bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic connectivity profiles characteristic of conscious states are associated with enhanced conscious processing of external stimuli
Authors: Türker Başak , Manasova Dragana , Béranger Benoît , Naccache Lionel , Sergent Claire , Sitt Jacobo D.
Published: January 2024

One of the goals of the neuroscience of consciousness is to identify neural markers capable of distinguishing brain dynamics in awake, healthy individuals from unconscious conditions. This problem also has a clinical diagnostic interest in disorders of consciousness. Recent research has shown that brain connectivity patterns characterized by long-range interactions and anticorrelations are associated with conscious states and diminish with loss of consciousness in human and non-human primates. However, the precise contribution of these patterns to conscious processing and subjective experience formation remains unclear. In this study, we investigated the functional role of these brain patterns in shaping conscious content by examining their influence on participants’ ability to process external information during wakefulness. Participants underwent fMRI recordings during an auditory detection task. Phase coherence-based functional connectivity and k-means clustering confirmed that the ongoing dynamics were underpinned by brain patterns consistent with those identified in previous research, including the “high pattern” characteristic of conscious states. We found that the detection of auditory stimuli at threshold was specifically improved when the connectivity pattern at the time of presentation corresponded to this high-pattern. In return, the occurrence of the high-pattern increased after detection, indicating that participants were more likely to transition to a high-pattern following stimulus detection. Our findings suggest that ongoing brain dynamics and conscious perception mutually influence each other and that certain brain configurations are more favorable for conscious processing of external stimuli. In the future, targeting these moments of favorable patterns in patients with disorders of consciousness may help us identify windows of greater receptivity to the external world, paving the way for developing individualized patient care protocols.
A Subcortical Model for Auditory Forward Masking with Efferent Control of Cochlear Gain
Authors: Maxwell Braden N. , Farhadi Afagh , Brennan Marc A. , Svec Adam , Carney Laurel H.
Published: January 2024

Previous physiological and psychophysical studies have explored whether feedback to the cochlea from the efferent system influences forward masking. The present work proposes that the limited growth-of-masking (GOM) observed in auditory-nerve (AN) fibers may have been misunderstood; namely, that this limitation may be due to the influence of anesthesia on the efferent system. Building on the premise that the unanesthetized AN may exhibit GOM similar to more central nuclei, the present computational modeling study demonstrates that feedback from the medial olivocochlear (MOC) efferents may account for GOM observed physiologically in onset-type neurons in both the cochlear nucleus and inferior colliculus (IC). Additionally, the computational model of MOC efferents used here generates a decrease in masking with longer masker-signal delays similar to that observed in IC physiology and in psychophysical studies. An advantage of this explanation over alternative physiological explanations (e.g., that forward masking requires inhibition from the superior paraolivary nucleus) is that this theory can explain forward masking observed in the brainstem, early in the ascending pathway. For explaining psychoacoustic results, one strength of this model is that it can account for the lack of elevation in thresholds observed when masker level is randomly varied from interval-to-interval, a result that is difficult to explain using the conventional temporal-window model of psychophysical forward masking. Future directions for evaluating the efferent mechanism as a contributing mechanism for psychoacoustical results are discussed.

Significance Statement

The simulations presented here demonstrate that a recent computational model of the auditory subcortex including medial-olivocochlear efferents generates forward masking, an increase in detection threshold for a short probe tone following a preceding sound. This model explains results from physiological recordings and suggests potential connections to psychoacoustic experiments. The theory that efferent control of cochlear gain is a contributing mechanism for forward masking has several advantages. This theory can explain the strength of masking exhibited by cochlear nucleus neurons, a phenomenon not explained by current physiological theories in which the strength of forward-masking is not increased relative to the periphery until later in the ascending pathway. Additionally, this theory explains results for a psychoacoustic task with random variation in masker level, results not explained by the theory that persistent masker energy interferes with detection of the probe.
Retrieval of human aversive memories involves reactivation of gamma activity patterns in the hippocampus that originate in the amygdala during encoding
Authors: Costa Manuela , Pacheco Daniel , Gil-Nagel Antonio , Toledano Rafael , Imbach Lukas , Sarnthein Johannes , Strange Bryan A.
Published: January 2024

Emotional memories require coordinated activity of the amygdala and hippocampus. Human intracranial recordings have shown that formation of aversive memories involves an amygdala theta-hippocampal gamma phase code. Yet, the mechanisms engaged during translation of aversive experiences into memories and subsequent retrieval remain unclear. Directly recording from human amygdala and hippocampus, here we show that hippocampal gamma activity increases for correctly remembered aversive scenes, while exerting unidirectional oscillatory influence within the theta/beta frequency range on the amygdala for previously seen aversive scenes. Crucially, patterns of amygdala high amplitude gamma activity at encoding are reactivated in the hippocampus, but not amygdala, during both aversive encoding and retrieval. Trial-specific hippocampal gamma patterns showing highest representational similarity with amygdala activity at encoding are replayed in the hippocampus during aversive retrieval. This reactivation process occurs against a background of gamma activity that is otherwise decorrelated between encoding and retrieval. Thus, retrieval of aversive memories is hippocampal-centered, with hippocampal activity patterns apparently entrained by the amygdala during encoding.
Diffusion-limited cytokine signaling in T cell populations
Authors: Brunner Patrick , Kiwitz Lukas , Li Lisa , Thurley Kevin
Published: January 2024

Effective immune-cell responses depend on collective decision-making mediated by diffusible intercellular signaling proteins called cytokines. Here, we designed a spatio-temporal modeling framework and a precise finite-element simulation setup, to systematically investigate the origin and consequences of spatially inhomogeneous cytokine distributions in lymphoid tissues. We found that such inhomogeneities are critical for effective paracrine signaling, and they do not arise by diffusion and uptake alone, but rather depend on properties of the cell population such as an all-or-none behavior of cytokine secreting cells. Furthermore, we assessed the regulatory properties of negative and positive feedback in combination with diffusion-limited signaling dynamics, and we derived statistical quantities to characterize the spatio-temporal signaling landscape in the context of specific tissue architectures. Overall, our simulations highlight the complex spatiotemporal dynamics imposed by cell-cell signaling with diffusible ligands, which entails a large potential for fine-tuned biological control especially if combined with feedback mechanisms.
Altered physiological, affective, and functional connectivity responses to acute stress in patients with alcohol use disorder
Authors: Schwarze Yana , Voges Johanna , Schröder Alexander , Dreeßen Sven , Voß Oliver , Krach Sören , Paulus Frieder Michel , Junghanns Klaus , Rademacher Lena
Published: January 2024

Background

There is evidence that the processing of acute stress is altered in alcohol use disorder (AUD), but little is known about how this is manifested simultaneously across different stress parameters and which neural processes are involved. The present study examined physiological and affective responses to stress and functional connectivity in AUD.

Methods

Salivary cortisol samples, pulse rate, and affect ratings were collected on two days from 34 individuals with moderate or severe AUD and 34 controls. On one day, stress was induced, and on the other day, a non-stressful control task was performed. Following the intervention, participants underwent fMRI to assess functional connectivity, focusing on cortical and subcortical seed regions previously reported to be involved in AUD and/or stress.

Results

For pulse rate and cortisol, stress responses were blunted in AUD, whereas negative affect was increased. Furthermore, stress-related changes in pulse rate, cortisol, and affect were only correlated in healthy controls. Neuroimaging analyses revealed stress-related group differences in functional connectivity, involving the connectivity of striatal seeds with the posterior DMN, cerebellum and midcingulate cortex, and of the posterior DMN seed with the striatum and thalamus.

Conclusions

The results suggest a dissociation between subjective experienced distress and the physiological stress response in AUD as well as stress-related alterations in functional connectivity. These findings highlight the complex interplay between chronic alcohol use and acute stress regulation, offering valuable considerations for the development of therapeutic strategies.
Correlating fluorescence microscopy, optical and magnetic tweezers to study single chiral biopolymers such as DNA
Authors: Shepherd Jack W , Guilbaud Sebastien , Zhou Zhaokun , Howard Jamieson , Burman Matthew , Schaefer Charley , Kerrigan Adam , Steele-King Clare , Noy Agnes , Leake Mark C
Published: January 2024

Biopolymer topology is critical for determining interactions inside cell environments, exemplified by DNA where its response to mechanical perturbation is as important as biochemical properties to its cellular roles. The dynamic structures of chiral biopolymers exhibit complex dependence with extension and torsion, however the physical mechanisms underpinning the emergence of structural motifs upon physiological twisting and stretching are poorly understood due to technological limitations in correlating force, torque and spatial localization information. We present COMBI-Tweez (Combined Optical and Magnetic BIomolecule TWEEZers), a transformative tool that overcomes these challenges by integrating optical trapping, time-resolved electromagnetic tweezers, and fluorescence microscopy, demonstrated on single DNA molecules, that can controllably form and visualise higher order structural motifs including plectonemes. This technology combined with cutting-edge MD simulations provides quantitative insight into complex dynamic structures relevant to DNA cellular processes and can be adapted to study a range of filamentous biopolymers.
A robust and inducible precise genome editing via an all-in-one prime editor in human pluripotent stem cells
Authors: Wu Youjun , Zhong Aaron , Sidharta Mega , Kim Tae Wan , Ramirez Bernny , Persily Benjamin , Studer Lorenz , Zhou Ting
Published: January 2024

Prime editing (PE) allows for precise genome editing in human pluripotent stem cells (hPSCs), such as introducing single nucleotide modifications, small deletions, or insertions at a specific genomic locus, a strategy that shows great promise for creating “Disease in a dish” models. To improve the effectiveness of prime editing in hPSCs, we systematically compared and combined the “inhibition of mismatch repair pathway and p53” on top of the “PEmax” to generate an all-in-one “PE-Plus” prime editor. We show that PE-Plus conducts the most efficient editing among the current PE tools in hPSCs. We further established an inducible prime editing platform in hPSCs by incorporating the all-in-one PE vector into a safe-harbor locus and demonstrated temporal control of precise editing in both hPSCs and differentiated cells. By evaluating disease-associated mutations, we show that this platform allows efficient creation of both monoallelic and biallelic disease-relevant mutations in hPSCs. In addition, this platform enables the efficient introduction of single or multiple edits in one step, demonstrating potential for multiplex editing. Therefore, our method presents an efficient and controllable multiplex prime editing tool in hPSCs and their differentiated progeny.
Self-Supervised Transformer Model Training for a Sleep-EEG Foundation Model
Authors: Ogg Mattson , Coon William G.
Published: January 2024

The American Academy of Sleep Medicine (AASM) recognizes five sleep/wake states (Wake, N1, N2, N3, REM), yet this classification schema provides only a high-level summary of sleep and likely overlooks important neurological or health information. New, data-driven approaches are needed to more deeply probe the information content of sleep signals. Here we present a self-supervised approach that learns the structure embedded in large quantities of neurophysiological sleep data. This masked transformer training procedure is inspired by high performing self-supervised methods developed for speech transcription. We show that self-supervised pre-training matches or outperforms supervised sleep stage classification, especially when labeled data or compute-power is limited. Perhaps more importantly, we also show that our pre-trained model is flexible and can be fine-tuned to perform well on new EEG recording montages not seen in training, and for new tasks including distinguishing individuals or quantifying “brain age” (a potential health biomarker). This suggests that modern methods can automatically learn information that is potentially overlooked by the 5-class sleep staging schema, laying the groundwork for new sleep scoring schemas and further data-driven exploration of sleep.
Laying the Foundation: Modern Transformers for Gold-Standard Sleep Analysis and Beyond
Authors: Coon William G. , Ogg Mattson
Published: January 2024

Accurate sleep assessment is critical to the practice of sleep medicine and sleep research. The recent availability of large quantities of publicly available sleep data, alongside recent breakthroughs in AI like transformer architectures, present novel opportunities for data-driven discovery efforts. Transformers are flexible neural networks that not only excel at classification tasks, but also can enable data-driven discovery through un-or self-supervised learning, which requires no human annotations to the input data. While transformers have been extensively used in supervised learning scenarios for sleep stage classification, they have not been fully explored or optimized in forms designed from the ground up for use in un-or self-supervised learning tasks in sleep. A necessary first step will be to study these models on a canonical benchmark supervised learning task (5-class sleep stage classification). Hence, to lay the groundwork for future data-driven discovery efforts, we evaluated optimizations of a transformer-based architecture that has already demonstrated substantial success in self-supervised learning in another domain (audio speech recognition), and trained it to perform the canonical 5-class sleep stage classification task, to establish foundational baselines in the sleep domain. We found that small transformer models designed from the start for (later) self-supervised learning can match other state-of-the-art automated sleep scoring techniques, while also providing the basis for future data-driven discovery efforts using large sleep data sets.
Single-cell morphodynamical trajectories enable prediction of gene expression accompanying cell state change
Authors: Copperman Jeremy , Mclean Ian C. , Gross Sean M. , Singh Jalim , Chang Young Hwan , Zuckerman Daniel M. , Heiser Laura M.
Published: January 2024

Extracellular signals induce changes to molecular programs that modulate multiple cellular phenotypes, including proliferation, motility, and differentiation status. The connection between dynamically adapting phenotypic states and the molecular programs that define them is not well understood. Here we develop data-driven models of single-cell phenotypic responses to extracellular stimuli by linking gene transcription levels to “morphodynamics” – changes in cell morphology and motility observable in time-lapse image data. We adopt a dynamics-first view of cell state by grouping single-cell trajectories into states with shared morphodynamic responses. The single-cell trajectories enable development of a first-of-its-kind computational approach to map live-cell dynamics to snapshot gene transcript levels, which we term MMIST, Molecular and Morphodynamics-Integrated Single-cell Trajectories. The key conceptual advance of MMIST is that cell behavior can be quantified based on dynamically defined states and that extracellular signals alter the overall distribution of cell states by altering rates of switching between states. We find a cell state landscape that is bound by epithelial and mesenchymal endpoints, with distinct sequences of epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET) intermediates. The analysis yields predictions for gene expression changes consistent with curated EMT gene sets and provides a prediction of thousands of RNA transcripts through extracellular signal-induced EMT and MET with near-continuous time resolution. The MMIST framework leverages true single-cell dynamical behavior to generate molecular-level omics inferences and is broadly applicable to other biological domains, time-lapse imaging approaches and molecular snapshot data.

Epithelial cells change behavior and state in response to signals, which is necessary for the function of healthy tissue, while aberrant responses can drive diseases like cancer. To decode and potentially steer these responses, there is a need to link live-cell behavior to molecular programs, but high-throughput molecular measurement is generally destructive or requires fixation. Here we present a novel method which connects single-cell morphology and motility over time to bulk molecular readouts. Our model predicts gene expression from the observation of label-free live-cell imaging, as a step toward understanding and ultimately controlling cell state change.
Evaluation of the potential food allergy risks of recombinant human lactoferrin expressed inKomagataella phaffii
Authors: Anaya Yanisa , Rosario Martinez Raysa , Goodman Richard E. , Johnson Philip , Vajpeyi Shashwat , Lu Xiaoning , Peterson Ross , Weyers Sarah M. , Breen Bella , Newsham Kahler , Scottoline Brian , Clark Anthony , Malinczak Carrie-Anne
Published: January 2024

Prior to the introduction of novel food ingredients into the food supply, safety risk assessments are required, and numerous prediction models have been developed and validated to evaluate safety. The allergenic risk potential of Helaina recombinant human lactoferrin (rhLF, Effera™), produced inKomagataella phaffii(K. phaffii) was assessed by literature search, bioinformatics sequence comparisons to known allergens, glycan allergenicity assessment, and a simulated pepsin digestion model. The literature search identified no allergenic risk for Helaina rhLF,K. phaffii, or its glycans. Bioinformatics search strategies showed no significant risk for cross-reactivity or allergenicity between rhLF or the 36 residual host proteins and known human allergens. Helaina rhLF was also rapidly digested in simulated gastric fluid and its digestibility profile was comparable to human milk lactoferrin (hmLF), further demonstrating a low allergenic risk and similarity to the hmLF protein. Collectively, these results demonstrate a low allergenic risk potential of Helaina rhLF and do not indicate the need for further clinical testing or serum IgE binding to evaluate Helaina rhLF for risk of food allergy prior to introduction into the food supply.
Characterization of transcriptional heterogeneity and novel therapeutic targets using single cell RNA-sequencing of primary and circulating Ewing sarcoma cells
Authors: Goodspeed Andrew , Bodlak Avery , Duffy Alexis B. , Nelson-Taylor Sarah , Oike Naoki , Porfilio Timothy , Shirai Ryota , Walker Deandra , Treece Amy , Black Jennifer , Donaldson Nathan , Cost Carrye , Garrington Tim , Greffe Brian , Luna-Fineman Sandra , Demedis Jenna , Lake Jessica , Danis Etienne , Verneris Michael , Adams Daniel L , Hayashi Masanori
Published: January 2024

Ewing sarcoma is the second most common bone cancer in children, accounting for 2% of pediatric cancer diagnoses. Patients who present with metastatic disease at the time of diagnosis have a dismal prognosis, compared to the >70% 5-year survival of those with localized disease. Here, we utilized single cell RNA-sequencing to characterize the transcriptional landscape of primary Ewing sarcoma tumors and surrounding tumor microenvironment (TME). Copy-number analysis identified subclonal evolution within patients prior to treatment. Primary tumor samples demonstrate a heterogenous transcriptional landscape with several conserved gene expression programs, including those composed of genes related to proliferation and EWS targets. Single cell RNA-sequencing and immunofluorescence of circulating tumor cells at the time of diagnosis identified TSPAN8 as a novel therapeutic target.
Fluorescent tools for the standardized work in Gram-negative bacteria
Authors: Delgadillo-Guevara Mario , Halte Manuel , Erhardt Marc , Popp Philipp F.
Published: January 2024

Standardized and thoroughly characterized genetic tools are a prerequisite for studying cellular processes to ensure the reusability and consistency of experimental results. The discovery of fluorescent proteins (FPs) represents a milestone in the development of genetic reporters for monitoring transcription or protein localizationin vivo. FPs have revolutionized our understanding of cellular dynamics by enabling the real-time visualization and tracking of biological processes. Despite these advancements, challenges remain in the appropriate use of FPs, specifically regarding their proper application, protein turnover dynamics, and the undesired disruption of cellular functions. Here, we systematically compared a comprehensive set of 16 FPs and assessed their performancein vivoby focusing on key parameters, such as signal over background ratios and protein stability rates, using the gram-negative model organismSalmonella entericaas a representative host. We evaluated four protein degradation tags in both plasmid- and genome-based systems and our findings highlight the necessity of introducing degradation tags to analyze time-sensitive cellular processes. We demonstrate that the gain of dynamics mediated by the addition of degradation tags impacts the cell-to-cell heterogeneity of plasmid-based but not genome-based reporters. Finally, we probe the applicability of FPs for protein localization studies in living cells using super-resolution microscopy. In summary, our study underscores the importance of careful FP selection and paves the way for the development of improved genetic reporters to enhance the reproducibility and reliability of fluorescence-based research in gram- negative bacteria and beyond.
Counter-balancing X-linkedMecp2hypofunction by hyperfunction ameliorates disease features in a model of Rett syndrome: implications for genetic therapies
Authors: McGraw Christopher M , Soriano Sirena , Shuang Hao , Connolly Daniel R , Chahrour Ali , Wu Zhenyu , Liang Agnes J , Sun Yaling , Tang Jianrong , Samaco Rodney C
Published: January 2024

Treating monogenic neurodevelopmental disorders remains challenging and mostly symptomatic. X-linked disorders affecting women such as the postnatal neurodevelopmental disorder Rett syndrome (caused by mutations in the geneMECP2) have additional challenges due to dosage sensitivity and to cellular mosaicism caused by random X-chromosome inactivation. An approach to augmentMECP2expression from wild-type cells in RTT may be feasible and simpler than gene replacement but has never been tested due to known toxicity ofMECP2over-expression, as evidenced by the distinct neurological condition known asMECP2Duplication Syndrome. Here, using genetic techniques, we find that “counter-balancing”Mecp2-null cells in femaleMecp2-null/+ mice by a complementary population of cells harboring an X-linked transgene associated with 3X normal levels ofMECP2leads to normalization of multiple whole animal phenotypic outcomes without noticeable toxicity. In addition,in vivoLFP recordings demonstrate that counter-balancingMecp2loss-of-function improves select within-region and between-region abnormalities. By comparing the counter-balance approach with an approach based on cell autonomous restoration of MeCP2 using an autosomal transgene expressing 2X normal levels ofMECP2in all cells (mimicking gene replacement), we identify neurobehavioral and electrographic features best suited for preclinical biomarkers of a therapeutic response to cell autonomous versus non-cell autonomous correction. Notably, these proof-of-concept findings demonstrate how non-cell autonomous suppression of MeCP2 deficiency by boosting overall wild-type MeCP2 levels may be a viable disease-modifying therapy for RTT, with potential implications for genetic-based therapies of monogenic X-linked disorders.

One Sentence Summary

In a mouse model of Rett syndrome, counterbalancing mosaic LOF with complementary mosaic GOF improves phenotypic outcome.
Label-free biosensor assay decodes the dynamics of Toll-like receptor signaling
Authors: Holze Janine , Lauber Felicitas , Kostenis Evi , Weindl Günther
Published: January 2024

The discovery of Toll-like receptors (TLRs) represented a significant breakthrough that paved the way for the study of hostpathogen interactions in innate immunity. However, there are still major gaps in understanding TLR function, especially the early dynamics of downstream TLR pathways remains less clear. Here, we present a label-free optical biosensor-based assay as a powerful method for detecting TLR activation in a native and label-free environment and defining the dynamics of TLR pathway activation. This technology is sufficiently sensitive to detect TLR signaling and readily discriminates between different TLR signaling pathways. We define pharmacological modulators of cell surface and endosomal TLRs and downstream signaling molecules and uncover previously unrecognized TLR signaling signatures, including biased receptor signaling. These findings highlight that optical biosensor assays complement traditional assays that use a single endpoint and have the potential to facilitate the future design of selective drugs targeting TLRs and their downstream effector cascades.
Effects of High Fat Diet on Metabolic Health Vary by Age of Menopause Onset
Authors: Salinero Abigail E. , Venkataganesh Harini , Abi-Ghanem Charly , Riccio David , Kelly Richard D. , Gannon Olivia J. , Sura Avi , Brooks Heddwen L. , Zuloaga Kristen L.
Published: January 2024

Menopause accelerates metabolic dysfunction, including (pre-)diabetes, obesity and visceral adiposity. However, the effects of endocrine vs. chronological aging in this progression are poorly understood. We hypothesize that menopause, especially in the context of middle-age, will exacerbate the metabolic effects of a high fat diet. Using young-adult and middle-aged C57BL/6J female mice, we modeled diet-induce obesity via chronic administration of high fat (HF) diet vs. control diet. We modeled peri-menopause/menopause via injections of 4-vinylcyclohexene diepoxide, which accelerates ovarian failure vs. vehicle. We performed glucose tolerance tests 2.5 and 7 months after diet onset, during the peri-menopausal and menopausal phases, respectively. Peri-menopause increased the severity of glucose intolerance and weight gain in middle-aged, HF-fed mice. Menopause increased weight gain in all mice regardless of age and diet, while chronological aging drove changes in adipose tissue distribution towards more visceral vs. subcutaneous adiposity. These data are in line with clinical data showing that post-menopausal women are more susceptible to metabolic dysfunction and suggest that greater chorological age exacerbates the effects of endocrine aging (menopause). This work highlights the importance of considering both chronological and endocrine aging in studies of metabolic health.
Expanding the ligandable proteome by paralog hopping with covalent probes
Authors: Zhang Yuanjin , Liu Zhonglin , Hirschi Marsha , Brodsky Oleg , Johnson Eric , Won Sang Joon , Nagata Asako , Petroski Matthew D. , Majmudar Jaimeen D. , Niessen Sherry , VanArsdale Todd , Gilbert Adam M. , Hayward Matthew M. , Stewart Al E. , Nager Andrew R. , Melillo Bruno , Cravatt Benjamin
Published: January 2024

More than half of the ∼20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset of paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs that lack the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we mutated the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling (ABPP) that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-N112C-CCNE1 interaction into a NanoBRET-ABPP assay capable of identifying compounds that reversibly inhibit both N112C- and WT-CCNE1:CDK2 complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings thus provide a roadmap for leveraging electrophile-cysteine interactions to extend the ligandability of the proteome beyond covalent chemistry.
Δ9-tetrahydrocannabinol (THC) Increases the Rewarding Value of Oxycodone During Self-Administration in Rats
Authors: Nguyen Jacques D. , Grant Yanabel , Yang Celine , Taffe Michael A.
Published: January 2024

Background

Cannabis may reduce the nonmedical use of prescription opioids. Causality of polydrug use is difficult to establish from epidemiological data, and thus controlled laboratory models can test whether cannabinoid co-use with opioids can modulate opioid intake.

Methods

Male and female rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 6 h sessions. Separate groups were injected with the vehicle or with THC (5 mg/kg, i.p.; N=10) 30 minutes before sessions for the first three weeks. Treatments were swapped in the fourth week. One male group was trained in the intracranial self-stimulation (ICSS) procedure and assessed for brain reward thresholds prior to each IVSA session.

Results

THC treated animals self-administered less oxycodone during acquisition, with a larger differential expressed in the female group. Tolerance to the THC effect developed over the initial weeks, and increasing the dose of THC (10 mg/kg, i.p.) prolonged the suppressing effect on IVSA. While ICSS thresholds increased with sequential IVSA sessions, no differences between THC- and Vehicle-treated groups were observed. Oxycodone IVSA was increased following the first 60 h abstinence interval in THC-treated, but not vehicle-treated, rats. Acute injection of THC, when all animals had been THC abstinent for several weeks,increasedbreakpoints in a Progressive Ratio procedure.

Conclusion

These data support the interpretation that THC enhances the reinforcing efficacy of a given dose of oxycodone and may therefore increase the addiction liability.
Sac1 links phosphoinositide turnover to cryptococcal virulence
Authors: Gaylord Elizabeth A. , Choy Hau Lam , Chen Guohua , Briner Sydney L. , Doering Tamara L.
Published: January 2024

Cryptococcus neoformansis an environmentally-acquired fungal pathogen that causes over 140,000 deaths per year. Cryptococcal infection occurs when infectious particles are deposited into the lung, where they encounter host phagocytic cells.C. neoformansmay be engulfed by these phagocytes, an important step of infection that leads to outcomes ranging from termination of infection to cryptococcal dissemination. To study this critical process, we screened approximately 4,700 cryptococcal gene deletion mutants for altered uptake, using primary mouse and human phagocytic cells. Among the hits of these two screens, we identified 93 mutants with perturbed uptake in both systems, as well as others with differences in uptake by only one cell type. We further screened the hits for changes in thickness of the capsule, a protective polysaccharide layer around the cell which is an important cryptococcal virulence factor. The combination of our three screens yielded 45 mutants, including one lacking the phosphatidylinositol-4-phosphate phosphatase Sac1. In this work, we implicate Sac1 in both host cell uptake and capsule production. We found thatsac1mutants exhibit lipid trafficking defects, reductions in secretory system function, and changes in capsule size and composition. Many of these changes occur specifically in tissue culture media, highlighting the role of Sac1 phosphatase activity in responding to the stress of host-like conditions. Overall, these findings show how genome-scale screening can identify cellular factors that contribute to our understanding of cryptococcal biology and demonstrate the role of Sac1 in determining fungal virulence.

IMPORTANCE

Cryptococcus neoformansis a fungal pathogen with significant impact on global health. Cryptococcal cells inhaled from the environment are deposited into the lungs, where they first contact the human immune system. The interaction betweenC. neoformansand host cells is critical because this step of infection can determine whether the fungal cells die or proliferate within the human host. Despite the importance of this stage of infection, we have limited knowledge of cryptococcal factors that influence its outcome. In this study, we identify cryptococcal genes that affect uptake by both human and mouse cells. We also identify mutants with altered capsule, a protective coating that surrounds the cells to shield them from the host immune system. Finally, we characterize the role of one gene,SAC1, in these processes. Overall, this study contributes to our understanding of howC. neoformansinteracts with and protects itself from host cells.
Intranasally Administered EVs from hiPSC-derived NSCs Alter the Transcriptomic Profile of Activated Microglia and Conserve Brain Function in an Alzheimer’s Model
Authors: Madhu Leelavathi N , Kodali Maheedhar , Upadhya Raghavendra , Rao Shama , Shuai Bing , Somayaji Yogish , Attaluri Sahithi , Kirmani Maha , Gupta Shreyan , Maness Nathaniel , Rao Xiaolan , Cai James , Shetty Ashok K.
Published: January 2024

Antiinflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) hold promise as a disease-modifying biologic for Alzheimer’s disease (AD). This study directly addressed this issue by examining the effects of intranasal administrations of hiPSC-NSC-EVs to 3-month-old 5xFAD mice. The EVs were internalized by all microglia, which led to reduced expression of multiple genes associated with disease-associated microglia, inflammasome, and interferon-1 signaling. Furthermore, the effects of hiPSC-NSC-EVs persisted for two months post-treatment in the hippocampus, evident from reduced microglial clusters, inflammasome complexes, and expression of proteins and/or genes linked to the activation of inflammasomes, p38/mitogen-activated protein kinase, and interferon-1 signaling. The amyloid-beta (Aβ) plaques, Aβ-42, and phosphorylated-tau concentrations were also diminished, leading to better cognitive and mood function in 5xFAD mice. Thus, early intervention with hiPSC-NSC-EVs in AD may help maintain better brain function by restraining the progression of adverse neuroinflammatory signaling cascades.
The more attention you get, the better you feel? A study on the influence of being envied on inconspicuous consumption
Authors: Wang Siyun , Li Feng , Wang Huanzhang
Published: January 2024

Purpose

From a relational maintenance perspective, this study explores the impact of being envied (benignly vs maliciously) on consumers' feelings of social anxiety and its influence on their tendencies toward inconspicuous consumption, based on the resource conservation theory and the model of “Sensitivity about Being the Target of a Threatening Upward Comparison.” (STTUC)

Design/methodology/approach

Four studies were conducted in this paper. Studies 1a and 1b tested the main hypothesis that being maliciously envied (vs benignly) can increase consumers' inconspicuous consumption of luxury products and luxury hotel experiences. Study 2 replicated this finding and examined the mediating role of social anxiety. Study 3 investigated the moderating effect of ideal self-congruity (low vs high).

Findings

The findings reveal that being maliciously envied (vs benignly) is associated with higher levels of inconspicuous consumption and social anxiety acts as a mediating role. Moreover, when individuals have a strong sense of ideal self-congruity, the positive impact of being maliciously envied (vs benignly) on inconspicuous consumption is further amplified, confirming the moderating role of ideal self-congruity.

Originality/value

This study sheds light on a novel mechanism that elucidates how different types of being envied influence consumers' inconspicuous consumption and the conditions under which this impact is heightened.
Semianalytical modeling of squirrel-cage induction machines with consideration of iron permeability and eddy-currents using elementary subdomain technique
Authors: Roubache Lazhar , Boughrara Kamel , Dubas Frédéric , Ladghem Chikouche Brahim , Ibtiouen Rachid
Published: January 2024

Purpose

This paper aims to propose a semianalytical model of a squirrel-cage induction machine (SCIM), considering local magnetic saturation and eddy-currents induced in the rotor bars.

Design/methodology/approach

The regions of the rotor and stator are divided into elementary subdomains (E-SDs) characterized by general solutions at the first harmonic of the magneto-harmonic Maxwell’s equations. These E-SDs are connected in both directions (i.e., along the r- and θ-edges).

Findings

The calculation of the magnetic field has been validated for various values of slip and iron permeability. All electromagnetic quantities were compared with those obtained using a two-dimensional finite-element method. The semianalytical results are satisfactory compared with the numerical results, considering both the amplitude and waveform.

Originality/value

Expansion of the recent analytical model (E-SD technique) for the full prediction of the magnetic field in SCIMs, considering the local saturation effect and the eddy-currents induced in the rotor bars.
Influence of policies on stakeholders to drive the success of modular integrated construction in Hong Kong
Authors: Jin Xin , Shen Geoffrey , Luo Lizi , Zhou Xin
Published: January 2024

Purpose

Modular integrated construction (MiC) is an innovative and effective manufacturing-based method of construction that has become the mainstream development direction of projects in Hong Kong (HK). However, large-scale promotion of MiC practice still needs efforts. A pressing concern is that the impact of relevant policies on stakeholders during project implementation is rarely explored in depth. Therefore, to fill the research gap, this study aims to investigate the influence of policies on stakeholders to drive the successful implementation of MiC in HK.

Design/methodology/approach

This study uses a strategy of multiple methods. First, a comprehensively literature review and survey were adopted to identify critical policies and stakeholders. Second, semi-structured interviews with 28 experts were conducted to quantify their relationships. Third, three policy–stakeholder networks at initiation, planning and design and construction stages were established using social network analysis.

Findings

Environmental protection policy, COVID-19 pandemic policy and environmental protection policy and quality acceptance standard for project completion are found to be the most important policies of the three stages, respectively. The HK government and developers are highlighted as prominent stakeholders influencing policy implementation at all three stages. The dynamics of the influence stakeholders receive from critical policies at different stages of MiC are discussed. Valuable recommendations are accordingly proposed to enhance the successful implementation of MiC projects from the perspective of various stakeholders.

Originality/value

This study contributes to the body of knowledge by considering the mediating influence of stakeholders during policy implementation in the MiC uptake, and is valuable in helping policymakers to deeply understand the influence of policies to further forward successful MiC implementation and practicality in HK.
Leveraging blockchain to anchor information for supervision in PPP projects: a conceptual framework
Authors: Du Yanhui , Yuan Jingfeng , Wang ShouQing , Liu Yan , Zeng Ningshuang
Published: January 2024

Purpose

The information used for supervision by regulatory departments in public-private partnership (PPP) projects is primarily transmitted and processed by the PPP implementation department, which negatively impacts the information quality, leading to information asymmetry and undermining the overall effectiveness of supervision. This study aims to explore how to use blockchain to anchor the information used for supervision in PPP projects to the original information, to strengthen the oversight.

Design/methodology/approach

This paper adopts the principles of design science research (DSR) to design a conceptual framework that systematically organizes information along the information dissemination chain, ensuring the reliable anchoring of original information. Two-stage interviews involving experts from academia and industry are conducted, serving as formative and summative evaluations to guide the design.

Findings

The framework establishes a weak-centralized information organizing mode, including the design of governance community and on-chain and off-chain governance mechanisms. Feedback from experts is collected via interviews and the designed framework is thought to improve information used for supervision. Constructive suggestions are also collected and analyzed for further development.

Originality/value

This paper provides a novel example exploring the inspirations blockchain can bring to project governance, like exercising caution regarding the disorderly expansion of public sector authority in addressing information disadvantages and how to leverage blockchain to achieve this. Technical details conveyed by the framework deepen understanding of how blockchain benefits and the challenges faced in successful implementation for practitioners and policymakers. The targeted evaluation serves as rigorous validation, guiding experts to provide reliable feedback and richer insights by offering them a more cognitively convenient scenario.
The effect of bra design on wearing appearance
Authors: Wang Yilun , Ji Xiaofen , Pang Chen , Zhai Lina
Published: January 2024

Purpose

Esthetic trend changes with the development of society and cultural differences. A minimizer bra designed to make breasts appear smaller is now popular with large-breasted women in China. To conform to the requirements of modern aesthetics in China, this paper aims to investigate vital features of breast appearance that influence people’s subjective evaluation of breast size and analyze how bra design parameters affect breast shape and make breasts appear smaller.

Design/methodology/approach

This study used 3D scanning technology and reverse engineering software to obtain objective breast measurements in detail. A subjective evaluation experiment was conducted to evaluate the overall performance of seven minimizer bras compared to a basic comparison bra. Around 20 design parameters of 8 sample bras were identified to make a further study about the correlation between bra design features and breast shaping effect. To gain a deeper understanding of how bras interact with breast tissue, this study presented heat maps of the breast surface to visualize the deformation of breast shape.

Findings

Nine breasts' characteristics, such as the distance between bust points, breast depth, outer breast curvature and slope, etc. have been determined to be highly correlated with the visual reduction effect of breasts. In addition, for the bras in this experiment, the high-performance bra for women with large breasts tends to have a wider side panel, a wider under band, higher gore and a stronger transverse rigidity of the bra cup. According to the observation of heat maps of the breast surface, soft full-figure bras provide a wider range of compression to the breasts and effectively flatten the breasts.

Originality/value

This paper first aimed at the need to shape the ideal breast appearance for large-breasted women and make a further study of several hot-selling minimizer bras in China. The suggestions given in this paper help lingerie manufacturers better understand how design features of bras can affect their shaping effect and improve the wearing effect of minimizer bras for large-breasted women.
Affect-based dimensions of trust: a study of buyer-supplier relationships in Thai manufacturing
Authors: Rungsithong Rapeeporn , Meyer Klaus E.
Published: January 2024

Purpose

Trust is an important facilitator of successful B2B relationships. The purpose of this study is to investigate affect-based antecedents of both interpersonal and interorganizational trust, and their impact on the performance of buyer–supplier relationships. The authors ask two research questions: (1) What are affect-based dimensions of interpersonal and interorganizational trust? (2) How do interpersonal and interorganizational trust influence buyers’ operational performance?

Design/methodology/approach

The authors use data from an original survey of 156 buyer–supplier relationships between multinational enterprise subsidiaries and local suppliers in the Thai manufacturing sector to develop a structural model in which the authors test the hypotheses.

Findings

Consistent with social exchange theory and social psychology, the empirical analysis shows that affect-based dimensions at the individual level, namely, likeability, similarity and frequent social contact, and at the organizational level, namely, supplier firm willingness to customize and institutionalization of cooperation, are important for establishing trust. In addition, interpersonal trust enhances buyers’ operational performance indirectly via interorganizational trust.

Practical implications

Buying and selling firms may develop organizational trust by developing processes that enhance organizational trust. Individuals with purchasing or sales responsibilities may enhance trust in their personal relationship. However, such interpersonal trust needs to be translated to the organizational level to benefit organizational performance.

Originality/value

The findings contribute to the literature on affect-based antecedents and outcomes of trust. Specifically, the authors offer theory and empirical evidence regarding the contribution of salespersons toward affect-based dimensions of trust and its impact on buyer’s operational performance.