bluuebunny/crossref_metadata_2025 huggingface dataset:
Circ0087385 promotes DNA damage in benzo(a)pyrene-induced lung cancer development by upregulating CYP1A1
Authors: Zhang Nan , Qiu Miaoyun , Yao Shuwei , Zhou Hanyu , Zhang Han , Jia Yangyang , Li Xin , Chen Xintong , Li Xun , Zhou Yun , Jiang Yiguo
Published: February 2024

Increasing environmental genotoxic chemicals have been shown to induce epigenetic alterations. However, the interaction between genetics and epigenetics in chemical carcinogenesis is still not fully understood. Here, we constructed an in vitro human lung carcinogenesis model (16HBE-T) by treating human bronchial epithelial cells with a typical significant carcinogen benzo(a)pyrene (BaP). We identified a novel circular RNA, circ0087385, which was overexpressed in 16HBE-T and human lung cancer cell lines, as well as in lung cancer tissues and serum exosomes from lung cancer patients. The upregulated circ0087385 after exposure to BaP promoted DNA damage in the early stage of chemical carcinogenesis and affected the cell cycle, proliferation, and apoptosis of the malignantly transformed cells. Overexpression of circ0087385 enhanced the expression of cytochrome P450 1A1 (CYP1A1), which is crucial for metabolically activating BaP. Interfering with circ0087385 or CYP1A1 reduced the levels of ultimate carcinogen benzo(a)pyrene diol epoxide (BPDE) and BPDE-DNA adducts. Interfering with CYP1A1 partially reversed the DNA damage induced by high expression of circ0087385, as well as decreased the level of BPDE and BPDE-DNA adducts. These findings provide novel insights into the interaction between epigenetics and genetics in chemical carcinogenesis which are crucial for understanding the epigenetic and genetic toxicity of chemicals.
Electrical Burn and Amputations in a Burn Center in Addis Ababa, Ethiopia
Authors: Abebe Metasebia W. , Ewing Emily L. , Weldemicheal Hanna A.
Published: February 2024

Background:

Burn injuries are a global public health problem and continue to be one of the leading causes of unintentional death and injury. Electrical injuries, a relatively rare cause of burns, are increasingly being reported with higher rates of mortality in low and middle-income countries due to rapid industrialization in the absence of safety regulations. Electrical burn injuries can result in death, various organ system dysfunctions, or limb amputations.

Methods:

A 5-year retrospective, cross-sectional study was conducted to assess the rate of amputation and associated risk factors in electrical burn injuries among burn patients at AaBET Hospital in Addis Ababa, Ethiopia.

Results:

The rate of amputation among the 150 patients admitted with electrical burn in the study period was 33.3% (n = 50). A majority (62%; n = 31) of the patients were men (M:F 1.6:1) in the age range of 18–65 years. A fallen electrical wire coming in contact with the patients was the cause of the electrical burns in 50% of the cases. 65.3% of the patients had upper limb amputations, whereas 34.7% had lower limb amputations. Major amputations were more likely to occur when the entry site was the hand, whereas minor amputations were more likely to occur when the entry site was the scalp (P = 0.005).

Conclusions:

Younger male patients were identified as the main victims of electrical burns that resulted in amputations. Electrical burns showed substantial morbidity and mortality of patients. Total body surface area and entry site being the hand significantly affected the level and site of amputation.
A Data-Driven Latent Variable Approach to Validating the Research Domain Criteria Framework
Authors: Quah S.K.L. , Jo B. , Geniesse C. , Uddin L.Q. , Mumford J.A. , Barch D.M. , Fair D.A. , Gotlib I.H. , Poldrack R.A. , Saggar M.
Published: February 2024

Despite the widespread use of the Research Domain Criteria (RDoC) framework in psychiatry and neuroscience, recent studies suggest that the RDoC is insufficiently specific or excessively broad relative to the underlying brain circuitry it seeks to elucidate. To address these concerns, we employed a latent variable approach using bifactor analysis. We examined 84 whole-brain task-based fMRI (tfMRI) activation maps from 19 studies with 6,192 participants. A curated subset of 37 maps with a balanced representation of RDoC domains constituted the training set, and the remaining held-out maps formed the internal validation set. External validation was conducted using 36 peak coordinate activation maps from Neurosynth, using terms of RDoC constructs as seeds for topic meta-analysis. Here, we show that a bifactor model incorporating a task-general domain and splitting the cognitive systems domain better fits the examined corpus of tfMRI data than the current RDoC framework. We also identify the domain of arousal and regulatory systems as underrepresented. Our data-driven validation supports revising the RDoC framework to reflect underlying brain circuitry more accurately.
Grayscale 4D Biomaterial Customization at High Resolution and Scale
Authors: Batalov Ivan , Filteau Jeremy R. , Francis Ryan M. , Jaindl Georg , Orr Luke , Rapp Teresa L. , Yang Shiyu , Filteau Jordan A. , Xie Weisi , Bretherton Ross C. , Glaser Adam K. , Liu Jonathan T.C. , Stevens Kelly R. , DeForest Cole A.
Published: February 2024

Hydrogel biomaterials have proven indispensable for three-dimensional (3D) cell culture but have fallen short in replicating the innate physiochemical complexity of real tissue. Though traditional photolithography affords localized material manipulation, robust methods that govern when, where, and to what extent such phototailoring occurs throughout materials would be profoundly enabling towards fabricating more-realistic 3D tissue constructs. Here, we introduce “grayscale image z-stack-guided multiphoton optical-lithography” (GIZMO) as a generalizable and intuitive strategy to rapidly photomodulate materials in full 3D non-binary patterns at submicron resolutions spanning large volumes (>mm3). Highlighting its versatility, we employ GIZMO to variably photopattern biomolecule release from, protein immobilization to, and degradation within hydrogels based on biologically derived or synthetic grayscale image stacks with unprecedented complexity. We anticipate that GIZMO will enable new opportunities to probe and manipulate cell fates, as well as to engineer complex functional tissue.
Counter-regulation of RNA stability by UPF1 and TDP43
Authors: Gomez Nicolas , Hsieh Caroline , Li Xingli , Dykstra Megan , Waksmacki Jacob , Altheim Christopher , Bechar Yoel , Klim Joseph , Zaepfel Benjamin , Rothstein Jeffrey , Tank Elizabeth EM , Barmada Sami J
Published: February 2024

RNA quality control is crucial for proper regulation of gene expression. Disruption of nonsense mediated mRNA decay (NMD), the primary RNA decay pathway responsible for the degradation of transcripts containing premature termination codons (PTCs), can disrupt development and lead to multiple diseases in humans and other animals. Similarly, therapies targeting NMD may have applications in hematological, neoplastic and neurological disorders. As such, tools capable of accurately quantifying NMD status could be invaluable for investigations of disease pathogenesis and biomarker identification. Toward this end, we assemble, validate, and apply a next-generation sequencing approach (NMDq) for identifying and measuring the abundance of PTC-containing transcripts. After validating NMDq performance and confirming its utility for tracking RNA surveillance, we apply it to determine pathway activity in two neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) characterized by RNA misprocessing and abnormal RNA stability. Despite the genetic and pathologic evidence implicating dysfunctional RNA metabolism, and NMD in particular, in these conditions, we detected no significant differences in PTC-encoding transcripts in ALS models or disease. Contrary to expectations, overexpression of the master NMD regulator UPF1 had little effect on the clearance of transcripts with PTCs, but rather restored RNA homeostasis through differential use and decay of alternatively poly-adenylated isoforms. Together, these data suggest that canonical NMD is not a significant contributor to ALS/FTD pathogenesis, and that UPF1 promotes neuronal survival by regulating transcripts with abnormally long 3’UTRs.
First positronium image of the human brainin vivo
Authors: Moskal P. , Baran J. , Bass S. , Choiński J. , Chug N. , Curceanu C. , Czerwiński E. , Dadgar M. , Das M. , Dulski K. , Eliyan K.V. , Fronczewska K. , Gajos A. , Kacprzak K. , Kajetanowicz M. , Kaplanoglu T. , Kapłon Ł. , Klimaszewski K. , Kobylecka M. , Korcyl G. , Kozik T. , Krzemień W. , Kubat K. , Kumar D. , Kunikowska J. , Mączewska J. , Migdał W. , Moskal G. , Mryka W. , Niedźwiecki S. , Parzych S. , Perez del Rio E. , Raczyński L. , Sharma S. , Shivani  , Shopa R.Y. , Silarski M. , Skurzok M. , Tayefi F. , Tayefi K. , Tanty P. , Wiślicki W. , Królicki L. , Stępień E. Ł.
Published: February 2024

Positronium, an unstable atom consisting of an electron and a positron, is abundantly produced within the molecular voids of a patient’s body during positron emission tomography (PET) diagnosis. Its properties, such as its average lifetime between formation and annihilation into photons, dynamically respond to the submolecular architecture of the tissue and the partial pressure of oxygen molecules. However, the diagnostic information that positronium may deliver about early molecular alterations remains unavailable in clinics with state-of-the-art PET scanners.

This study presents the firstin vivoimages of positronium lifetime in humans. We developed a dedicated J-PET system with multiphoton detection capability for imaging. The measurements of positronium lifetime were performed on a patient with a glioblastoma tumor in the brain. The patient was injected intratumorally with the68Ga radionuclide attached to Substance-P, which accumulates in glioma cells, and intravenously with68Ga attached to the PSMA-11 ligand, which is selective to glioma cells and salivary glands. The68Ga radionuclide is routinely used in PET for detecting radiopharmaceutical accumulation and was applied for positronium imaging because it can emit an additional prompt gamma. The prompt gamma enables the determination of the time of positronium formation, while the photons from positronium annihilation were used to reconstruct the place and time of its decay. The determined positronium mean lifetime in glioblastoma cells is shorter than in salivary glands, which in turn is shorter than in healthy brain tissues, demonstrating for the first time that positronium imaging can be used to diagnose diseasein vivo. This study also demonstrates that if current total-body PET systems were equipped with multiphoton detection capability and the44Sc radionuclide was applied, it would be possible to perform positronium imaging at 6500 times greater sensitivity than achieved in this research. Therefore, it is anticipated that positronium imaging has the potential to bring a new quality of cancer diagnosis in clinics.
Comparison of lipidomic profiles sampled with electroporation-based biopsy from healthy skin, squamous cell carcinoma, and basal cell carcinoma
Authors: Louie Leetal , Wise Julia , Berl Ariel , Shir-az Ofir , Kravtsov Vladimir , Yakhini Zohar , Shalom Avshalom , Golberg Alexander , Vitkin Edward
Published: February 2024

Incidence rates of cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are increasing, while the current diagnostic process is time consuming. We introduce a high-throughput sampling approach, termed e-biopsy, utilizing electroporation-based biopsy for efficient collection of tissue lipids. Our study identified 168 lipids using ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS-MS). The e-biopsy technique demonstrated its ability to profile the human skin lipidome. Comparative analysis revealed 27 differentially expressed lipids (p<0.05). The observed trend of lipidomic profiles was low diglycerides in cSCC and BCC, elevated phospholipids in BCC, and increased lyso-phospholipids in cSCC compared to healthy skin samples. These findings contribute to understanding skin cancers and highlight the potential of e-biopsy for lipidomic analysis in skin tissues.
A Nomogram to Predict Pneumothorax Requiring Chest Tube Placement following Percutaneous CT-guided Lung Biopsy
Authors: Bondarenko Masha , Zhang Jianxiang , Baal Ulysis Hugo , Lam Brian , Chaudhari Gunvant , Lee Yoo Jin , Schroeder Jamie , Vella Maya , Haas Brian , Vu Thienkhai , Kallianos Kimberly , Liu Jonathan , Sridhar Shravan , Elicker Brett , Sohn Jae Ho
Published: February 2024

Background

Pneumothorax requiring chest tube after CT-guided transthoracic lung biopsy is one of the common complications, and the required hospital stay after chest tube placement represents an added clinical risk to patients and cost to the healthcare system. Identifying high-risk patients can prompt alternative biopsy modes and/or better preparation for more focused post-procedural care.

Purpose

To develop and externally validate a risk nomogram for pneumothorax requiring chest tube placement following CT-guided lung biopsy, leveraging quantitative emphysema algorithm.

Materials & Methods

This two-center retrospective study included patients who underwent CT-guided lung biopsy from between 1994 and 2023. Data from one hospital was set aside for validation (n=613). Emphysema severity was quantified and categorized to 3-point scale using a previously published algorithm based on 3×3×3 kernels and Hounsfield thresholding, and a risk calculator was developed using forward variable selection and logistic regression. The model was validated using bootstrapping and Harrell’s C-index.

Results

2,512 patients (mean age, 64.47 years +/-13.38 [standard deviation]; 1250 men) were evaluated, of whom 157 (6.7%) experienced pneumothorax complications requiring chest tube placement. After forward variable selection to reduce the covariates to maximize clinical usability, the risk score was developed using age over 60 (OR 1.80 [1.15-2.93]), non-prone patient position (OR 2.48 [1.63-3.75]), and severe emphysema (OR 1.99 [1.35-2.94]). The nomogram showed mean absolute error of 0.5% in calibration and Harrell’s C-index of 0.664 in discrimination in the internal cohort.

Conclusion

The developed nomogram predicts age over 60, non-prone position during biopsy, and severe emphysema to be most predictive of pneumothorax requiring chest tube placement following CT-guided lung biopsy.
Human-like dissociations between confidence and accuracy in convolutional neural networks
Authors: Shekhar Medha , Rahnev Dobromir
Published: February 2024

Prior research has shown that manipulating stimulus energy by changing both stimulus contrast and variability results in confidence-accuracy dissociations in humans. Specifically, even when performance is matched, higher stimulus energy leads to higher confidence. The most common explanation for this effect is the positive evidence heuristic where confidence neglects evidence that disconfirms the choice. However, an alternative explanation is the signal-and-variance-increase hypothesis, according to which these dissociations arise from low-level changes in the separation and variance of perceptual representations. Because artificial neural networks lack built-in confidence heuristics, they can serve as a test for the necessity of confidence heuristics in explaining confidence-accuracy dissociations. Therefore, we tested whether confidence-accuracy dissociations induced by stimulus energy manipulations emerge naturally in convolutional neural networks (CNNs). We found that, across three different energy manipulations, CNNs produced confidence-accuracy dissociations similar to those found in humans. This effect was present for a range of CNN architectures from shallow 4-layer networks to very deep ones, such as VGG-19 and ResNet -50 pretrained on ImageNet. Further, we traced back the reason for the confidence-accuracy dissociations in all CNNs to the same signal-and-variance increase that has been proposed for humans: higher stimulus energy increased the separation and variance of the CNNs’ internal representations leading to higher confidence even for matched accuracy. These findings cast doubt on the necessity of the positive evidence heuristic to explain human confidence and establish CNNs as promising models for adjudicating between low-level, stimulus-driven and high-level, cognitive explanations of human behavior.
A Neural Signature of the Bias Towards Self-Focus
Authors: Geisler Danika , Meyer Meghan L.
Published: February 2024

People are remarkably self-focused, disproportionately choosing to think about themselves relative to other topics. Self-focus can be adaptive, helping individuals fulfill their needs. It can also go haywire, with maladaptive self-focus a risk and maintenance factor for internalizing disorders like depression. Yet, the drive to focus on the self remains to be fully characterized. We discovered a brain state that when spontaneously brought online during a quick mental break predicts the desire to focus on oneself just a few seconds later. In Study 1, we identified a default network neural signature from pre-trial activity that predicts multiple indicators of self-focus within our sample. In Study 2, we applied our neural signature to independent resting-state data from the Human Connectome project. We found that individuals who score high on internalizing, a form of maladaptive self-focus, similarly move in-and-out of this pattern during rest, suggesting a systematic trajectory towards self-focused thought. This is the first work to “decode” the bias to focus on the self and paves the way towards stopping maladaptive self-focus in its course.

Significance Statement

Self-help aisles in bookstores, the popularity of self-care culture, curating identities on social media, and the mental health crisis surrounding the rise in depression and anxiety are all symptoms of modern life’s emphasis on the self. Why are people so preoccupied with themselves? Our results suggest self-focus may emerge spontaneously because of the brain state people enter in the default network as soon as they have a mental break. The brain state participants entered in the first few seconds of rest could be used to decode whether they next chose to focus on themselves, as well as subjective and neural markers of self-focus. Moreover, internalizing, a maladaptive form of self-focus, corresponded with systematic timing of the pre-self pattern during a resting state scan, perhaps shaping the timecourse of spontaneous, self-focused thought.
Aging hastens locomotor decline in PINK1 knockout rats in association with decreased nigral, but not striatal, dopamine and tyrosine hydroxylase expression
Authors: Soto Isabel , McManus Robert , Navarrete-Barahona Walter , Kasanga Ella A. , Doshier Kirby , Nejtek Vicki A. , Salvatore Michael F.
Published: February 2024

Parkinson’s disease (PD) rodent models provide insight into the relationship between nigrostriatal dopamine (DA) signaling and locomotor function. Although toxin-based rat models produce frank nigrostriatal neuron loss and eventual motor decline characteristic of PD, the rapid nature of neuronal loss may not adequately translate premotor traits, such as cognitive decline. Unfortunately, rodent genetic PD models, like the Pink1 knockout (KO) rat, often fail to replicate the differential severity of striatal DA and tyrosine hydroxylase (TH) loss, and a bradykinetic phenotype, reminiscent of human PD. To elucidate this inconsistency, we evaluated aging as a progression factor in the timing of motor and non-motor cognitive impairments. Male PINK1 KO and age-matched wild type (WT) rats were evaluated in a longitudinal study from 3 to 16 months old in one cohort, and in a cross-sectional study of young adult (6-7 months) and aged (18-19 months) in another cohort. Young adult PINK1 KO rats exhibited hyperkinetic behavior associated with elevated DA and TH in the substantia nigra (SN), which decreased therein, but not striatum, in the aged KO rats. Additionally, norepinephrine levels decreased in aged KO rats in the prefrontal cortex (PFC), paired with a higher DA content in young and aged KO. Although a younger age of onset characterizes familial forms of PD, our results underscore the critical need to consider age-related factors. Moreover, the results indicate that compensatory mechanisms may exist to preserve locomotor function, evidenced by increased DA in the SN early in the lifespan, in response to deficient PINK1 function, which declines with aging and the onset of motor impairment.
Altered nuclear envelope homeostasis is a key pathogenic event in C9ORF72-linked ALS/FTD
Authors: Sirtori Riccardo , Gregoire Michelle , Collins Alicia , Santangelo Serena , Chatragadda Bhavya , Cullen Robert , Ratti Antonia , Fallini Claudia
Published: February 2024

ALS and FTD are complex neurodegenerative disorders that primarily affects motor neurons in the brain and spinal cord, and cortical neurons in the frontal lobe. Although the pathogenesis of ALS/FTD is unclear, recent research spotlights nucleocytoplasmic transport impairment, DNA damage, and nuclear abnormalities as drivers of neuronal death. In this study, we show that loss of nuclear envelope (NE) integrity is a key pathology associated with nuclear pore complex (NPC) injury inC9ORF72mutant neurons. Importantly, we show that mechanical stresses generated by cytoskeletal forces on the NE can lead to NPC injury, loss of nuclear integrity, and accumulation of DNA damage. Importantly, we demonstrate that restoring NE tensional homeostasis, by disconnecting the nucleus from the cytoskeleton, can rescue NPC injury and reduce DNA damage inC9ORF72mutant cells. Together, our data suggest that modulation of NE homeostasis and repair may represent a novel and promising therapeutic target for ALS/FTD.
TMEM63B functions as a mammalian thirst receptor
Authors: Zou Wenjie , Chen Xingyu , Ruan Jiamin , Deng Siqi , Wang Huize , Zhan Wuqiang , Wang Jingxin , Liu Zhiyong , Yan Zhiqiang
Published: February 2024

Thirst drives animals to reinstate water homeostasis by fluid intake. An increase of blood osmolality is thought to induce thirst by activating a thirst receptor expressed in the subfornical organ (SFO), but the molecular identity of this receptor remains elusive. Here, we provide behavioral and functional evidence to show that TMEM63B functions as a mammalian thirst receptor in the SFO and mediates osmotic and dehydrated thirst. First, we showed that TMEM63B is expressed in SFO excitatory neurons and required for the neuronal responses to hypertonic stimulation. Heterologously expressed TMEM63B is activated by hypertonic stimuli and point mutations can alter the reversal potential of the channel. More importantly, purified TMEM63B in liposomes establishes osmolarity-gated currents. Finally, Tmem63b knockout mice have profound deficits in thirst, and deleting TMEM63B within the SFO neurons recapitulated this phenotype. Taken together, these results provide a molecular basis for thirst 82and demonstrate TMEM63B is the long-sought mammalian thirst receptor.
Representational dissimilarity component analysis (ReDisCA)
Authors: Ossadtchi Alexei , Semenkov Ilia , Zhuravleva Anna , Kozunov Vladimir , Serikov Oleg , Voloshina Ekaterina
Published: February 2024

The principle of Representational Similarity Analysis (RSA) posits that neural representations reflect the structure of encoded information, allowing exploration of spatial and temporal organization of brain information processing. Traditional RSA when applied to EEG or MEG data faces challenges in accessing activation time series at the brain source level due to modeling complexities and insufficient geometric/anatomical data.

To address this, we introduce Representational Dissimilarity Component Analysis (ReDisCA), a method for estimating spatial-temporal components in EEG or MEG responses aligned with a target representational dissimilarity matrix (RDM). ReDisCA yields informative spatial filters and associated topographies, offering insights into the location of “representationally relevant” sources. Applied to evoked response time series, ReDisCA produces temporal source activation profiles with the desired RDM. Importantly, while ReDisCA does not require inverse modeling its output is consistent with EEG and MEG observation equation and can be used as an input to rigorous source localization procedures.

Demonstrating ReDisCA’s efficacy through simulations and comparison with conventional methods, we show superior source localization accuracy and apply the method to real EEG and MEG datasets, revealing physiologically plausible representational structures without inverse modeling. ReDisCA adds to the family of inverse modeling free methods such as independent component analysis [34], Spatial spectral decomposition [41], and Source power comodulation [9] designed for extraction sources with desired properties from EEG or MEG data. Extending its utility beyond EEG and MEG analysis, ReDisCA is likely to find application in fMRI data analysis and exploration of representational structures emerging in multilayered artificial neural networks.
Multiple Loci for Foveolar Vision in Macaque Monkey
Authors: Qian Meizhen , Wang Jianbao , Gao Yang , Chen Ming , Liu Yin , Zhou Dengfeng , Lu Haidong , Zhang Xiaotong , Hu Jiaming , Roe Anna Wang
Published: February 2024

A common tenet of neural sensory representation is that species-specific behaviors are reflected in specialized brain organizations1. In humans and nonhuman primates, the central one degree of vision is processed by the foveola2, a retinal structure which comprises a high density of photoreceptors and is crucial for primate-specific high acuity vision, color vision, and gaze-directed visual attention3,4,5. In this study, we have developed high spatial resolution ultrahigh field 7T fMRI methods for functional mapping of foveolar visual cortex in awake monkeys. We provide evidence that, in the ventral pathway (V1-V4 and TEO), viewing of a central small spot elicits a ring of multiple (at least 8) foveolar representations per hemisphere. This ring surrounds a large area called the ‘foveolar core’. This is an area populated by millimeter-scale functional domains sensitive to fine stimuli and high spatial frequencies, consistent with foveolar visual acuity, as well as color and achromatic information, and motion. The unique position of the foveolar core suggests it may be a hub subserving higher order needs of foveolar function, such as integrating different spatial scales of representation, integrating local and global features in object perception, and bringing together the four quadrants of visual space. Thus, this elaborate re-representation of central vision signifies a cortical specialization for various foveation behaviors.
Direct modulation of TRPM8 ion channels by rapamycin and analog macrolide immunosuppressants
Authors: Tóth Balázs István , Bazeli Bahar , Janssens Annelies , Lisztes Erika , Racskó Márk , Kelemen Balázs , Herczeg Mihály , Nagy Tamás Milán , Kövér Katalin E. , Mitra Argha , Borics Attila , Bíró Tamás , Voets Thomas
Published: February 2024

Rapamycin (sirolimus), a macrolide compound isolated from the bacteriumStreptomyces hygroscopicus, is widely used as oral medication for the prevention of transplant rejection and the treatment of lymphangioleiomyomatosis. It is also incorporated in coronary stent coatings to prevent restenosis and in topical preparations for the treatment of skin disorders. Rapamycin’sin vivoactivities are generally ascribed to its binding to the protein FKBP12, leading to potent inhibition of the mechanistic target of rapamycin kinase (mTOR) by the FKBP12-rapamycin complex. The specific rapamycin-induced interaction between domains from mTOR and FKBP12 is also frequently employed in cell biological research, for rapid chemically-induced protein dimerization strategies. Here we show that rapamycin activates TRPM8, a cation channel expressed in sensory nerve endings that serves as the primary cold sensor in mammals. Using a combination of electrophysiology, Saturation Transfer Triple-Difference (STTD) NMR spectroscopy and molecular docking-based targeted mutagenesis, we demonstrate that rapamycin directly binds to TRPM8. We identify a rapamycin-binding site in the groove between voltage sensor-like domain and the pore domain, distinct from the interaction sites of cooling agents and known TRPM8 agonists menthol and icilin. Related macrolide immunosuppressants act as partial TRPM8 agonists, competing with rapamycin for the same binding site. These findings identify a novel molecular target for rapamycin and provide new insights into the mechanisms of TRPM8 activation, which may assist in the development of therapies targeting this ion channel. Moreover, our findings also indicate that caution is needed when using molecular approaches based on rapamycin-induced dimerization to study ion channel regulation.
The timescale and functional form of context-dependence during human value-learning
Authors: Tohidi-Moghaddam Maryam , Tsetsos Konstantinos
Published: February 2024

Contrary to the predictions of normative theories, choices between two high-value alternatives can be biased by the introduction of a third low-value alternative (dubbed the distractor effect). Normalization-based theories, like divisive and range normalization, explain different forms of the distractor effect by suggesting that the value of each alternative is normalized by a summary statistic of the values encountered in a particular decision context. The decision context can include alternatives encountered over an extended timeframe (temporal context); and alternatives that are available for choice on a given instance (immediate context). To date, the extent to which the immediate and temporal context (co-) shape context-dependent value representations remains unclear. To investigate this, we designed a task in which participants learned the values associated with three different alternatives and provided explicit value estimates before making a series of choices among ternary and binary combinations of those alternatives. We show that context-dependence already emerges in the pre-choice value estimates and is equally present in binary and ternary choice trials. Based on these findings, we conclude that the temporal (and not the immediate) context modulates subjective value representations. Interestingly, the functional form of context-dependence we report runs against both divisive and range normalization theories. Instead, our data are best explained by a stochastic rank-based model, according to which the value of an alternative is distorted by a series of memory-based binary comparisons with previously encountered alternatives.
Energy scarcity and impaired mitochondrial translation induce perinuclear stress granule clustering
Authors: Fernandez-Pelayo Uxoa , Muñoz-Oreja Mikel , Villar-Fernandez Marina , de Arbina Amaia Lopez , Aiestaran-Zelaia Irati , Sánchez-Guisado María Jesús , Pantic Boris , Elicegui Amaia , Zufiria Monica , Iruzubieta Pablo , Sagartzazu-Aizpurua Maialen , Aizpurua Jesús M. , Gegg Matthew , Alonso-Martin Sonia , Ruiz-Cabello Jesus , Gil-Bea Francisco , Spinazzola Antonella , de Munain Adolfo Lopez , Holt Ian James
Published: February 2024

Many proteins linked to amyotrophic lateral sclerosis and fronto-temporal dementia (ALS-FTD) change their cellular location and coalesce in cytoplasmic inclusion bodies in the disease state; yet the factors that govern protein relocation and organization remain unclear. Here, we show that inhibition of glycolysis and mitochondrial protein synthesis causes many proteins involved in ALS-FTD to change location, and form a novel structure comprising a ring of stress granules encircling the aggresome, a focal microtubule-based structure beside the nucleus. A perinuclear ring of stress granules also forms in activated microglia of mice exposed to the glycolytic inhibitor, 2-Deoxy-D-glucose. We propose that the new arrangement increases the risk of the stress granules merging and converting from the liquid phase to the insoluble inclusion characteristic of ALS-FTD. Thus, our findings suggest that that compromised nutrient and energy metabolism can precipitate a molecular cascade that ultimately leads to the pathological hallmark of ALS-FTD the perinuclear inclusion body.

Graphical abstract

Inhibition of glycolysis and mitochondrial protein synthesis induces translocation of a swathe of ALS-FTD related proteins in primary human fibroblasts. The relocated proteins form concentric cytoplasmic rings (CCR) comprising stress granules, the Golgi and the aggresome, beside the nucleus. A perinuclear ring of stress granules forms in the mouse brain following intermittent nutrient restriction, with the glucose analog 2DG. The CCR is potentially a key intermediate step in the formation of pathological inclusions and so perturbed nutrient and energy metabolism encompassing impaired mitochondrial translation could precipitate the ALS-FTD disease cascade.
Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Mice
Authors: Chang Wei-li , Tegang Karly , Samuels Benjamin A. , Saxe Michael , Wichmann Juergen , David Denis J. , David Indira Mendez , Augustin Angélique , Fischer Holger , Golling Sabrina , Lamerz Jens , Roth Doris , Graf Martin , Zoffmann Sannah , Santarelli Luca , Jagasia Ravi , Hen René
Published: February 2024

BACKGROUND

Impairments in behavioral pattern separation (BPS)—the ability to distinguish between similar contexts or experiences—contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, PTSD, dementia, and age-related cognitive decline. While BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis (AHN), its significance as a pharmacological target has not been tested.

METHODS

In this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis. One compound with a favorable profile, RO6871135, was then tested in BPS in mice.

RESULTS

Chronic treatment with RO6871135, 7.5 mg/kg increased AHN and improved BPS in a fear discrimination task in both young and aged mice. RO6871135 treatment also lowered innate anxiety-like behavior, which was more apparent in mice exposed to chronic corticosterone. Ablation of AHN by hippocampal irradiation supported a neurogenesis-dependent mechanism for RO6871135-induced improvements in BPS. To identify possible mechanisms of action, in vitro and in vivo kinase inhibition and chemical proteomics assays were performed. These tests indicated that RO6871135 inhibited CDK8, CDK11, CaMK2a, CaMK2b, MAP2K6, and GSK3b. An analog compound also demonstrated high affinity for CDK8, CaMK2a, and GSK3b.

CONCLUSIONS

These studies demonstrate a method for empirical identification and preclinical testing of novel neurogenic compounds that can improve BPS, and points to possible novel mechanisms that can be interrogated for the development of new therapies to improve specific endophenotypes such as impaired BPS.
Distractor suppression operates exclusively in retinotopic coordinates
Authors: Ilksoy Yayla A. , van Moorselaar Dirk , Wang Benchi , Los Sander A. , Theeuwes Jan
Published: February 2024

Our attention is influenced by past experiences, and recent studies have shown that individuals learn to extract statistical regularities in the environment, resulting in attentional suppression of locations that are likely to contain a distractor (high-probability location). However, little is known as to whether this learned suppression operates in retinotopic (relative to the eyes) or spatiotopic (relative to the world) coordinates. In the current study, two circular search arrays were presented side by side. Participants learned the high-probability location from a learning array presented on one side of the display (e.g., left). After several trials, participants shifted their gaze to the center of the other search array (e.g., located on the right side) and continued searching without any location probability (labelled as “test array”). Due to the saccade, the test array contained both a spatiotopic and a retinotopic matching location relative to the original high-probability location. The current findings show that, following saccadic eye movements, the learned suppression remained in retinotopic coordinates only, with no measurable transfer to spatiotopic coordinates. Even in a rich environment, attentional suppression still operated exclusively in retinotopic coordinates. We speculate that learned suppression may be resolved by changing synaptic weights in early visual areas.

Significance statement

In our daily lives, attention is shaped by past experiences, guiding us to suppress locations that are likely to contain distractions. While this phenomenon has been studied extensively with static search displays, the real world is dynamic - we are constantly moving our eyes. This study addressed this issue by investigating what happens when we learn to suppress a likely distractor location while making eye movements. Do we suppress the same location in space (spatiotopic), or does the learned suppression persist relative to our eyes (retinotopic)? The current findings provide clear evidence of suppression in retinotopic coordinates only.
Neural substrates underlying the expectation of rewards resulting from effortful exertion
Authors: Kim Aram , Chib Vikram S.
Published: February 2024

Expectations as a reference point shape our decisions to motivate effortful activity. Despite the important role of reference points in human performance, little is known about how the brain processes expectations to guide motivated exertion. Participants completed a reward-based effort task in an MRI scanner. During each trial, participants were presented with a risky option that would either result in a fixed monetary payment, regardless of their effort exertion, or a piece-rate payment where the payment was proportional to the amount of effort exerted. We found that participants exerted more effort as the fixed payment increased, suggesting that the fixed payment influenced the reference point for effort exertion. The strength of this reference-dependent behavior was correlated with neural activity in the ventral striatum, which was significantly modulated by the deviation from the payoff to reward expectations after effort exertion. Our results suggest that value-related brain areas, particularly the ventral striatum, encode expectations of reward as a reference point to motivate effort exertion.

One-Sentence Summary

Value-related brain areas process reward expectations and how we evaluate outcomes based on that.
Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst
Authors: Simon Claire S. , McCarthy Afshan , Woods Laura , Staneva Desislava , Huang Qiulin , Linneberg-Agerholm Madeleine , Faulkner Alex , Papathanasiou Athanasios , Elder Kay , Snell Phil , Christie Leila , Garcia Patricia , Shaikly Valerie , Taranissi Mohamed , Choudhary Meenakshi , Herbert Mary , Brickman Joshua M. , Niakan Kathy K.
Published: February 2024

Studies in the mouse demonstrate the importance of fibroblast growth factor (FGF) and extra-cellular receptor tyrosine kinase (ERK) in specification of embryo-fated epiblast and yolk-sac-fated hypoblast cells from uncommitted inner cell mass (ICM) cells prior to implantation. Molecular mechanisms regulating specification of early lineages in human development are comparatively unclear. Here we show that exogenous FGF stimulation leads to expanded hypoblast molecular marker expression, at the expense of the epiblast. Conversely, we show that specifically inhibiting ERK activity leads to expansion of epiblast cells functionally capable of giving rise to naïve human pluripotent stem cells. Single-cell transcriptomic analysis indicates that these epiblast cells downregulate FGF signalling and upregulate molecular markers associated with naïve pluripotency. Our functional study demonstrates for the first time the molecular mechanisms governing ICM specification in human development, whereby segregation of the epiblast and hypoblast lineages occurs during maturation of the mammalian embryo in an ERK signal-dependent manner.
Deep learning-based location decoding reveals that across-day representational drift is better predicted by rewarded experience than time
Authors: Freud Kipp , Lepora Nathan , Jones Matt W. , O’Donnell Cian
Published: February 2024

Neural representations of locational and spatial relations in the hippocampus and related brain areas change over timescales of days-weeks, even in familiar contexts and when behavior appears stable. It remains unclear how this ‘representational drift’ is driven by combinations of the passage of time, general experience or specific features of experience. We present a novel deep-learning approach for measuring network-level representational drift, quantifying drift as the rate of change in decoder error of deep neural networks as a function of train-test lag. Using this method, we analyse a longitudinal dataset of 0.5–475 Hz broadband local field potential (LFP) data recorded from dorsal hippocampal CA1, medial prefrontal cortex and parietal cortex of six rats over ∼30 days, during learning of a spatial navigation task in an initially unfamiliar environment. All three brain regions contained clear spatial representations which evolve and drift over training sessions. We find that the rate of drift slows for later training sessions. Finally, we find that drift is statistically better explained by task-relevant experiences within the maze, rather than the passage of time or number of sessions the animal spent on the maze. While previous research has focused on drift as a measure of the changes in spiking activities of units, here we examine drift as a measure of change in oscillatory activity of local field potentials; our approach of using of deep neural networks to quantify drift in broadband neural time series unlocks new possibilities for defining the drivers and functional consequences of representational drift.
NeuroTri2-VISDOT: An open-access tool to harness the power of second trimester human single cell data to inform models of Mendelian neurodevelopmental disorders
Authors: Clark Kelly J. , Lubin Emily E. , Gonzalez Elizabeth M. , Sangree Annabel K. , Layo-Carris Dana E. , Durham Emily L. , Ahrens-Nicklas Rebecca C. , Nomakuchi Tomoki T. , Bhoj Elizabeth J.
Published: February 2024

Whole exome and genome sequencing, coupled with refined bioinformatic pipelines, have enabled improved diagnostic yields for individuals with Mendelian conditions and have led to the rapid identification of novel syndromes. For many Mendelian neurodevelopmental disorders (NDDs), there is a lack of pre-existing model systems for mechanistic work. Thus, it is critical for translational researchers to have an accessible phenotype- and genotype-informed approach for model system selection. Single-cell RNA sequencing data can be informative in such an approach, as it can indicate which cell types express a gene of interest at the highest levels across time. For Mendelian NDDs, such data for the developing human brain is especially useful. A valuable single-cell RNA sequencing dataset of the second trimester developing human brain was produced by Bhaduri et al in 2021, but access to these data can be limited by computing power and the learning curve of single-cell data analysis. To reduce these barriers for translational research on Mendelian NDDs, we have built the web-based tool,Neurodevelopment inTrimester2-VIsualization ofSingle cellDataOnlineTool (NeuroTri2-VISDOT), for exploring this single-cell dataset, and we have employed it in several different settings to demonstrate its utility for the translational research community.
Task-irrelevant phase but not contrast variability unlocks generalization in visual perceptual learning
Authors: Akkoyunlu Beyza , Schwiedrzik Caspar M.
Published: February 2024

Performance on visual tasks can be improved by practice, a process called visual perceptual learning. However, learning-induced performance improvements are often limited to the specific stimuli and visual field locations used during training. Recent research has shown that variability along task-irrelevant stimulus dimensions during training can reduce this specificity. This has been related to higher stages of visual processing that harbor neurons which are invariant to the task-irrelevant dimension. Here, we test whether task-irrelevant trial-by-trial variability in two visual features for which invariances arise at different stages of processing, contrast and spatial phase, results in different degrees of generalization in space in an orientation discrimination task. We find that randomizing spatial phase results in complete generalization of learning to a new spatial location, contrary to randomizing contrast. Our results thus suggest that the neural population undergoing plasticity in visual perceptual learning is determined by the training task, which, in turn, affects generalization. This lends further support to the hypothesis that task-irrelevant variability is an independent factor in determining the specificity of perceptual learning.
Rapid Invisible Frequency Tagging (RIFT) in a novel setup with EEG
Authors: Arora Kabir , Gayet Surya , Kenemans J. Leon , Van der Stigchel Stefan , Chota Samson
Published: February 2024

Steady-State Visual Evoked Potentials (SSVEPs) provide a report-free and continuous measure of neural processing. Recent progress in display technology has allowed for the tagging of multiple stimuli simultaneously at >60Hz frequencies - high enough to evade perceptibility, while still evoking an oscillatory neural response. Known as Rapid Invisible Frequency Tagging (RIFT), this technique has currently only been used in combination with Magnetoencephalography (MEG), which is less accessible compared to Electroencephalography (EEG). Although responses to LEDs flickering at similar frequencies have been shown in EEG, it is currently unclear whether RIFT, using a more conventional stimulus display, can sufficiently evoke a response in EEG, and therefore whether it is worth adding the RIFT-EEG pairing to the cognitive neuroscientist’s toolkit. Here, we successfully implement the first RIFT-EEG setup. We show that the oscillatory input is measurable in the EEG trace, what its topographical spread is, a rough range of applicable frequencies, and that this response is comparable to that evoked in MEG.