bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel combination treatment for fragile X syndrome predicted using computational methods
Authors: Chadwick Wayne , Angulo-Herrera Ivan , Cogram Patricia , Deacon Robert J M , Mason Daniel J , Brown David , Roberts Ian , O’Donovan Daniel J , Tranfaglia Michael R , Guilliams Tim , Thompson Neil T
Published: January 2024

Fragile X syndrome is a neurodevelopmental disorder caused by silencing of the fragile X messenger ribonucleotide gene. Patients display a wide spectrum of symptoms ranging from intellectual and learning disabilities to behavioural challenges including autism spectrum disorder. In addition to this, patients also display a diversity of symptoms due to mosaicism. These factors make fragile X syndrome a difficult syndrome to manage and suggest that a single targeted therapeutic approach cannot address all the symptoms. To this end, we utilized Healx’s data-driven drug discovery platform to identify a treatment strategy to address the wide range of diverse symptoms among patients. Computational methods identified the combination of ibudilast and gaboxadol as a treatment for several pathophysiological targets that could potentially reverse multiple symptoms associated with fragile X syndrome. Ibudilast is an approved broad-spectrum phosphodiesterase inhibitor, selective against both phosphodiesterase 4 and phosphodiesterase 10, and has demonstrated to have several beneficial effects in the brain. Gaboxadol is a GABAA receptor agonist, selective against the delta subunit, which has previously displayed encouraging results in a fragile X syndrome clinical trial. Alterations in GABA and cyclic adenosine monophosphate metabolism have long since been associated with the pathophysiology of fragile X syndrome; however, targeting both pathways simultaneously has never been investigated. Both drugs have a good safety and tolerability profile in the clinic making them attractive candidates for repurposing. We set out to explore whether the combination of ibudilast and gaboxadol could demonstrate therapeutic efficacy in a fragile X syndrome mouse model. We found that daily treatment with ibudilast significantly enhanced the ability of fragile X syndrome mice to perform a number of different cognitive assays while gaboxadol treatment improved behaviours such as hyperactivity, aggression, stereotypy and anxiety. Importantly, when ibudilast and gaboxadol were co-administered, the cognitive deficits as well as the aforementioned behaviours were rescued. Moreover, this combination treatment showed no evidence of tolerance, and no adverse effects were reported following chronic dosing. This work demonstrates for the first time that by targeting multiple pathways, with a combination treatment, we were able to rescue more phenotypes in a fragile X syndrome mouse model than either ibudilast or gaboxadol could achieve as monotherapies. This combination treatment approach holds promise for addressing the wide spectrum of diverse symptoms in this heterogeneous patient population and may have therapeutic potential for idiopathic autism.
Modulations in high-density EEG during the suppression of phantom-limb pain with neurostimulation in upper limb amputees
Authors: Kleeva Daria , Soghoyan Gurgen , Biktimirov Artur , Piliugin Nikita , Matvienko Yury , Sintsov Mikhail , Lebedev Mikhail
Published: January 2024

Phantom limb pain (PLP) is a distressing and persistent sensation that occurs after the amputation of a limb. While medication-based treatments have limitations and adverse effects, neurostimulation is a promising alternative approach whose mechanism of action needs research, including electroencephalographic (EEG) recordings for the assessment of cortical manifestation of PLP relieving effects. Here we collected and analyzed high-density EEG data in 3 patients (P01, P02, and P03). Peripheral nerve stimulation suppressed PLP in P01 but was ineffective in P02. In contrast, transcutaneous electrical nerve stimulation was effective in P02. In P03, spinal cord stimulation was used to suppress PLP. Changes in EEG oscillatory components were analyzed using spectral analysis and Petrosian fractal dimension. With these methods, changes in EEG spatio-spectral components were found in the theta, alpha, and beta bands in all patients, with these effects being specific to each individual. The changes in the EEG patterns were found for both the periods when PLP level was stationary and the periods when PLP was gradually changing after neurostimulation was turned on or off. Overall, our findings align with the proposed roles of brain rhythms in thalamocortical dysrhythmia or disruption of cortical excitation and inhibition which has been linked to neuropathic pain. The individual differences in the observed effects could be related to the specifics of each patient’s treatment and the unique spectral characteristics in each of them. These findings pave the way to the closed-loop systems for PLP management where neurostimulation parameters are adjusted based on EEG-derived markers.
Strengthening of alpha synchronization is a neural correlate of cognitive transfer
Authors: Ericson Julia , Palva Satu , Palva Matias , Klingberg Torkel
Published: January 2024

Cognitive training can lead to improvements in both task-specific strategies and general capacities, such as visuo-spatial working memory (VSWM). The latter emerge slowly and linearly throughout training, in contrast to strategy where changes typically occur within the first days of training. Changes in strategy and capacity have not been separated in prior neuroimaging studies. Here, we used a within-participants design with dense temporal sampling to capture the time dynamics of neural mechanisms associated with change in capacity. In four participants, neural activity was recorded with magnetoencephalography on seven occasions over two months of visuo-spatial working memory training. During scanning, the participants performed a trained visuo-spatial working memory task, a transfer task, and a control task. First, we extracted an individual visuo-spatial working memory-load-dependent synchronization network for each participant. Next, we identified linear changes over time in the network, congruent with the temporal dynamics of capacity change. Three out of four participants showed a gradual strengthening of alpha synchronization. Strengthening of the same connections was also found in the transfer task but not in the control task. This suggests that cognitive transfer occurs through slow, gradual strengthening of alpha synchronization between cortical regions that are vital for both the trained task and the transfer task.
Parenting links to parent–child interbrain synchrony: a real-time fNIRS hyperscanning study
Authors: Liu Sihan , Han Zhuo Rachel , Xu Jianjie , Wang Qiandong , Gao Mengyu (Miranda) , Weng Xiaofang , Qin Shaozheng , Rubin Kenneth H
Published: January 2024

Parent–child interaction is crucial for children’s cognitive and affective development. While bio-synchrony models propose that parenting influences interbrain synchrony during interpersonal interaction, the brain-to-brain mechanisms underlying real-time parent–child interactions remain largely understudied. Using functional near-infrared spectroscopy, we investigated interbrain synchrony in 88 parent–child dyads (Mage children = 8.07, 42.0% girls) during a collaborative task (the Etch-a-Sketch, a joint drawing task). Our findings revealed increased interbrain synchrony in the dorsolateral prefrontal cortex and temporo-parietal areas during interactive, collaborative sessions compared to non-interactive, resting sessions. Linear regression analysis demonstrated that interbrain synchrony in the left temporoparietal junction was associated with enhanced dyadic collaboration, shared positive affect, parental autonomy support, and parental emotional warmth. These associations remained significant after controlling for demographic variables including child age, child gender, and parent gender. Additionally, differences between fathers and mothers were observed. These results highlight the significant association between brain-to-brain synchrony in parent–child dyads, the quality of the parent–child relationship, and supportive parenting behaviors. Interbrain synchrony may serve as a neurobiological marker of real-time parent–child interaction, potentially underscoring the pivotal role of supportive parenting in shaping these interbrain synchrony mechanisms.
Developmental noise and phenotypic plasticity are correlated in Drosophila simulans
Authors: Saito Keita , Tsuboi Masahito , Takahashi Yuma
Published: January 2024

Non-genetic variation is the phenotypic variation induced by the differential expression of a genotype in response to varying environmental cues and is broadly categorized into two types: phenotypic plasticity and developmental noise. These aspects of variation have been suggested to play an important role in adaptive evolution. However, the mechanisms by which these two types of non-genetic variations influence the evolutionary process are currently poorly understood. Using a machine-learning-based phenotyping tool, we independently quantified phenotypic plasticity and developmental noise in the wing morphological traits of the fruit fly Drosophila simulans. Utilizing a rearing experiment, we demonstrated plastic responses in both wing size and shape as well as non-zero heritability of both phenotypic plasticity and developmental noise, which suggests that adaptive phenotypic plasticity can evolve via genetic accommodation in the wing morphology of D. simulans. We found a positive correlation between phenotypic plasticity and developmental noise, while the correlation between the plastic response to three kinds of environmental factors that were examined (nutrient condition, temperature, and light–dark cycle) was poor. These results suggest that phenotypic plasticity and developmental noise contribute to evolvability in a similar manner, however, the mechanisms that underlie the correspondence between these two types of variation remain to be elucidated.
Does cycle commuting reduce the risk of mental ill-health? An instrumental variable analysis using distance to nearest cycle path
Authors: Berrie Laurie , Feng Zhiqiang , Rice David , Clemens Tom , Williamson Lee , Dibben Chris
Published: January 2024

Background

Previous studies have linked cycling with improved mental wellbeing but these studies tend to use cross-sectional survey data that have small sample sizes and self-reported health measures, and are potentially susceptible to omitted-variable bias and reverse causation. We use an instrumental variable approach and an objective measure of mental ill-health taken from linked administrative data to ask: ‘Does cycle commuting reduce the risk of mental ill-health?’

Methods

Our study links data on commuting in Edinburgh and Glasgow from the Scottish population census with mental health prescriptions from the National Health Service Prescribing Information System records. We use road distance from home to nearest cycle path as an instrumental variable for cycle commuting.

Results

In total, 378 253 people aged 16–74 years living and working in the City of Edinburgh and Glasgow City council areas at the 2011 census were included in our study; 1.85% of commuters in Glasgow and 4.8% of commuters in Edinburgh cycled to work. Amongst cyclists, 9% had a prescription for mental health compared with 14% amongst non-cyclists. Using a bivariate probit model, we estimate a mean average reduction in prescriptions for antidepressants and/or anxiolytics in the 5 years following the census of –15.1% (95% CI: –15.3% to –15.0%) amongst cycle commuters compared with those who use any other mode to commute.

Conclusions

This work suggests that cycle commuting is causally related to reduced mental ill-health and provides further evidence in support of the promotion of active travel to encourage commuters travelling shorter distances to shift to cycle commutes.
Dimension reduction based on approximate gramians via Laguerre polynomials for coupled systems
Authors: Qi Zhen-Zhong , Xiao Zhi-Hua , Yuan Jia-Wei
Published: January 2024

In this paper, we focus on the topic of model order reduction (MOR) for coupled systems. At first, an approximation via Laguerre polynomials expansions to controllability and observability gramians for such systems are presented, which provides a low-rank decomposition form whose factors are constructed from a recurrence formula instead of Lyapunov equations. Then, in combination of balanced truncation and dominant subspace projection method, a series of MOR algorithms are proposed that preserve the coupled structures. What’s more, some main properties of reduced-order models, such as stability preservation, are well discussed. Finally, three numerical simulations are provided to illustrate the effectiveness of our algorithms.
Bureaucracy and Cyber Coercion
Authors: Demarest Heidi , Jost Tyler , Schub Robert
Published: January 2024

States are increasingly incorporating militarized cyber technologies, or cyber weapons, into their defense arsenals, but there is vigorous debate about their coercive utility. Existing scholarship often adjudicates the debate by parsing technical differences between cyber and conventional weapons. This technical approach overlooks a critical consideration: bureaucrats who inform state assessments may hold unique perspectives on coercion due to their organizational affiliation. We make an empirical intervention by fielding a survey experiment on bureaucrats inside US Cyber Command, offering a rare glimpse into elite perceptions. We find little evidence that technical differences between weapons yield systematically different assessments. Bureaucrats perceive that conventional and cyber weapons have statistically indistinguishable coercive utility and battlefield effects. Replicating the study on a public sample, we find that bureaucrats are more optimistic about coercion across all domains and their optimism stems from organizational culture, rather than parochial interests or technical expertise. The findings show how who is responsible for assessing a technology's coercive value can shape estimates even more than which technology is being assessed. Unique perspectives clustered within influential bureaucracies may shape state assessments and policies in ways that diverge from the expectations of analyses that emphasize technical characteristics of military capabilities.
Using Eye-Tracking to Demonstrate Children’s Attention to Detail When Evaluating Low-Fidelity Prototypes
Authors: Sim Gavin , Read Janet C
Published: January 2024

This study used eye-tracking glasses to better understand how children explore low-fidelity prototypes in the context of user experience studies and to explore the potential of eye tracking in this context. The main research question that was being explored was whether the aesthetic refinement, either wireframe or high-resolution images, would affect children’s self-report and if so, or if not, what could be learned from knowing where children looked when exploring the prototypes. The results showed that the aesthetic refinement had little influence over the children’s overall ratings of the game. The eye-tracking data demonstrated that there were no differences in the time spent viewing the prototypes and most of the children focused on both the visuals and text on all the pages. However, there were a higher number of fixations recorded in the wireframe prototype compared to the photo-realistic version. This paper contributes to the design of prototypes through an understanding of how children interact with prototypes, demonstrating the importance of the text along with the visuals when evaluating game concepts with children. Further research is required to understand the differences and whether similar results are replicated with different games.
To kill a microRNA: emerging concepts in target-directed microRNA degradation
Authors: Buhagiar Amber F , Kleaveland Benjamin
Published: January 2024

MicroRNAs (miRNAs) guide Argonaute (AGO) proteins to bind mRNA targets. Although most targets are destabilized by miRNA–AGO binding, some targets induce degradation of the miRNA instead. These special targets are also referred to as trigger RNAs. All triggers identified thus far have binding sites with greater complementarity to the miRNA than typical target sites. Target-directed miRNA degradation (TDMD) occurs when trigger RNAs bind the miRNA–AGO complex and recruit the ZSWIM8 E3 ubiquitin ligase, leading to AGO ubiquitination and proteolysis and subsequent miRNA destruction. More than 100 different miRNAs are regulated by ZSWIM8 in bilaterian animals, and hundreds of trigger RNAs have been predicted computationally. Disruption of individual trigger RNAs or ZSWIM8 has uncovered important developmental and physiologic roles for TDMD across a variety of model organisms and cell types. In this review, we highlight recent progress in understanding the mechanistic basis and functions of TDMD, describe common features of trigger RNAs, outline best practices for validating trigger RNAs, and discuss outstanding questions in the field.
A tentative anatomy of Christian responses to anthropogenic climate change
Authors: Siddall Mark
Published: January 2024

This pilot study addresses the differences in responses to anthropogenic climate change expressed in published normative statements for a cross section of Christian denominations and groupings from the UK and USA as well as international groupings. Grid-group cultural theory is tentatively employed to better understand these differences. Because the cosmologies identified by grid-group theory have as their basis the metaphor of the body, this is in effect a tentative anatomy of Christian responses to anthropogenic climate change. As a test case, this paper explores whether or not it is fruitful to attempt to challenge a given cosmological outlook to better communicate climate change and how this might be achieved or whether to speak to that cosmological perspective and how this might be achieved. In addition, this paper explores how each distinctive cosmology might contribute helpfully in responding to anthropogenic climate change. Finally, avenues of further work to expand this approach are explored.
Outcomes of Follow-up Imaging After Pediatric Spinal Trauma Confirmed With Magnetic Resonance Imaging
Authors: Sirén Aapo , Syvänen Johanna , Nyman Mikko , Mattila Kimmo , Hirvonen Jussi
Published: January 2024

Background:

Imaging plays a crucial role in the diagnostic workup of pediatric spinal trauma. Computed tomography and conventional radiographs are widely used as the primary imaging methods. Magnetic resonance imaging (MRI) is a radiation-free alternative with high sensitivity for bony and soft tissue injuries. There is no consensus on the optimal use of follow-up imaging in pediatric spinal trauma without immediate surgical treatment, especially if the injury is primarily confirmed with MRI. This study aimed to assess the diagnostic value of follow-up imaging after MRI-confirmed spinal trauma in children.

Methods:

The medical records and the imaging data of children and adolescents with emergency spinal MRI and follow-up imaging over 8 years were retrospectively reviewed. The primary study outcome was the outcome of follow-up imaging and its effect on management.

Results:

The study population consisted of 127 patients. The follow-up imaging did not alter the management in any patient with presumably stable injury in emergency MRI. Short-term follow-up imaging showed no clinically significant progression in thoracolumbar compression fractures. Flexion-extension radiographs had no additional value in cases with stable cervical spinal injury on emergency MRI.

Conclusions:

The clinical utility of short-term follow-up imaging is low in children with stable spinal injury on emergency MRI.

Level of evidence:

Level III—retrospective observational study.
Outcomes of the Nuss procedure in children with pectus excavatum: 14 years of experience
Authors: Chu Chih-Chun , Chang Jei-Wen , Yang Hui-Hsin , Kuo Fang-Cheng , Tsai Hsin-Lin
Published: January 2024

Background:

We aimed to assess the effectiveness of the Nuss procedure for pectus excavatum (PE) and explore the impacts of sex and age on outcomes.

Methods:

We retrospectively reviewed 594 consecutive children ≤18 years of age who underwent the thoracoscopy-assisted Nuss technique between January 2006 and July 2019. The severity of pectus deformity was calculated according to the Haller index (HI). The classification of PE and clinical data including complications was analyzed.

Results:

Of the 594 patients, 456 (76.8%) were boys and 138 (23.2%) were girls. The mean age at surgery was 10.0 ± 5.0 years. The most common types of PE were 1A and 2A2 according to Park classification. Intraoperative and postoperative complication rates were 2/594 (0.3%) and 74/594 (12.5%), respectively. The most common complication was bar displacement. The bar was removed in 414 patients 3.5 ± 0.8 years later. The mean preoperative HI, postoperative HI with bar, and HI after bar removal were 4.2 ± 1.7, 2.4 ± 0.3, and 2.7 ± 0.5, respectively. Compared to the preoperative HI, both the postoperative HI with bar and HI after bar removal were significantly lower (p < 0.001). For preschool-age children, the preoperative HI was significantly higher (p = 0.027) and the change in HI significantly improved compared to school-age children (p = 0.004). Boys and adolescents needed significantly more bars and stabilizers.

Conclusion:

Surgical correction of PE using the Nuss procedure is a safe procedure and improves the HI in children of different ages, even in those younger than 6 years of age.
Bidirectional Associations Between Pain and Perceived Stress Among Veterans: Depressive Disorder as a Predisposing Factor
Authors: Saba Shaddy K. , Davis Jordan P. , Prindle John J. , Howe Esther , Tran Denise D. , Bunyi John , Hummer Justin F. , Castro Carl Andrew , Pedersen Eric R.
Published: January 2024

Objective

Military veterans who were injured in combat very often report pain along with co-occurring perceived stress and preexisting depressive disorder. The systems model of pain is a theoretical model suggesting that pain and perceived stress are bidirectionally associated at the within-person level, and associations are heightened among those with depressive disorder. However, the systems model of pain has not been adequately tested. Testing the systems model of pain could illuminate salient treatment targets for combat-injured veterans with pain and co-occurring psychological problems.

Methods

The present study empirically tests the systems model of pain among a sample of combat-injured veterans (N = 902) surveyed five times during an 18-month period. We used a multigroup, autoregressive latent trajectory with structured residual statistical model to test the within-person associations between pain and perceived stress and determine whether associations differ between veterans with and without a positive screen for depressive disorder.

Results

In line with the systems model of pain, pain and perceived stress were bidirectionally associated only among combat-injured veterans with depressive disorder. Among such veterans, perceived stress was positively associated with subsequent pain (b = 0.12; 95% confidence interval = 0.06–0.17), and pain was positively associated with subsequent perceived stress (b = 0.44; 95% CI = 0.11–0.77).

Conclusions

Our work highlights the interplay between pain and its psychological correlates among a particularly at-risk population. Clinicians addressing pain and perceived stress among combat-injured veterans should be prepared to identify and address depressive disorder.
Validity of Entrustable Professional Activities in a National Sample of General Surgery Residency Programs
Authors: Montgomery Kelsey B , Mellinger John D , Jones Andrew , McLeod M Chandler , Zmijewski Polina , Sarosi George A , Brasel Karen J , Klingensmith Mary E , Minter Rebecca M , Buyske Jo , Lindeman Brenessa
Published: January 2024

BACKGROUND:

The American Board of Surgery has endorsed competency-based education as vital to the assessment of surgical training. From 2018 to 2020, a national pilot study was conducted at 28 general surgery programs to evaluate feasibility of implementing entrustable professional activities (EPAs) for 5 common general surgical conditions. ACGME core competency Milestones were also rated for each resident by program clinical competency committees. This study aimed to evaluate the validity of general surgery EPAs compared with Milestones.

STUDY DESIGN:

Prospectively collected, de-identified EPA Pilot Study data were analyzed. EPAs studied were EPA-1 (gallbladder), EPA-2 (inguinal hernia), EPA-3 (right lower quadrant pain), EPA-4 (trauma), and EPA-5 (consult). Variables abstracted included levels of EPA entrustment (1 to 5) and corresponding ACGME Milestone subcompetency ratings (1 to 5) for the same study cycle. Spearman’s correlations were used to evaluate the relationship between summative EPA scores and corresponding Milestone ratings.

RESULTS:

A total of 493 unique residents received a summative entrustment decision. EPA summative entrustment scores had moderate-to-strong positive correlation with mapped Milestone subcompetencies, with median rho value of 0.703. Among operation-focused EPAs, median rho values were similar between EPA-1 (0.688) and EPA-2 (0.661), but higher for EPA-3 (0.833). EPA-4 showed a strong positive correlation with diagnosis and communication competencies (0.724), whereas EPA-5, mapped to the most Milestone subcompetencies, had the lowest median rho value (0.455).

CONCLUSIONS:

Moderate-to-strong positive correlation was noted between EPAs and patient care, medical knowledge, and communication Milestones. These findings support the validity of EPAs in general surgery and suggest that EPA assessments can be used to inform Milestone ratings by clinical competency committees.
From conformal infinity to equations of motion: conserved quantities in general relativity
Authors: Penrose Roger
Published: January 2024

This paper describes conservation laws in general relativity (GR) dating back to the mass-energy conservation of Bondi and Sachs in the early 1960s but using 2-spinor techniques. The notion of conformal infinity is employed, and the highly original ideas of E. T. Newman are discussed in relation to twistor theory. The controversial NP constants are introduced, and their meaning is considered in a new light related to the problem of equations of motion in GR.

This article is part of a discussion meeting issue ‘At the interface of asymptotics, conformal methods and analysis in general relativity’.
At the interface of asymptotics, conformal methods and analysis in general relativity
Authors: Taujanskas G. , Valiente Kroon J. A.
Published: January 2024

This is an introductory article for the proceedings associated with the Royal Society Hooke discussion meeting of the same title which took place in London in May 2023. We review the history of Penrose’s conformal compactification, null infinity and a number of related fundamental developments in mathematical general relativity from the last 60 years.

This article is part of a discussion meeting issue ‘At the interface of asymptotics, conformal methods and analysis in general relativity’.
Metformin protects the heart against chronic intermittent hypoxia through AMPK-dependent phosphorylation of HIF-1α
Authors: Moulin Sophie , Blachot-Minassian Britanny , Kneppers Anita , Thomas Amandine , Paradis Stéphanie , Bultot Laurent , Arnaud Claire , Pépin Jean-Louis , Bertrand Luc , Mounier Rémi , Belaidi Elise
Published: January 2024

Chronic intermittent hypoxia (IH), a major feature of obstructive sleep apnea syndrome (OSA), is associated with a more severe myocardial infarction. In this study, we performed RNA sequencing of cardiac samples from mice exposed to IH, which reveals a specific transcriptomic signature of the disease, relative to mitochondrial remodeling and cell death. Corresponding to its activation under chronic IH, we stabilized the Hypoxia Inducible Factor-1α (HIF-1α) in cardiac cellsin vitro,and observed its association with an increased autophagic flux. In accordance, IH induced autophagy and mitophagy that is decreased in HIF-1α+/_mice compared to wild-type animals suggesting that HIF-1 plays a significant role in IH-induced mitochondrial remodeling. Next, we showed that the AMPK metabolic sensor, typically activated by mitochondrial stress, is inhibited after 3 weeks of IH in hearts. Therefore, we assessed the effect of metformin, an anti-diabetic drug and potent activator of AMPK, on myocardial response to ischemia-reperfusion (I/R) injury. Daily administration of metformin significantly decreases infarct size without any systemic beneficial effect on insulin-resistance under IH conditions. The cardioprotective effect of metformin is lost in AMPKα2 knock-out mice demonstrating that AMPKα2 isoform promotes metformin-induced cardioprotection in mice exposed to IH. Mechanistically, we found that metformin inhibits IH-induced mitophagy in myocardium and decreases HIF-1α nuclear expression in mice subjected to IH.In vitrodemonstrated that metformin induces HIF-1α phosphorylation, decreases its nuclear localization and subsequently HIF-1 transcriptional activity. Collectively, these results identify the AMPKα2 metabolic sensor as a novel modulator of HIF-1 activity. Our data suggest that metformin could be considered as a cardioprotective drug in OSA patients independently of their metabolic status.
Constitutive Photomorphogenesis Protein 1 homolog (COP1) sustains nuclear factor-4 alpha function in human hepatocyte models
Authors: Soubeyrand Sébastien , Lau Paulina , McPherson Ruth
Published: January 2024

Constitutive Photomorphogenesis Protein 1 homolog (COP1) is a conserved E3 ligase with key roles in several biological systems. Prior work in hepatocyte derived tumors categorized COP1 as an oncogene but its role in untransformed hepatocytes remains largely unexplored. Here we have investigated the role of COP1 in primary human hepatocytes as well as in two transformed hepatocyte models, HepG2 and HuH-7 cells. Contrary to a previous report, COP1 suppression via siRNA had no noticeable impact on HepG2 and HuH-7 proliferation and was associated with contrasting rather than congruent transcriptome changes. Clustering analyses identified patterns indicative of perturbed metabolism in primary hepatocytes and HepG2 cells whereas patterns pointed to cell proliferation impacts in HuH-7 cells. In HepG2 and primary hepatocytes, COP1 suppression reduced the expression important hepatic regulators and markers, which could be restored by the introduction of a siRNA resistant COP1 transgene. COP1 downregulation reduced hepatic nuclear factor-4 alpha (HNF4A) abundance and function, as assessed by lower abundance of key HNF4A targets and reduced APOB secretion. HNF4A restoration partially rescued COP1 silencing in HepG2 cells. This study identifies COP1 as a key regulator of hepatocyte function, in part via HNF4A. COP1 was required to maintain HNF4A abundance and function in primary hepatocytes and in HepG2 cells, but not in HuH-7 cells. Lastly, by demonstrating contrasting roles of COP1 in HuH-7 and HepG2 cells, our findings also challenge previous work linking COP1 to hepatic tumorigenesis.
How altricial birds respond to a heat challenge: organismal perspectives on coping with a future climate scenario
Authors: Woodruff Mary J. , Tsueda Susanna N. , Cutrell Tiernan S. , Guardado Ethan A. , Rusch Douglas B. , Buechlein Aaron , Rosvall Kimberly A.
Published: January 2024

The ability to cope with heatwaves is likely to influence species success amidst climate change. However, relatively little is known about heat-coping mechanisms in endotherms, which are increasingly pushed to their thermoregulatory limits. We experimentally elevated nest temperatures by 4.5°C for 4 hours, focused on 12-day-old tree swallows (Tachycineta bicolor).

Nestlings exposed to sub-lethal heat moved towards cooler air at the nest box entrance, they panted more, and they weighed less than controls, suggesting panting-induced water loss. They also exhibited higher heat shock protein (HSP) gene expression in the blood, alongside widespread transcriptional differences related to antioxidant defenses, inflammation, and apoptosis. Nestlings exposed to milder heat were more likely to recruit into the breeding population, suggesting these coping mechanisms may be quite effective.

We also tested hypotheses on the drivers of variation in HSP gene expression, which was especially marked after heat-exposure. Even siblings in the same nest differed in HSP gene expression by over 14-fold. Heat-induced HSP levels were unrelated to individual body mass, or among-nest differences in brood size, temperature, and behavioral thermoregulation. However, nest ID explained a significant amount of HSP variation, which was larger between nests than within nests, pointing to genetic or early developmental factors

These results fill key knowledge gaps on thermoregulatory mechanisms in birds. We document ample individual variation upon which selection may act in the context of climate change and we underscore the need to understand intra-specific variation, an oft-ignored element that nevertheless shapes what is possible for future adaptation or acclimation to heat.
Targeted-Neuroinflammation Mitigation Using Inflammasome-Inhibiting Nanoligomers is Therapeutic in Experimental Autoimmune Encephalomyelitis (EAE) Mouse Model
Authors: Sharma Sadhana , Risen Sydney , Gilberto Vincenzo , Boland Sean , Chatterjee Anushree , Moreno Julie A. , Nagpal Prashant
Published: January 2024

Multiple Sclerosis (MS) is a debilitating autoimmune disease that impacts millions of patients worldwide, disproportionately impacting women (4:1), and often presenting at highly productive stages of life. This disease affects the spinal cord and brain, and is characterized by severe neuroinflammation, demyelination, and subsequent neuronal damage, resulting in symptoms like loss of mobility. While untargeted and pan-immunosuppressive therapies have proven to be disease-modifying and manage (or prolong the time between) symptoms in many patients, a significant fraction are unable to achieve remission. Recent work has suggested more targeted neuroinflammation mitigation through selective inflammasome-inhibition can offer relief to patients, while preserving key components of immune function. Here we show a screening of potential therapeutic targets using inflammasome-inhibiting Nanoligomers (NF-κB1, TNFR1, TNF-α, IL-6), that meet or far-exceed commercially available small-molecule counterparts like Ruxolitinib, MCC950, and Deucravacitinib. Using the human brain organoid model, top Nanoligomer combinations (NF-κB1+TNFR1: NI111, and NF-κB1+NLRP3: NI112) were shown to significantly reduce neuroinflammation, without any observable negative impact on organoid function. Further testing of these top Nanoligomer combinations in an aggressive Experimental Autoimmune Encephalomyelitis (EAE) mouse model for MS using intraperitoneal (IP) injections showed that NF-κB1and NLRP3 targeting Nanoligomer combination NI112 rescues mice without observable loss of mobility or disability, minimal inflammation in brain and spinal cord histology, and minimal to no immune cell infiltration of the spinal cord and no demyelination, similar to or at par with mice that received no EAE injections (negative control). Mice receiving NI111 (NF-κB1+TNFR1) also showed reduced neuroinflammation compared to saline (sham) treated EAE mice and at par/similar to other inflammasome-inhibiting small molecule treatments, although it was significantly higher than NI112 leading to subsequent worsening clinical outcomes. Furthermore, treatment with an oral formulation of NI112 at lower doses showed a significant reduction in EAE severity, albeit with higher variance owing to administration and formulation/fill-and-finish variability. Overall, these results point to the potential of further development and testing these inflammasome targeting Nanoliogmers as an effective neuroinflammation treatment for multiple neurodegenerative diseases, and potentially benefit several patients suffering from such debilitating autoimmune diseases like MS.

TOC GRAPHIC
Male contributions to female-male mutualism overcome the twofold cost of sex
Authors: Yasui Yukio , Hasegawa Eisuke
Published: January 2024

The increasing rate of anisogamy (fusion between eggs and sperm) against asexual thelytoky is necessarily halved under a 1:1 sex ratio because males lay no eggs. The present dominance of anisogamy despite this twofold cost of male production is the greatest enigma in evolutionary biology. Various benefits of sex are insufficient to overcome this cost. How can anisogamy be maintained? Here, we propose hypotheses that anisogamy evolved as a female-male mutualism in which females produce large eggs to ensure zygote development and males produce many sperm to ensure fertilisation. In the real world with finite resources, thelytoky cannot express its twofold increasing potential, and various male functions reduce the thelytoky’s performance. Thus, the twofold cost is an artefact of the infinite resource assumption. Simple mathematical models and simulations showed that when males and thelytokous females are equally competitive and acquire the same amount of resources but males can develop with fewer resources than females, anisogamy outcompetes thelytoky. When males need more growth costs than females, as in sexually selected species, the excess mating activity of “harmful” males reduces the fitness of thelytokous females. The significance of sexes, a question since Aristotle’s time, is explained by male contribution to sustaining mutualism.
Shrimp Hemocyanin elicits a potent humoral response in mammals and is favorable to hapten conjugation
Authors: Sun Huiwen , Wei Moris , Guo Amber , Zhang Ci , Wang Yuefeng , Huang Renhui , Li Xiaoxiao , Zhan Jeffrey , Wu Jonny , Jiang Bruce
Published: January 2024

Conjugation to a carrier protein is essential to give rise to the antigenicity of hapten, which is a small molecule and cannot induce an immune response by itself alone. Three carrier proteins e.g. KLH (Keyhole Limpet Hemocyanin), BSA (Bovine Serum Albumin), and OVA (Ovalbumin) were used mostly. KLH is advantageous to the others, majorly owing to its strong immunogenicity and limited usage in other biological assays. However, the solubility of KLH is not as well as the others, especially after hapten conjugation. Besides, the high market price of KLH results in high costs in vaccine and antibody development. Here, we extracted the shrimp hemocyanin (SHC) fromPenaeus vannamei (P. vannamei)with a production yield of > 1 g proteins (98 % pure) per 1 kg shrimp. Compared to KLH, the peptide-SHC conjugates exhibit higher solubility after hapten conjugation. Furthermore, compared with KLH, SHC induces comparable antibody production efficiency in mammals, with or without conjugation. Finally, rabbit polyclonal antibodies or mouse monoclonal antibodies were generated by immunizing SHC-peptide conjugates, and their applications in western blot, immunofluorescence and immunohistochemistry were confirmed. Therefore, we demonstrated that SHC may be used as a substitute for KLH in future antibody and vaccine development.
Identification of a distinct cluster of GDF15highmacrophages exhibiting anti-inflammatory activities
Authors: Dai Chaochao , Zhang Hongyu , Zheng Zhijian , Li Chun Guang , Ma Mingyuan , Gao Haiqing , Zhang Qunye , Cui Xiaopei , Jiang Fan
Published: January 2024

Macrophage-mediated inflammatory response may have crucial roles in the pathogenesis of a variety of human diseases. Growth differentiation factor 15 (GDF15) is a cytokine of the transforming growth factor-β superfamily, with potential anti-inflammatory activities. Previous studies observed in human lungs some macrophages which expressed a high level of GDF15. In the present study, we employed multiple techniques, including immunofluorescence, flow cytometry, and single-cell RNA sequencing, in order to further clarify the identity of such GDF15highmacrophages. We demonstrated that macrophages derived from human peripheral blood mononuclear cells and rat bone marrow mononuclear cells byin vitrodifferentiation with granulocyte-macrophage colony stimulating factor contained a minor population (∼1%) of GDF15highcells. GDF15highmacrophages did not exhibit a typical M1 or M2 phenotype, but had a unique molecular signature as revealed by single-cell RNA sequencing. Functionally, GDF15highmacrophages were associated with reduced responsiveness to pro-inflammatory activation; furthermore, GDF15highmacrophages could inhibit the pro-inflammatory functions of other macrophages via a paracrine mechanism. We further confirmed that GDF15per sewas a key mediator of the anti-inflammatory effects of GDF15highmacrophage. Also, we provided direct evidence showing that GDF15highmacrophages were also present in other macrophage-residing human tissues in addition to the lungs. Our results suggest that the GDF15highmacrophage may represent a distinct cluster of macrophage cells with intrinsic anti-inflammatory functions. The (patho)physiological importance of these cellsin vivowarrants further investigation.
Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma
Authors: Chattopadhyay Chandrani , Roszik Jason , Bhattacharya Rajat , Alauddin Md , Mahmud Iqbal , Yadugiri Sirisha , Ali Mir Mustafa , Khan Fatima S. , Prabhu Varun Vijay , Lorenzi Phillip , Burton Elizabeth , Morey Rohini R. , Lazcano Rossana , Davies Michael A. , Patel Sapna P. , Grimm Elizabeth A.
Published: January 2024

Purpose

Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, CLPP activators which reduce OXPHOS indirectly and have demonstrated safety in patients.

Experimental Design

We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201, ONC212) on the growth, survival, signaling and metabolism of UM cell linesin vitro,and for therapeutic effectsin vivoin UM liver metastasis models.

Results

CLPP expression was confirmed in primary and mUM patient samples. ONC201/212 treatment of UM cell linesin vitrodecreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis. ONC212 increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survivalin vivoin two UM liver metastasis models.

Conclusion

Imipridones are a promising strategy for further testing and development in mUM.
A multi-scale feature fusion model based on biological knowledge graph and transformer-encoder for drug-drug interaction prediction
Authors: Wang Tao , Deng Qiang , Hu Jialu , Wang Yongtian , Peng Jiajie , Chen Jing , Shang Xuequn
Published: January 2024

Drug-Drug Interaction (DDI) refers to the combined effects that occur when a patient takes multiple medications simultaneously or within the same period. This interaction can either enhance the therapeutic effects of the drugs or inhibit their efficacy, and in severe cases, it can even lead to adverse drug reactions (ADRs). Thus, it is crucial to identify potential DDIs, as this information is significant for both biological research and clinical medicine. However, most existing works only consider the information of individual drugs or focus on the local correlation between a few medical entities, thus overlooking the global performance of the entire human medical system and the potential synergistic effects of multi-scale information. Consequently, these limitations hinder the predictive ability of models. In this paper, we propose an innovative multi-scale feature fusion model called ALG-DDI, which can comprehensively incorporate attribute information, local biological information, and global semantic information. To achieve this, we first employ the Attribute Masking method to obtain the embedding vector of the molecular graph. Next, ALG-DDI leverages heterogeneous graphs to capture the local biological information between drugs and several highly related biological entities. The global semantic information is also learned from the medicine-oriented large knowledge graphs. Finally, we employ a transformer encoder to fuse the multi-scale drug representations and feed the resulting drug pair vector into a fully connected neural network for prediction. Experimental evaluations on datasets of varying sizes and different classification tasks demonstrate that ALG-DDI outperforms other state-of-the-art models.
Beyond microtubules: The cellular environment at the endoplasmic reticulum attracts proteins to the nucleus, enabling nuclear transport
Authors: Chae Seok Joo , Kim Dae Wook , Igoshin Oleg A. , Lee Seunggyu , Kim Jae Kyoung
Published: January 2024

All proteins are translated in the cytoplasm, yet many, including transcription factors, play vital roles in the nucleus. While previous research has concentrated on molecular motors for the transport of these proteins to the nucleus, recent observations reveal perinuclear accumulation even in the absence of an energy source, hinting at alternative mechanisms. Here, we propose that structural properties of the cellular environment, specifically the endoplasmic reticulum (ER), can promote molecular transport to the perinucleus without requiring additional energy expenditure. Specifically, physical interaction between proteins and the ER impedes their diffusion and leads to their accumulation near the nucleus. This result explains why larger proteins, more frequently interacting with the ER membrane, tend to accumulate at the perinucleus. Interestingly, such diffusion in a heterogeneous environment follows Chapman’s law rather than the popular Fick’s law. Our findings suggest a novel protein transport mechanism arising solely from characteristics of the intracellular environment.

Highlights

The interaction of proteins with ER slows down their diffusion at the perinucleus.

This leads proteins to migrate toward the perinucleus without ATP consumption.

Frequent ER interaction of larger proteins promotes perinuclear accumulation.

Diffusion with the physical interaction can be described by Chapman’s law.

Graphical abstract
Circatidal control of gene expression in the deep-sea hot vent shrimpRimicaris leurokolos
Authors: Zhang Hongyin , Yahagi Takuya , Miyamoto Norio , Chen Chong , Jiang Qingqiu , Qian Pei-Yuan , Sun Jin
Published: January 2024

Biological clocks are a ubiquitous feature of all life, enabling the use of natural environmental cycles to track time. Although studies on circadian rhythms have contributed greatly to the knowledge of chronobiology, biological rhythms in dark biospheres such as the deep sea remain poorly understood. Here, based on a laboratory free-running experiment, we reveal potentially endogenous rhythms in gene expression of the deep-sea hydrothermal vent shrimpRimicaris leurokolos. Oscillations with ∼12-hour periods, likely reflecting tidal influence, greatly prevail over others in the temporal transcriptome, indicatingR. leurokoloslikely depends on a circatidal clock consisting of at least some components independent of the circadian clocks. The tidal transcripts exhibit an antiphased expression pattern divided into two internally synchronized clusters, correlated with wide-ranging biological processes that occur in the nucleus and cytoplasm, respectively. In addition, comparing the tidal transcripts with the ∼12-hour ultradian rhythms genes in fruit flies and mice shows large similarity, indicating the likely scenario of broad impact of the tide on the ∼12-hour oscillations across the metazoan. These findings not only provide new insights into the temporal adaptations in deep-sea organisms but also highlight deep-sea hydrothermal vent organisms as intriguing models for chronobiological, particularly 12-hour ultradian rhythms, studies.