta Shingo , Kikawada Takahiro
Published: September 2023

Pv11 is the only animal cell culture that, when preconditioned with a high concentration of trehalose, can be preserved in the dry state at room temperature for more than one year while retaining the ability to resume proliferation. This extreme desiccation tolerance is referred to as anhydrobiosis. Here we identified a novel transporter that contributes to the recovery of Pv11 cells from anhydrobiosis. In general, the SLC5 family of secondary active transporters co-transport Na+and carbohydrates including glucose. Here we identified a novel transporter STRT1 (sodium-ion trehalose transporter 1) belonging to the SLC5 family that is highly expressed in Pv11 cells and transports trehalose with Na+dependency. This is the first report of an SLC5 family member that transports a naturally occurring disaccharide, such as trehalose. Knockout of theStrt1gene significantly reduced the viability of Pv11 cells upon rehydration after desiccation. During rehydration, when intracellular trehalose is no longer needed,Strt1-knockout cells released the disaccharide more slowly than the parent cell line. During rehydration, Pv11 cells became roughly spherical due to osmotic pressure changes, but then returned to their original spindle shape after about 30 min.Strt1-knockout cells, however, required about 50 min to adopt their normal morphology. STRT1 probably regulates intracellular osmolality by releasing unwanted intracellular trehalose with Na+, thereby facilitating the recovery of normal cell morphology during rehydration. STRT1 likely improves the viability of dried Pv11 cells by rapidly alleviating the significant physical stresses that arise during rehydration.

Significance Statement

This is the first report of an SLC5 family member, STRT1 (sodium ion trehalose transporter 1), with Na+-dependent trehalose transport activity. AStrt1-knockout cell line revealed that STRT1 likely plays an important role during anhydrobiosis in Pv11 cells: it efficiently discharges unwanted trehalose in the presence of Na+during rehydration of dried Pv11 cells, effectively reducing intracellular osmolality and thereby restoring cell morphology to a normal state.
Aedes albopictusis present in the lowlands of southern Zambia
Authors: Matute Daniel R. , Cooper Brandon S.
Published: September 2023

Identifying the current geographic range of disease vectors is a critical first step towards determining effective mechanisms for controlling and potentially eradicating them. This is particularly true given that historical vector ranges may expand due to changing climates and human activity. TheAedessubgenusStegomyiacontains over 100 species, and among them,Ae. aegyptiandAe. albopictusmosquitoes represent the largest concern for public health, spreading dengue, chikungunya, and Zika viruses. WhileAe. aegyptihas been observed in the country of Zambia for decades,Ae. albopictushas not. In 2015 we sampled four urban and two rural areas in Zambia forAedesspecies. Using DNA barcoding, we confirmed the presence of immature and adultAe. albopictusat two rural sites: Siavonga and Livingstone. These genotypes seem most closely related to specimens previously collected in Mozambique based on CO1 sequence from mtDNA. We resampled Siavonga and Livingstone sites in 2019, again observing immature and adultAe. albopictusat both sites. RelativeAe. albopictusfrequencies were similar between sites, with the exception of immature life stages, which were higher in Siavonga than in Livingstone in 2019. WhileAe. albopictusfrequencies did not vary through time in Livingstone, both immature and adult frequencies increased through time in Siavonga. This report serves to document the presence ofAe. albopictusin Zambia, which will contribute to the process of determining the potential public health implications of this disease vector in Central Africa.
Repurposing efavirenz, the HIV antiretroviral drug for Chikungunya virus infection
Authors: Nehul Sanketkumar , Rani Ruchi , Panda Prasan Kumar , Kumar Pravindra , Tomar Shailly
Published: September 2023

Chikungunya virus (CHIKV) has frequently recurred in recent decades, causing outbreaks worldwide in tropical and subtropical regions. The re-emergence of CHIKV poses a substantial risk to human health as no efficacious drugs are currently available to curb new outbreaks. Here, the anti-CHIKV activity of efavirenz was investigated byin vitrocell culture-based antiviral assay, immunofluorescence assay (IFA), and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used for treatment of acquired immunodeficiency syndrome (AIDS), and it has good oral bioavailability, long half-life and affordable low cost. This study demonstrated dose-dependent robust anti-CHIKV activity of efavirenz at low micromolar concentration (EC50= 1.33 µM). To determine potential broad anti-alphavirus activity of efavirenz, its inhibitory activity against Sindbis virus (SINV) was detected. Interestingly, efavirenz also inhibited the replication of SINV at a low micromolar range (EC50= 0.7 µM). Time of addition assay, direct transfection of virus replicon RNA and minus-sense specific RT-PCR elucidated that efavirenz hinders the viral replication at an early stage after the virus entry by inhibiting the viral RNA synthesis. Efavirenz showed a binding affinity with purified CHIKV capsid protein (CHIKV CP) and it is known that CHIKV CP plays a novel role in the early phase of viral protein synthesis, suggesting CP might be one of the potential protein targets in addition to viral or host proteins involved in viral genome replication. The present study underscores the repurposing of efavirenz for antiviral therapy against CHIKV to curb future viral outbreaks.

Highlights

Identification ofin vitroanti-CHIKV activity of efavirenz.

Efavirenz disrupts the early phase of virus replication by interfering in the CHIKV minus-sense RNA synthesis.

Efavirenz and tomatidine also inhibit SINV replication indicating potential broad spectrum anti-alphavirus activity.

Efavirenz holds potential as therapeutic treatment for clinical infections of Chikungunya.
Relating Ecological Diversity to Genetic Discontinuity across Bacterial Species
Authors: Passarelli-Araujo Hemanoel , Venancio Thiago M. , Hanage William P
Published: September 2023

Bacterial genetic discontinuity, representing abrupt breaks in genomic identity among species, is crucial for grasping microbial diversity and evolution. Advances in genomic sequencing have enhanced our ability to track and characterize genetic discontinuity in bacterial populations. However, exploring systematically the degree to which bacterial diversity exists as a continuum or is sorted into discrete and readily defined species remains a challenge in microbial ecology. Here, we aimed to quantify the genetic discontinuity (δ) and investigate how this metric is related to ecology. We harnessed a dataset comprising 210,129 genomes to systematically explore genetic discontinuity patterns across several distantly related species, finding clear breakpoints which varied depending on the taxa in question. By delving into pangenome characteristics, we uncovered a significant association between pangenome saturation and genetic discontinuity. Closed pangenomes were associated with more pronounced breaks, exemplified byMycobacterium tuberculosis. Additionally, through a machine learning approach, we detected key features that impact genetic discontinuity prediction. Our study enhances the understanding of bacterial genetic patterns and their ecological implications, offering insights into species boundaries for prokaryotes.
A Low-Cost Stage-Top Incubation Device For Human Cell Imaging Using Rapid Prototyping Methods
Authors: Worcester Michael , Gomez Melissa , Mishra Pratyasha , Meyers Quintin , Kuhlman Thomas E.
Published: September 2023

Live imaging of human or other mammalian cells at multi-hour time scales with minimal perturbation to their growth state requires that the specimen’s optimal growth conditions are met while fixed to a microscope stage. In general, ideal conditions include culturing in complete growth media, an ambient temperature of 36-37 C, and a humidity-controlled atmosphere comprising typically 5-7% CO2. Commercially available devices that achieve these conditions are not a financially viable option for many labs, with the price ranging anywhere from $12000 to $40000. The advent of 3D printing technology has allowed for low-cost rapid prototyping with precision comparable to traditional fabrication methods, opening the possibility for in-lab design and production of otherwise prohibitively expensive equipment such as stage-top incubation devices. The continued usefulness and widespread availability of single-board computers (SBC) such as Arduino and Raspberry Pi also simplify the process by which these devices can be controlled. Here we report the production of a do-it-yourself (DIY) device for stage-top incubation with temperature and atmospheric control with a cost reduction of approximately 100x.
Discovery of essential kinetoplastid-insect adhesion proteins and their function inLeishmania-sand fly interactions
Authors: Yanase Ryuji , Pružinová Katerina , Rea Edward , Moreira-Leite Flávia , Taniguchi Atsushi , Nonaka Shigenori , Sádlová Jovana , Vojtkova Barbora , Volf Petr , Sunter Jack D.
Published: September 2023

Leishmaniaspecies, members of the kinetoplastid parasites, cause leishmaniasis, a neglected tropical disease, in millions of people worldwide1.Leishmaniahas a complex life cycle with multiple developmental forms, as it cycles between a sand fly vector and a mammalian host; understanding their life cycle is critical to understanding disease spread2. One of the key life cycle stages is the haptomonad form, which is attached to the insect through its flagellum. This adhesion, which is conserved across kinetoplastid parasites, is implicated to have an important function within their life cycles and hence on disease transmission3–5. Here, we discovered kinetoplastid-insect adhesion proteins (KIAPs), which are localised in the attached haptomonad flagellum. Deletion of these KIAPs impaired cell adhesionin vitroand preventedLeishmaniafrom colonising the stomodeal valve in the sand fly, without affecting cell growth. This result will provide important insights for a comprehensive understanding of theLeishmanialife cycle.
Attention-dependent coupling with forebrain and brainstem neuromodulatory nuclei changes across the lifespan
Authors: Cicero Nicholas G. , Riley Elizabeth , Swallow Khena M. , De Rosa Eve , Anderson Adam
Published: September 2023

Attentional states continuously reflect the predictability and uncertainty in one’s environment having important consequences for learning and memory. Beyond well known cortical contributions, rapid shifts in attention are hypothesized to also originate from deep nuclei, such as the basal forebrain (BF) and locus coeruleus (LC) neuromodulatory systems. These systems are also the first to change with aging. Here we characterized the interplay between these systems and their regulation of afferent targets – the hippocampus (HPC) and posterior cingulate cortex (PCC) – across the lifespan. To examine the role of attentional salience on task-dependent functional connectivity, we used a target-distractor go/no go task presented during functional MRI. In younger adults, BF coupling with the HPC, and LC coupling with the PCC, increased with behavioral relevance (targets vs distractors). Although the strength and presence of significant regional coupling changed in middle age, the most striking change in network connectivity was in old age, such that in older adults BF and LC coupling with their cortical afferents was largely absent and replaced by stronger interconnectivity between LC-BF nuclei. Overall rapid changes in attention related to behavioral relevance revealed distinct roles of subcortical neuromodulatory systems. The pronounced changes in functional network architecture across the lifespan suggest a decrease in these distinct roles, with deafferentation of cholinergic and noradrenergic systems associated with a shift towards mutual support during attention guided to external stimuli.

Significance statement

Changes in attentional control across the lifespan may originate from cortical control networks or subcortical neuromodulatory systems, which are the first sites of age-related neuropathology. In young adults, we demonstrated functional coupling of the basal forebrain with the hippocampus, and locus coeruleus with the posterior cingulate cortex varies with task relevance. This coupling changed in middle age and most strikingly in older adults. In old age, task-dependent coupling between the locus coeruleus and basal forebrain was the predominant connection remaining within the observed network. Older adults exhibit reduced subcortical-cortical connectivity, consistent with a relative neuromodulatory deafferentation, replaced by subcortical-subcortical deep nuclear connectivity. This alteration in noradrenergic and cholinergic signaling has important implications for attention and memory formation and neurocognitive aging.
Adolescent oligodendrogenesis and myelination restrict experience-dependent neuronal plasticity in adult visual cortex
Authors: Xin Wendy , Kaneko Megumi , Roth Richard H. , Zhang Albert , Nocera Sonia , Ding Jun B. , Stryker Michael P. , Chan Jonah R.
Published: September 2023

BACKGROUND

Developmental myelination is a protracted process in the mammalian brain. One theory for why oligodendrocytes mature so slowly posits that myelination may stabilize neuronal circuits and temper neuronal plasticity as animals age. We tested this hypothesis in the visual cortex, which has a well-defined critical period for experience-dependent neuronal plasticity.

OBJECTIVES/METHODS

To prevent myelin progression, we conditionally deleted Myrf, a transcription factor necessary for oligodendrocyte maturation, from oligodendrocyte precursor cells (Myrf cKO) in adolescent mice. To induce experience-dependent plasticity, adult control and Myrf cKO mice were monocularly deprived by eyelid suture. Functional and structural neuronal plasticity in the visual cortex were assessed in vivo by intrinsic signal optical imaging and longitudinal two photon imaging of dendritic spines, respectively.

RESULTS

During adolescence, visual experience modulated the rate of oligodendrocyte maturation in visual cortex. Myrf deletion from oligodendrocyte precursors during adolescence led to inhibition of oligodendrocyte maturation and myelination that persisted into adulthood. Following monocular deprivation, visual cortex activity in response to visual stimulation of the deprived eye remained stable in adult control mice, as expected for post-critical period animals. By contrast, visual cortex responses to the deprived eye decreased significantly following monocular deprivation in adult Myrf cKO mice, reminiscent of the plasticity observed in adolescent mice. Furthermore, visual cortex neurons in adult Myrf cKO mice had fewer dendritic spines and a higher level of spine turnover. Finally, monocular deprivation induced spatially coordinated spine size decreases in adult Myrf cKO, but not control, mice.

CONCLUSIONS

These results demonstrate a critical role for oligodendrocytes in shaping the maturation and stabilization of cortical circuits and support the concept of myelin acting as a brake on neuronal plasticity during development.
Anin vivoDissection, and Analysis of Socio-Affective Symptoms related to Cerebellum-Midbrain Reward Circuitry in Humans
Authors: Hoffman Linda J. , Foley Julia M. , Leong Josiah K. , Sullivan-Toole Holly , Elliott Blake L. , Olson Ingrid R.
Published: September 2023

Emerging research in non-human animals implicates cerebellar projections to the ventral tegmental area (VTA) in appetitive behaviors, but these circuits have not been characterized in humans. Here, we mapped cerebello-VTA white-matter connectivity in humans using probabilistic tractography on diffusion imaging data from the Human Connectome Project. We uncovered the topographical organization of these connections by separately tracking from parcels of cerebellar lobule VI, crus I/II, vermis, paravermis, and cerebrocerebellum. Results revealed that connections from the cerebellum to the VTA predominantly originate in the right hemisphere, interposed nucleus, and paravermal cortex, and terminate mostly ipsilaterally. Paravermal crus I sends the most connections to the VTA compared to other lobules. We discovered a medial-to-lateral gradient of connectivity, such that the medial cerebellum has the highest connectivity with the VTA. Individual differences in microstructure were associated with measures of negative affect and social functioning. By splitting the tracts into quarters, we found that the socio-affective effects were driven by the third quarter of the tract, corresponding to the point at which the fibers leave the deep nuclei. Taken together, we produced detailed maps of cerebello-VTA structural connectivity for the first time in humans and established their relevance for trait differences in socio-affective regulation.
Characterization of binding kinetics and intracellular signaling of new psychoactive substances targeting cannabinoid receptor using transition-based reweighting method
Authors: Dutta Soumajit , Shukla Diwakar
Published: October 2023

New psychoactive substances (NPS) targeting cannabinoid receptor 1 pose a significant threat to society as recreational abusive drugs that have pronounced physiological side effects. These greater adverse effects compared to classical cannabinoids have been linked to the higher downstreamβ-arrestin signaling. Thus, understanding the mechanism of differential signaling will reveal important structure-activity relationship essential for identifying and potentially regulating NPS molecules. In this study, we simulate the slow (un)binding process of NPS MDMB-Fubinaca and classical cannabinoid HU-210 from CB1using multi-ensemble simulation to decipher the effects of ligand binding dynamics on downstream signaling. The transition-based reweighing method is used for the estimation of transition rates and underlying thermodynamics of (un)binding processes of ligands with nanomolar affinities. Our analyses reveal major interaction differences with transmembrane TM7 between NPS and classical cannabinoids. A variational autoencoder-based approach, neural relational inference (NRI), is applied to assess the allosteric effects on intracellular regions attributable to variations in binding pocket interactions. NRI analysis indicate a heightened level of allosteric control of NPxxY motif for NPS-bound receptors, which contributes to the higher probability of formation of a crucial triad interaction (Y7.53-Y5.58-T3.46) necessary for strongerβ-arrestin signaling. Hence, in this work, MD simulation, data-driven statistical methods, and deep learning point out the structural basis for the heightened physiological side effects associated with NPS, contributing to efforts aimed at mitigating their public health impact.
Redescription ofDendrophthoe falcata(L. f.) Ettingsh (Loranthaceae) with notes on haustorium
Authors: Bhakat Somnath
Published: October 2023

Morphology ofDendrophthoe falcata(L. f.) Ettingsh var coccinea is described in detail from West Bengal with notes on the histology of haustorium. Structural peculiarity of the style is explained in the light of embryo sac development. Section of immature fruit shows different zones including embryo.

Three types of haustoria namely woody gall, clasping union ad epicortical root is observed in different species of the host plant. Section of haustorium shows penetration peg which reach the host xylem to suck the sap. In guava plant, two types of haustoria develop – primary or true haustorium which penetrate the host stem and secondary haustorium which develop in between two roots of the parasite. Secondary haustorium is oval in shape with a few concentric rings like thickening and never develops penetration peg.
A feature ranking algorithm for clustering medical data
Authors: Shpigelman Eran , Shamir Ron
Published: September 2023

Objective

Clustering methods are often applied to electronic medical records (EMR) for various objectives, including the discovery of previously unrecognized disease subtypes. The abundance and redundancy of information in EMR data raises the need to rank the features by their relevance to clustering.

Methods

Here we propose FRIGATE, an ensemble feature ranking algorithm for clustering. FRIGATE ranks the features by solving multiple clustering problems on subgroups of features, using game-theoretic principles to rank and weigh features. In every such problem, a Shapley-like framework is utilized to rank a selected set of features. In another version of the algorithm, multiplicative weights are employed to reduce the randomness in feature set selection. The code for the algorithms is available in:https://github.com/Shamir-Lab/FRIGATE.

Results

On simulated data and on eleven real genomics and EMR datasets, FRIGATE outperforms extant ensemble ranking algorithms, in solution quality and in speed.

Conclusion

Frigate can improve disease understanding by enabling better subtype discovery from EMR data.
Asynchronous Detection of Erroneous Behaviors in Human-Robot Interaction with EEG: A Comparative Analysis of Machine Learning Models
Authors: Ren Zhezheng , Xia Xuzhe , Tang Yuzhi , Zhao Bo , Wong Chun Pang , Xiao Dongsheng
Published: October 2023

We present a comparative analysis of two distinct machine-learning models designed to detect asynchronous errors during Human-Robot Interaction (HRI). The models under scrutiny are a customized ResNet model and an ensemble model, both trained and validated using EEG data. The ResNet model is a unique adaptation of the Residual Network, comprising a one-dimensional convolutional layer followed by batch normalization and ReLU activation. It also features a custom Residual Block structure and an adaptive average pooling layer, concluding with a fully connected linear layer for binary classification. The ensemble model, on the other hand, incorporates various machine learning models such as MLP, logistic regression, SVM, random forest, and XGBoost, unified in a pipeline with feature extraction and transformation steps. A critical component of our research is the innovative probability map, which maintains a granularity of 0.1 seconds. This map forecasts the likelihood of forthcoming one-second intervals being classified as either Error or Non-error. Our comparative analysis reveals significant variations in the performance of the two models, both of which exhibit promising results in detecting erroneous behaviors during HRI. We provide detailed validation results, including the accuracy, F1 score, and confusion matrix for each model. This study offers valuable insights into the potential of machine learning in enhancing HRI efficiency and accuracy, indicating promising directions for future research.
53BP1 mediates sensitivity to chemotherapy and is associated with poor clinical outcomes in high-grade serous ovarian cancer
Authors: Skulimowski Michael , Bourbonnais Jessica , Malaquin Nicolas , Fleury Hubert , Clément Isabelle , Communal Laudine , Rahimi Kurosh , Provencher Diane , Mes-Masson Anne-Marie , Rodier Francis
Published: October 2023

High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecological malignancy in North American women. At a cellular level, the current first-line chemotherapies cause DNA-damage and activate the DNA damage response signalling cascade. Here we explore the role of 53BP1, a central mediator of the DNA damage response, in HGSOC chemotherapy outcomes. Tissue 53BP1 protein levels were quantified in two independent HGSOC cohorts, the COEUR validation cohort (n = 173) and CHUM cohort (n = 56). Univariate and multivariate analyses showed that high nuclear 53BP1 levels in ovarian cancer cells were strongly associated with poor disease-specific survival in both cohorts. High 53BP1 was associated with poor progression-free survival (PFS) in the COEUR cohort, and trended towards poor PFS in the CHUM cohort. These findings were validated by whole-tumourTP53BP1mRNA of the TCGA Firehose Legacy cohort (n = 591) in which highTP53BP1mRNA levels were associated with poor overall survival on multivariate analysis. In HGSOC cell lines, 53BP1 levels were positively correlated with resistance to carboplatin using colony formation assay, and depletion of 53BP1 sensitized resistant cell lines to genotoxic therapies. These results suggest that 53BP1 is associated with poor prognosis in HGSOC and may mediate this relationship by modulating cellular sensitivity to chemotherapy.

Statement of translational relevance

Current first-line chemotherapies in ovarian cancer cause DNA damage and activate the DNA damage response, culminating in the taking of cell fate decisions. 53BP1 is a central mediator in this signalling cascade, where it is involved at multiple levels: signal amplification, recruitment of effectors, DNA repair pathway choice, and cell cycle regulation. However, its role in ovarian cancer treatment outcomes remains unknown. In this study, we found that 53BP1 correlated with poor clinical outcomes in three ovarian cancer patient cohorts and mediated carboplatin sensitivity in ovarian cancer cells. These results reveal 53BP1 and the DNA damage response as important actors in ovarian cancer treatment response. Though further studies are necessary to gain a more complete understanding of their involvement in clinical outcomes, they appear as promising candidates for potential therapeutic targeting in ovarian cancer.
A Specialized Epithelial Cell Type Regulating Mucosal Immunity and Driving Human Crohn’s Disease
Authors: Li Jia , Simmons Alan J. , Chiron Sophie , Ramirez-Solano Marisol A. , Tasneem Naila , Kaur Harsimran , Xu Yanwen , Revetta Frank , Vega Paige N. , Bao Shunxing , Cui Can , Tyree Regina N. , Raber Larry W. , Conner Anna N. , Beaulieu Dawn B. , Dalal Robin L. , Horst Sara N. , Pabla Baldeep S. , Huo Yuankai , Landman Bennett A. , Roland Joseph T. , Scoville Elizabeth A. , Schwartz David A. , Washington M. Kay , Shyr Yu , Wilson Keith T. , Coburn Lori A. , Lau Ken S. , Liu Qi
Published: October 2023

Crohn’s disease (CD) is a complex chronic inflammatory disorder that may affect any part of gastrointestinal tract with extra-intestinal manifestations and associated immune dysregulation. To characterize heterogeneity in CD, we profiled single-cell transcriptomics of 170 samples from 65 CD patients and 18 non-inflammatory bowel disease (IBD) controls in both the terminal ileum (TI) and ascending colon (AC). Analysis of 202,359 cells identified a novel epithelial cell type in both TI and AC, featuring high expression ofLCN2,NOS2, andDUOX2, and thus is named LND. LND cells, confirmed by high-resolution in-situ RNA imaging, were rarely found in non-IBD controls, but expanded significantly in active CD. Compared to other epithelial cells, genes defining LND cells were enriched in antimicrobial response and immunoregulation. Moreover, multiplexed protein imaging demonstrated that LND cell abundance was associated with immune infiltration. Cross-talk between LND and immune cells was explored by ligand-receptor interactions and further evidenced by their spatial colocalization. LND cells showed significant enrichment of expression specificity of IBD/CD susceptibility genes, revealing its role in immunopathogenesis of CD. Investigating lineage relationships of epithelial cells detected two LND cell subpopulations with different origins and developmental potential, early and late LND. The ratio of the late to early LND cells was related to anti-TNF response. These findings emphasize the pathogenic role of the specialized LND cell type in both Crohn’s ileitis and Crohn’s colitis and identify novel biomarkers associated with disease activity and treatment response.
Light-induced trapping of endogenous proteins reveals spatiotemporal roles of microtubule and kinesin-1 in dendrite patterning ofDrosophilasensory neurons
Authors: Xu Yineng , Wang Bei , Bush Inle , Saunders Harriet AJ , Wildonger Jill , Han Chun
Published: October 2023

Animal development involves numerous molecular events, whose spatiotemporal properties largely determine the biological outcomes. Conventional methods for studying gene function lack the necessary spatiotemporal resolution for precise dissection of developmental mechanisms. Optogenetic approaches are powerful alternatives, but most existing tools rely on exogenous designer proteins that produce narrow outputs and cannot be applied to diverse or endogenous proteins. To address this limitation, we developed OptoTrap, a light-inducible protein trapping system that allows manipulation of endogenous proteins tagged with GFP or split GFP. This system turns on fast and is reversible in minutes or hours. We generated OptoTrap variants optimized for neurons and epithelial cells and demonstrate effective trapping of endogenous proteins of diverse sizes, subcellular locations, and functions. Furthermore, OptoTrap allowed us to instantly disrupt microtubules and inhibit the kinesin-1 motor in specific dendritic branches ofDrosophilasensory neurons. Using OptoTrap, we obtained direct evidence that microtubules support the growth of highly dynamic dendrites. Similarly, targeted manipulation of Kinesin heavy chain revealed differential spatiotemporal requirements of kinesin-1 in the patterning of low- and high-order dendritic branches, suggesting that different cargos are needed for the growth of these branches. OptoTrap allows for precise manipulation of endogenous proteins in a spatiotemporal manner and thus holds great promise for studying developmental mechanisms in a wide range of cell types and developmental stages.
A Retina-inspired Optoelectronic Synapse Using Quantum Dots for Neuromorphic Photostimulation of Neurons
Authors: Balamur Ridvan , Eren Guncem Ozgun , Kaleli Humeyra Nur , Karatum Onuralp , Kaya Lokman , Hasanreisoglu Murat , Nizamoglu Sedat
Published: October 2023

Neuromorphic electronics, inspired by the functions of neurons, have the potential to enable biomimetic communication with cells. Such systems require operation in aqueous environments, generation of sufficient levels of ionic currents for neurostimulation, and plasticity. However, their implementation requires a combination of separate devices, such as sensors, organic synaptic transistors, and stimulation electrodes. Here, we present a compact neuromorphic synapse that combines photodetection, memory, and neurostimulation functionalities all-in-one. The artificial photoreception is facilitated by a photovoltaic device based on cell-interfacing InP/ZnS quantum dots, which induces photo-faradaic charge-transfer mediated plasticity. The device sends excitatory post-synaptic currents exhibiting paired-pulse facilitation and post-tetanic potentiation to the hippocampal neurons via the biohybrid synapse. The electrophysiological recordings indicate modulation of the probability of action potential firing due to biomimetic temporal summation of excitatory post-synaptic currents. Our results pave the way for the development of novel bioinspired neuroprosthetics and soft robotics and highlight the potential of quantum dots for achieving versatile neuromorphic functionality in aqueous environments.
Sleepiness, not total sleep amount, increases seizure risk
Authors: Cuddapah Vishnu Anand , Hsu Cynthia T , Li Yongjun , Shah Hrishit M , Saul Christopher , Killiany Samantha , Shon Joy , Yue Zhifeng , Gionet Gabrielle , Putt Mary E , Sehgal Amita
Published: October 2023

Sleep loss has been associated with increased seizure risk since antiquity. Despite this observation standing the test of time, how poor sleep drives susceptibility to seizures remains unclear. To identify underlying mechanisms, we restricted sleep inDrosophilaepilepsy models and developed a method to identify spontaneous seizures using quantitative video tracking. Here we find that sleep loss exacerbates seizures but only when flies experience increased sleep need, orsleepiness, and not necessarily with reduced sleep quantity. This is supported by the paradoxical finding that acute activation of sleep-promoting circuits worsens seizures, because it increases sleep need without changing sleep amount. Sleep-promoting circuits become hyperactive after sleep loss and are associated with increased whole-brain activity. During sleep restriction, optogenetic inhibition of sleep-promoting circuits to reduce sleepiness protects against seizures. Downregulation of the 5HT1A serotonin receptor in sleep-promoting cells mediates the effect of sleep need on seizures, and we identify an FDA-approved 5HT1A agonist to mitigate seizures. Our findings demonstrate that while homeostatic sleep is needed to recoup lost sleep, it comes at the cost of increasing seizure susceptibility. We provide an unexpected perspective on interactions between sleep and seizures, and surprisingly implicate sleep- promoting circuits as a therapeutic target for seizure control.
Expression of modified FcγRI enables myeloid cells to elicit robust tumor-specific cytotoxicity
Authors: Farhat-Younis Leen , Na Manho , Zarfin Amichai , Khateeb Aseel , Santana-Magal Nadine , Richter Alon , Gutwillig Amit , Rasoulouniriana Diana , Gleiberman Annette , Beck Lir , Giger Tamar , Ashkenazi Avraham , Barzel Adi , Rider Peleg , Carmi Yaron
Published: October 2023

Despite the central role of T cells in tumor immunity, attempts to harness their cytotoxic capacity as a therapy have met limited efficacy, partially as a result of the suppressive microenvironment which limits their migration and activation. In contrast, myeloid cells massively infiltrate tumors and are well adapted to survive these harsh conditions. While they are equipped with cell-killing abilities, they often adopt an immunosuppressive phenotype upon migration to tumors. Therefore, the questions of how to modify their activation programming against cancer, and what signaling cascades should be activated in myeloid cells to elicit their cytotoxicity have remained unclear.

Here, we found that activation of IgM-induced signaling in myeloid cells results in secretion of lytic granules and massive tumor cell death. These findings open venues for designing novel immunotherapy by equipping monocytes with chimeric receptors that target tumor antigens and consequently, signal through IgM receptor. Nonetheless, we found that myeloid cells do not express the antibody-derived portion used to recognize the tumor antigen due to the induction of an ER stress response. To overcome this limitation, we designed chimeric receptors that are based on the high-affinity FcγRI for IgG. Incubation of macrophages expressing these receptors along with tumor-binding IgG induced massive tumor cell killing and secretion of reactive oxygen species and Granzyme B.

Overall, this work highlights the challenges involved in genetically reprogramming the signaling in myeloid cells and provides a framework for endowing myeloid cells with antigen-specific cytotoxicity.
Evaluation of ChatGPT’s Pathology Knowledge using Board-Style Questions
Authors: Geetha Saroja D , Khan Anam , Khan Atif , Kannadath Bijun S , Vitkovski Taisia
Published: October 2023

Objectives

ChatGPT is an artificial intelligence (AI) chatbot developed by OpenAI. Its extensive knowledge and unique interactive capabilities enable it to be utilized in various innovative ways in the medical field such as writing clinical notes, simplifying radiology reports. Through this study we aim to analyze its pathology knowledge to advocate its role in transforming pathology education.

Methods

American Society for Clinical Pathology (ASCP) Resident Question bank (RQB) 2022 was used to test ChatGPT v4. Practice tests were created in each sub-category and were answered based on the input provided by ChatGPT. Questions that required interpretation of images were excluded. ChatGPT’s performance was analyzed and compared with the average peer performance.

Results

The overall performance of ChatGPT was 56.98%, lower than that of the average peer performance of 62.81%. ChatGPT performed better on clinical pathology (60.42%) than anatomic pathology (54.94%). Furthermore, its performance was better on easy questions (68.47%) compared to intermediate (52.88%) and difficult questions (37.21%).

Conclusions

ChatGPT has the potential to be a valuable resource in pathology education if trained on a larger, specialized medical dataset. Relying on it solely for the purpose of pathology training should be with caution, in its current form.

Key points

ChatGPT is an AI chatbot, that has gained tremendous popularity in multiple industries, including healthcare. We aim to understand its role in revolutionizing pathology education.

We found that ChatGPT’s overall performance in Pathology Practice Tests were lower than that expected from an AI tool, furthermore its performance was subpar compared to pathology residents in training.

In its current form ChatGPT is not a reliable tool for pathology education, but with further refinement and training it has the potential of being a learning asset.