bluuebunny/crossref_metadata_2025 huggingface dataset:
Refractory Thrombocytopenia is the Earliest Diagnostic Criterion for Sinusoidal Obstruction Syndrome in Children
Authors: Consonni Filippo , Ciulli Alice , Cuzzubbo Daniela , Frenos Stefano , Sanvito Maria Chiara , Tondo Annalisa , Tintori Veronica , Gambineri Eleonora
Published: August 2024

Sinusoidal obstruction syndrome (SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT), whose diagnostic criteria changed over time to achieve a timelier diagnosis. Recently, pediatric-specific criteria presented by the European Society for Blood and Marrow Transplantation (pEBMT) incorporated transfusion-refractory thrombocytopenia (RT) as an early indicator of SOS in children. However, a comparison of all individual diagnostic parameters belonging to pEBMT and former SOS diagnostic criteria has never been performed. This retrospective study conducted at a pediatric tertiary care hospital analyzed all pediatric HSCT cases diagnosed with SOS among 170 children transplanted from 2009 to 2023. Eleven patients developed SOS during this period (incidence: 11/170, 6.5%). pEBMT, Seattle, and Baltimore criteria were retrospectively applied to the 11 cases and compared, showing that RT was the earliest fulfilled parameter (median onset: 6 d post-HSCT). pEBMT and Seattle criteria identified 11/11 SOS cases, with pEBMT leading to an earlier diagnosis. RT typically manifested before diagnosis, with significantly higher platelet transfusion requirements before diagnosis than after. RT is the earliest satisfied criterion in pediatric SOS and typically occurs in the initial stages of the disease before diagnosis. Further research is needed to identify additional early indicators of pediatric SOS.
Symptoms and Health-Related Quality of Life Among Older Adults Living With HIV
Authors: Lee Jung Eun , Haynes Emily R. , Chan Philip A.
Published: August 2024

Background

As individuals living with HIV age, they often experience both physical and psychological symptoms—along with potential reductions in social support—which can significantly affect their health-related quality of life (HRQOL)—a crucial measure in HIV care. However, research exploring the potential predictive roles of social support and symptom experiences in HRQOL among older people living with HIV (PLWH) is limited.

Objectives

This cross-sectional study aimed to investigate relationships between social support, symptom experiences, and HRQOL in older adults with HIV.

Methods

Older adults with HIV aged ≥50 years completed surveys on demographic and HIV-related characteristics, social support, four symptoms, and HRQOL. Hierarchical multiple linear regression analyses were used to determine predictors for six HRQOL domains.

Results

Among the 141 PLWH, significant associations were found between fatigue and health perceptions, physical functioning, and role functioning. Sleep disturbance was a significant predictor of health perceptions and social functioning. Anxiety displayed associations with physical functioning, role functioning, mental health, and pain. Depression was linked to health perceptions and mental health aspects of HRQOL. Notably, social support was not associated with any HRQOL domains.

Discussion

These findings underscore the importance of assessing a range of common symptoms to enhance HRQOL among older adults living with HIV, necessitating tailored symptom management strategies for this growing population.
Family education for safe social media use
Authors: Mersiovsky Amy
Published: August 2024

Children participate in social media challenges to satisfy their developmental needs. Unfortunately, joining these challenges may subject children to peer pressure, cyber-bullying, and physical dangers. Nurses must be well-versed in social media benefits, risks, and safety to provide appropriate guidance to families and advocate for them and safe social media use.
Patients’ Experiences of Health After Surgical Treatment for Paraesophageal Hernia Grades III and IV
Authors: Wennström Berith , Lindberg Susan , Svensson Johanna , Larsson Elin , Stensby Helen , Larsson Per-Anders
Published: August 2024

Surgery is the only available treatment for the longstanding chronic symptoms associated with large paraesophageal hernias except for reflux disease. The aim of this study was to illuminate how patients who previously suffered from grade III-IV hiatal hernia experience their life and health 2–6 months after surgery. The study is based on semi-structured interviews with 17 patients who received elective laparoscopic hernia repair for a large paraesophageal hernia. The data were analyzed using qualitative content analysis, resulting in three main themes: “Experiences of health,” “Being unable to leave the disease behind,” and “Still feeling unwell” and seven subthemes: “Escaping suffering”; “Learning to interpret bodily signals”; “Looking to the future with confidence”; “Finding oneself in a vicious circle of worry”; “The fear of relapse as a constant companion”; “Lingering disabling symptoms,” and “New and frightening symptoms.” Our study demonstrates large individual variations in the way patients experience their life and health after laparoscopic hernia repair. Central to the patients’ descriptions is that simply feeling physically healthy is insufficient for achieving overall health. Health care personnel can benefit from learning about patients’ experiences of health and suffering after surgery.
Management of Perianal Fistulas Associated with Crohn Disease
Authors: Greveson Kay , Haj Ola , Hart Ailsa , Geransar Parnia , Zmora Oded
Published: August 2024

Crohn disease perianal fistulas are associated with considerable morbidity and impaired quality of life. Nurses who specialize in inflammatory bowel disease (IBD) play a vital role in the management of Crohn disease perianal fistulas from diagnosis to long-term care; however, there is little evidence available to inform Crohn associated perianal fistula management strategies for nurses. This narrative review aims to provide IBD nurses with an up-to-date overview of Crohn perianal fistulas. It discusses the vital role IBD nurses play within the multidisciplinary team; the physical, social, and psychological impacts of Crohn perianal fistulas on patients; available treatment options; and how IBD nurses can support patients in their perianal fistula journey to enable optimum outcomes for patients. It also reviews diagnostic techniques and IBD nurses’ involvement in Crohn perianal fistula diagnosis. While this article is aimed at IBD nurses, it is relevant to all nurses irrespective of their role (unit, clinic, community, and stoma) who interact with patients with Crohn perianal fistulas because awareness of the signs and symptoms of this condition will enable timely referrals and diagnosis.
Kenneth Walters. 14 September 1934—28 March 2022
Authors: Russell Davies A. , Tanner FRS Roger I.
Published: August 2024

Kenneth (Ken) Walters was a leading international figure in the field of rheology. He applied his mathematical training to the analysis of many common test procedures, and contributed to the formulation of nonlinear constitutive equations for viscoelastic fluids. He also pioneered computational studies in rheology, and engaged in fruitful collaborations with industry—notably the oil and china clay industries. He was born in Swansea, South Wales, and he remained a devoted Welshman throughout his life. He studied under James Oldroyd at Swansea and was awarded the PhD degree in 1959. In 1960, after a stint in the USA, he was appointed as a lecturer at Aberystwyth, and he remained there until his death in 2022. He built a very strong research team at Aberystwyth, which became a dominant factor in the rheological scene in the United Kingdom. He was a keen promoter of rheology and assisted in the organization of many conferences and meetings. He was the founding editor of the
Journal of Non-Newtonian Fluid Mechanics
, and authored or co-authored four well-known books on rheology plus several tracts of a religious nature—Ken was always a devoted Christian. He was also a very able sportsman, especially at cricket and golf. He is survived by his wife Mary, three children and seven grandchildren.
Alwyn George Davies. 13 May 1926—1 September 2023
Authors: Puddephatt FRS Richard J.
Published: August 2024

Alwyn Davies was one of the last surviving members of Christopher Ingold (FRS)'s research group, a set of chemists who together transformed our understanding of mechanistic organic chemistry and laid the foundation for modern teaching of the subject. His early independent research on organic peroxides led into organometallic peroxides and thence into organometallic chemistry. His monographs
Organic peroxides
(1961, Butterworths) and
Organotin chemistry
(1997, 2004, Wiley) helped to promote the rapid growth of these topics. One route to organometallic peroxides was the reaction of organometallic compounds with dioxygen, and Alwyn Davies showed that these reactions occurred by a free radical chain reaction. Perhaps his greatest contribution was to establish that radical reactions would often occur at the metal centres in main group organometallic compounds, sometimes a million times faster than at hydrogen. He used electron spin resonance (ESR) spectroscopy to monitor the products and rates of these reactions, and to study the properties of the organic radicals that were produced. The theme of metals behaving as hydrogen surrogates permeated much of the work. In his later career, he developed improved methods for generating organic radical cations, and he recorded and analysed their unusual ESR spectra.
Montane rainforest dynamics under changes in climate and human impact during the past millennia in northern Madagascar
Authors: Montade Vincent , Bremond Laurent , Teixeira Helena , Kasper Thomas , Daut Gerhard , Rouland Sylvie , Rasoamanana Elysée , Ramavovolona Perle , Favier Charly , Arnaud Fabien , Radespiel Ute , Behling Hermann
Published: August 2024

Although it is well known that humans substantially altered the Malagasy ecosystems, the timing of the human arrival as well as the extension of their environmental impact is yet not well understood. This research aims to study the influence of early human impact and climate change on rainforests and wildlife in northern Madagascar during the past millennia. Results obtained from the lake sediment in a montane environment showed significant changes in vegetation within the lake catchment associated with a major drought that started approximately 1100 years ago. Human impact, revealed by fires, began at roughly the same time and occurred outside the lake catchment. Although this does not dismiss the impacts that humans had at a regional scale, this result demonstrates that the late Holocene natural drought also significantly impacted the ecosystems independently of anthropogenic activities. At a regional scale, a review of species demographic history revealed a substantial number of population bottlenecks during the last millennia, probably resulting from this combination of human-related impact and natural climate changes. This research highlights the importance of a multi-site and multi-proxy comparison for deciphering the nature and succession of environmental changes.
Accelerating AI for science: open data science for science
Authors: Lawrence Neil D. , Montgomery Jessica
Published: August 2024

Aspirations for artificial intelligence (AI) as a catalyst for scientific discovery are growing. High-profile successes deploying AI in domains such as protein folding have highlighted AI’s potential to unlock new frontiers of scientific knowledge. However, the pathway from AI innovation to deployment in research is not linear. Those seeking to drive a new wave of scientific progress through the application of AI require a diffusion engine that can enhance AI adoption across disciplines. Lessons from previous waves of technology change, experiences of deploying AI in real-world contexts and an emerging research agenda from the AI for science community suggest a framework for accelerating AI adoption. This framework requires action to build supply chains of ideas between disciplines; rapidly transfer technological capabilities through open research; create AI tools that empower researchers; and embed effective data stewardship. Together, these interventions can cultivate an environment of open data science that deliver the benefits of AI across the sciences.
An extensive re-evaluation of evidence and analyses of the Randomised Badger Culling Trial (RBCT) I: Within proactive culling areas
Authors: Mills Cathal L. , Woodroffe Rosie , Donnelly Christl A.
Published: August 2024

Here, in the first of two investigations, we evaluate and extend the analyses of the Randomised Badger Culling Trial (RBCT) to estimate the effectiveness of proactive badger culling for reducing incidence of tuberculosis (TB) in cattle within culling areas. Using previously reviewed, publicly available data, alongside frequentist and Bayesian approaches, we re-estimate culling effects for confirmed incidence of herd breakdowns (TB incidents in cattle) within proactive culling areas. We appraise the varying assumptions and statistical structures of individual models to determine model appropriateness. Our re-evaluation of frequentist models provides results consistent with peer-reviewed analyses of RBCT data, due to the consistency of beneficial effects across three analysis periods. Furthermore, well-fitting Bayesian models with weakly informative prior distribution assumptions produce high probabilities (91.2%–99.5%) of beneficial effects of proactive culling on confirmed herd breakdowns within culling areas in the period from the initial culls (between 1998 and 2002) until 2005. Similarly high probabilities of beneficial effects were observed post-trial (from 1 year after last culls until March 2013). Thus, irrespective of statistical approach or study period, we estimate substantial beneficial effects of proactive culling within culling areas, consistent with separate, existing, peer-reviewed analyses of the RBCT data.
Digital: accelerating the pathway
Authors: Davis Andrew , Waldon Chris , Muldrew Stuart I. , Patel Bhavin S. , Verrier Patricia , Barrett Thomas R. , Politis Gerasimos A.
Published: August 2024

The Spherical Tokamak for Energy Production (STEP) programme is an ambitious but challenging endeavour to design and deliver a prototype fusion power plant. It is a rapid, fast-moving programme, designing a first of a kind device in a Volatile, Uncertain, Complex and Ambiguous (VUCA) environment, and digital tools play a pivotal role in managing and navigating this space. Digital helps manage the complexity and sheer volume of information. Advanced modelling and simulation techniques provide a platform for designers to explore various scenarios and iteratively refine designs, providing insights into the intricate interplay of requirements, constraints and design factors across physics, technology and engineering domains and aiding informed decision-making amidst uncertainties. It also provides a means of building confidence in the new scientific, technological and engineering solutions, given that a full-scale-integrated precursor test is not feasible, almost by definition. The digital strategy for STEP is built around a vision of a digital twin of the whole plant. This will evolve from the current digital shadow formed by system architecting codes and complex workflows and will be underpinned by developing capabilities in plasma, materials and engineering simulation, data management, advanced control, industrial cybersecurity, regulation, digital technologies and related digital disciplines. These capabilities will help address the key challenges of managing the complexity and quantity of information, improving the reliability and robustness of the current digital shadow and developing an understanding of its validity and performance.

This article is part of the theme issue ‘Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)’.
Unlocking maintenance—architecting STEP for maintenance and realizing remountable magnet joints
Authors: van Arkel Adrian , Lamb Chris , Robinson Harry , Dieudonné Yannik
Published: August 2024

The architecture of the Spherical Tokamak for Energy Production (STEP) has been developed to enable a hybrid maintenance approach using ports in the vacuum vessel for a limited list of tasks that must be performed shortly after shutdown, and larger openings to simplify and speed up major refits. Robotic handling systems in zero-human entry facilities will prevent workers from being exposed to the most hazardous environments. While the approach is largely grounded in existing technologies, the scale and environment of STEP will require significant technology development. Notably, programmes have been established to develop service connections and in-vessel robotic technologies. The engineering integration of the maintenance strategy into the tokamak remains a priority, as does ongoing work to simplify and reduce the cost of the buildings required to facilitate maintenance. Remountable magnet joints are critical to ensuring life-limited magnet components can be replaced during the STEP lifetime and realizing the STEP maintenance strategy. It is a high-risk endeavour owing to the low technology maturity of the potential solutions and owing to the tough and intertwined technical challenges and constraints imposed by both the fundamental physics and the STEP requirements and architecture. An integrated design approach has been taken to balance many competing factors and integrate with interfacing systems, and a multi-faceted technology development programme has been established to address technical risk and to inform, verify and validate the STEP remountable magnet design.

This article is part of the theme issue ‘Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)’.
Biallelic variants inDAP3result in reduced assembly of the mitoribosomal small subunit with altered intrinsic and extrinsic apoptosis and a Perrault syndrome-spectrum phenotype
Authors: Smith Thomas B. , Kopajtich Robert , Demain Leigh A.M. , Rea Alessandro , Thomas Huw B. , Schiff Manuel , Beetz Christian , Joss Shelagh , Conway Gerard S. , Shukla Anju , Yeole Mayuri , Radhakrishnan Periyasamy , Azzouz Hatem , Chehida Amel Ben , Elmaleh-Bergès Monique , Glasgow Ruth I.C. , Thompson Kyle , Oláhová Monika , He Langping , Jenkinson Emma M. , Jahic Amir , Belyantseva Inna A. , Barzik Melanie , Urquhart Jill E. , O’ Sullivan James , Williams Simon G. , Bhaskar Sanjeev S. , Carrera Samantha , Blakes Alexander J.M. , Banka Siddharth , Yue Wyatt W. , Ellingford Jamie M. , Houlden Henry ,   DDD Study, Munro Kevin J. , Friedman Thomas B. , Taylor Robert W. , Prokisch Holger , O’Keefe Raymond T. , Newman William G.
Published: August 2024

The mitoribosome synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders, and frequently show combined oxidative phosphorylation deficiency. Here, we describe five unrelated individuals with biallelic variants in theDAP3nuclear gene encoding mitoribosomal small subunit 29 (MRPS29), with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein levels, and consequently decreased levels of additional protein components of the mitoribosomal small subunit, associated with a combined complex I and IV deficiency. Lentiviral transduction of fibroblasts from affected individuals with wild-typeDAP3cDNA increased DAP3 mRNA expression, and partially rescued protein levels of MRPS7, MRPS9 and complex I and IV subunits, demonstrating the pathogenicity of theDAP3variants. Protein modelling suggested thatDAP3disease-associated missense variants can impact ADP binding, andin vitroassays demonstratedDAP3variants can consequently reduce both intrinsic and extrinsic apoptotic sensitivity, DAP3 thermal stability and DAP3 GTPase activity. Our study presents genetic and functional evidence that biallelic variants inDAP3result in a multisystem disorder of combined oxidative phosphorylation deficiency with pleiotropic presentations, consistent with mitochondrial dysfunction.
Neither fifty percent slow-wave sleep suppression nor fifty percent rapid eye movement sleep suppression does impair memory consolidation
Authors: Ukraintseva Yulia V. , Saltykov Konstantin A. , Tkachenko Olga N.
Published: August 2024

Establishing well-defined relationships between sleep features and memory consolidation is essential in comprehending the pathophysiology of cognitive decline commonly seen in patients with insomnia, depression, and other sleep-disrupting conditions.

Twenty-eight volunteers participated in two experimental sessions: a session with selective SWS suppression during one night and a session with undisturbed night sleep (as a control condition). Fifteen of them also participated in a third session with REM suppression. Suppression was achieved by presenting an acoustic tone. In the evening and the morning, the participants completed procedural and declarative memory tasks and the Psychomotor vigilance task (PVT). Heart rate variability analysis and salivary cortisol were used to control possible stress reactions on sleep interference.

SWS and REM suppression led to more than 50 percent reduction in amount of these stages. Neither vigilance nor memory consolidation was impaired after SWS or REM suppression. Unexpectedly, a beneficial effect of selective SWS suppression on PVT performance was found. Similarly, after a night with SWS suppression, the overnight improvement in procedural skills was higher than after a night with REM suppression and after a night with undisturbed sleep.

Our data brings into question the extent to which SWS and REM are truly necessary for effective memory consolidation to proceed. Moreover, SWS suppression may even improve the performance of some tasks, possibly by reducing sleep inertia associated with undisturbed sleep.

Highlights

Our data brings into question the extent to which SWS and REM are truly necessary for effective memory consolidation to proceed.

Provided that sleep disturbances do not cause stress, half the usual amount of SWS or REM is sufficient for procedural and declarative memory consolidation.

Moreover, SWS suppression may even improve the performance of psychomotor vigilance task and finger sequence tapping task, possibly by reducing sleep inertia associated with undisturbed night sleep.
The Lomb-Scargle periodogram-based differentially expressed gene detection along pseudotime
Authors: Iuchi Hitoshi , Hamada Michiaki
Published: August 2024

Motivation

In recent years, single-cell RNA sequencing (scRNA-seq) has provided high-resolution snapshots of biological processes and has contributed to the understanding of cell dynamics. Trajectory inference has the potential to provide a quantitative representation of cell dynamics, and several trajectory inference algorithms have been developed. However, the downstream analysis of trajectory inference, such as the analysis of differentially expressed genes (DEG), remains challenging.

Results

In this study, we introduce a Lomb-Scargle (LS) periodogram-based algorithm for identifying DEGs associated with pseudotime in a trajectory analysis. The algorithm is capable of analyzing any inferred trajectory, including tree structures with multiple branching points, leading to diverse cell types. We validated this approach using simulated data and real datasets, and our results showed that our approach was superior when performing DEG analysis on complex structured trajectories. Our approach will contribute to gene characterization in trajectory analysis and help gain deeper biological insights.

Availability

All code used in our proposed method can be found athttps://github.com/hiuchi/LS.

Contact

hitoshi.iuchi@hamadalab.com

Supplementary information

Supplementary data are available atJournal Nameonline.
Exploring mate choice and male strategies in a polymorphic moth
Authors: Selenius Eetu , De Pasqual Chiara , Hänninen Matleena , Kartano Liisa , Winters Sandra , Mappes Johanna
Published: August 2024

Color polymorphisms in natural populations often reflect the interplay between various selective pressures, such as natural and sexual selection. In this study, we investigate the dynamics of sexual selection operating on color polymorphism in wood tiger moths under different ecological contexts. Wood tiger moths exhibit polymorphism in male hindwing coloration, with individuals possessing one or two dominant W alleles displaying two forms of white coloration that differ in their UV reflectance (WW, Wy), while those with two recessive y alleles exhibit yellow coloration (yy). Females carry the color alleles, but do not express them phenotypically. We performed two mate choice experiments that simulated two ecological conditions: one with limited morph availability and low male encounter rates and the other with all morphs present and high potential for male encounters. We demonstrate that WW males consistently experience higher mating success compared to yy males, irrespective of the presence of Wy males and male encounter rates. Surprisingly, mating with a WW male does not confer direct reproductive benefits to females in terms of lifetime reproductive success; instead, Wy females exhibit overall higher reproductive success regardless of their mating partner. Although the precise mechanism driving the higher mating success of WW males remains unclear, a temporal decline in mating success of WW males suggests potential differences in male mating strategies. Our findings support the hypothesis that sexual selection contributes to the maintenance of polymorphism, revealing a stable mating advantage of a particular color morph that may be offset by other selective forces.
Flexible modeling of large-scale neural network stimulation: electrical and optical extensions to The Virtual Electrode Recording Tool for EXtracellular Potentials (VERTEX)
Authors: Pierce Anne F. , Shupe Larry , Fetz Eberhard , Yazdan-Shahmorad Azadeh
Published: August 2024

Background

Computational models that predict effects of neural stimulation can be used as a preliminary tool to informin-vivoresearch, reducing the costs, time, and ethical considerations involved. However, current models do not support the diverse neural stimulation techniques usedin-vivo, including the expanding selection of electrodes, stimulation modalities, and stimulation paradigms.

New Method

To develop a more comprehensive software, we created several extensions to The Virtual Electrode Recording Tool for EXtracellular Potentials (VERTEX), the MATLAB-based neural stimulation tool from Newcastle University. VERTEX simulates input currents in a large population of multi-compartment neurons within a small cortical slice to model electric field stimulation, while recording local field potentials (LFPs) and spiking activity. Our extensions to its existing electric field stimulation framework include allowing multiple pairs of parametrically defined electrodes and biphasic, bipolar stimulation delivered at programmable delays. To support the growing use of optogenetic approaches for targeted neural stimulation, we introduced a feature that models optogenetic stimulation through an additional VERTEX input function that converts irradiance to currents at optogenetically responsive neurons. Finally, we added extensions to allow complex stimulation protocols including paired-pulse, spatiotemporal patterned, and closed-loop stimulation.

Results

We demonstrated our novel features using VERTEX’s built-in functionalities, with results in alignment with other models and experimental work.

Conclusions

Our extensions provide an all in one platform to efficiently and systematically test diverse, targeted, and individualized stimulation patterns.
GPT-4V shows human-like social perceptual capabilities at phenomenological and neural levels
Authors: Santavirta Severi , Wu Yuhang , Nummenmaa Lauri
Published: August 2024

Humans navigate the social world by rapidly perceiving social features from other people and their interaction. Recently, large-language models (LLMs) have achieved high-level visual capabilities for detailed object and scene content recognition and description. This raises the question whether LLMs can perceive nuanced and tacit social information form images and videos, and whether the high-dimensional perceptual structure aligns with that of humans. We collected social perceptual evaluations for 138 social features from GPT-4V for images (N=468) and videos (N=234) that are derived from social movie scenes. These evaluations were compared with human evaluations (N=2254). The comparisons established that GPT-4V can achieve human-like social perceptual capabilities at the level of individual features as well as at the level of high-dimensional perceptual representations. We also modelled hemodynamic responses (N=97) to viewing socioemotional movie clips with feature annotations by human observers and GPT-4V. These results demonstrated that GPT-4V can also reproduce the social perceptual space at the neural level highly similar to reference human evaluations. These human-like social perceptual capabilities of LLMs could have wide range of real-life applications ranging from health care to business and would open exciting new avenues for behavioural and psychological research.
mCLAS adaptively rescues disease-specific sleep and wake phenotypes in neurodegeneration
Authors: Dias Inês , Baumann Christian R. , Noain Daniela
Published: August 2024

Sleep alterations are hallmarks of prodromal Alzheimer’s (AD) and Parkinson’s disease (PD), with fundamental neuropathological processes of both diseases showing susceptibility of change upon deep sleep modulation. However, promising pharmacological deep sleep enhancement results are hindered by specificity and scalability issues, thus advocating for noninvasive slow-wave activity (SWA) boosting methods to investigate the links between deep sleep and neurodegeneration. Accordingly, we have recently introduced mouse closed-loop auditory stimulation (mCLAS), which is able to successfully boost SWA during deep sleep in neurodegeneration models. Here, we aim at further exploring mCLAS’ acute effect onto disease-specific sleep and wake alterations in AD (Tg2576) and PD (M83) mice. We found that mCLAS adaptively rescues pathological sleep and wake traits depending on the disease-specific impairments observed at baseline in each model. Notably, in AD mice mCLAS significantly increases NREM long/short bout ratio, decreases vigilance state distances by decreasing transition velocities and increases the percentage of cumulative time spent in NREM sleep in the last three hours of the dark period. Contrastingly, in PD mice mCLAS significantly decreases NREM sleep consolidation, by potentiating faster and more frequent transitions between vigilance states, decreases average EMG muscle tone during REM sleep and increases alpha power in WAKE and NREM sleep. Overall, our results indicate that mCLAS selectively prompts an acute alleviation of neurodegeneration-associated sleep and wake phenotypes, by either potentiating sleep consolidation and vigilance state stability in AD or by rescuing bradysomnia and decreasing cortical hyperexcitability in PD. Further experiments assessing the electrophysiological, neuropathological and behavioural long-term effects of mCLAS in neurodegeneration may majorly impact the clinical establishment of sleep-based therapies.
Low extracellular pH protects cancer cells from ammonia toxicity
Authors: Dravecka Maria , Mikkola Ingvild , Johansen Terje , Seternes Ole Morten , Mejlvang Jakob
Published: August 2024

Ammonia is a natural waste product of cellular metabolism which, through its lysosomotropic ability, can have detrimental effects on various cellular functions. Increased levels of ammonia were recently detected in the interstitial fluid of various tumours, substantiating that high ammonia concentrations are a pathophysiological condition in the tumour microenvironment, alongside hypoxia and acidosis. Since little is known about how cancer cells respond to elevated levels of ammonia in the tumour microenvironment, we investigated how a panel of cancer cell lines derived from solid tumours behaved when exposed to increasing concentrations of ammonia. We found that ammonia represses cell growth, induces genome instability, and inhibits lysosome-mediated proteolysis in a dose-dependent manner. Unexpectedly, we also found that small fluctuations in the pH of the extracellular environment, had a significant impact on the cytotoxic effects of ammonia. In summary, our data suggest that the balance of pH and ammonia within the interstitial fluids of cancerous tumours can have a significant impact on the behaviour and fate of cancer cells.
Refining Martini Force Field Interactions for Accurate Glycoprotein Modeling
Authors: Heidari Maziar , Sikora Mateusz , Hummer Gerhard
Published: August 2024

Covalently attached sugar molecules play important roles as mediators of biomolecular interactions. Molecular dynamics simulations are an indispensable tool to explore these interactions at the molecular level. The large time and length scales involved frequently necessitate the use of coarse-grained representations, which heavily depend on the parameterization of sugar-protein interactions. Here, we adjust the sugar-protein interactions in the widely used Martini 2.2 force field to reproduce the experimental second virial coefficients between sugars and proteins. In simulations of two model proteins in glucose solutions with adjusted force field parameters, we observe weak protein-sugar interaction. The sugar molecules are thus acting mainly as crowding agents, in agreement with experimental measurements. The procedure to fine-tune sugar-protein interactions is generally applicable and could prove useful also for atomistic force fields.
Investigating the role of axonal localization of sex peptide receptor in post-mating responses of femaleDrosophila melanogaster
Authors: Zhang Tianmu , Zhou Xinyue , Kim Woo Jae
Published: August 2024

This study elucidates the molecular mechanisms underlying the axonal localization of the sex peptide receptor, a pivotal G-protein coupled receptor in theDrosophila melanogasterpost-mating response cascade. Utilizing transgenic expression, neuronal labeling, and bioinformatics analyses, we demonstrate that the N-terminal domain of SPR is indispensable for its axonal targeting in bothDrosophilalarval ventral nerve cord neurons and mouse hippocampal neurons. Deletion of the N-terminal domain abolished axonal localization, highlighting its critical role in this process. Intriguingly, the C-terminal domain of SPR appears to play a subordinate role in axonal targeting. Bioinformatical analysis revealed a striking homology between the N-terminus of SPR and the Broad-complex, Tramtrack, and Bric-a-brac/poxvirus and zinc finger family of proteins. The BTB domain, a conserved protein-protein interaction domain within this family, is implicated in diverse cellular processes and axonal targeting. Further investigation into the role of the BTB domain-like region in SPR could provide valuable insights into the molecular underpinnings of axonal targeting and post-mating responses inDrosophila. This research contributes to our understanding of the intricate mechanisms governing GPCR localization and function in the context of reproductive biology and neuronal signaling.
RBN-2397, a PARP7 Inhibitor, Synergizes with Paclitaxel to Inhibit Proliferation and Migration of Ovarian Cancer Cells
Authors: Spirtos Alexandra N. , Aljardali Marwa W. , Challa Sridevi , Koul Sneh , Lea Jayanthi S. , Kraus W. Lee , Camacho Cristel V.
Published: August 2024

Objectives

Mono(ADP-ribosyl)ation (MARylation), a post translational modification of proteins, is emerging as an important regulator of the biology of cancer cells. PARP7 (TiPARP), a mono (ADP-ribosyl) transferase (MART), MARylates its substrate α-tubulin in ovarian cancer cells, promoting destabilization of microtubules, cell growth, and migration. Recent development of RBN-2397, a potent inhibitor that selectively acts on PARP7, has provided a new tool for exploring the role of PARP7 catalytic activity in biological processes. In this study, we investigated the role of PARP7 catalytic activity in the regulation of ovarian cancer cell biology via MARylation of α-tubulin.

Methods

Ovarian cancer cell lines (OVCAR4, OVCAR3) were treated with RBN-2397 and paclitaxel, both separately and in combination. Western blotting and immunoprecipitation confirmed the effects of RBN-2397 on α-tubulin MARylation and stabilization. Cell proliferation and migration were assessed, and α-tubulin stabilization was quantified using immunofluorescent imaging. RNA-sequencing was performed to assess the effects on gene expression changes.

Results

RBN-2397 inhibited PARP7 activity, decreasing α-tubulin MARylation, leading to its stabilization, and reducing cancer cell proliferation and migration. The addition of paclitaxel further enhanced these effects, highlighting a synergistic interaction between the two drugs. Mutating the site of PARP7-mediated MARylation on α-tubulin similarly resulted in microtubule stabilization and decreased cell migration in the presence of paclitaxel.

Conclusions

This study demonstrates that targeting PARP7 with RBN-2397, particularly in combination with paclitaxel, offers an effective strategy for inhibiting aggressive ovarian cancer cell phenotypes. Our findings underscore the potential of combining PARP7 inhibitors with established chemotherapeutics to enhance treatment efficacy in ovarian cancer.
CryoSCAPE: Scalable Immune Profiling Using Cryopreserved Whole Blood for Multi-omic Single Cell and Functional Assays
Authors: Heubeck Alexander T. , Phalen Cole , Kaul Neel , Wittig Peter J. , Garber Jessica , Weiss Morgan , Genge Palak C. , Thomson Zachary , Gustafson Claire , Reading Julian , Skene Peter J.
Published: August 2024

Background

The field of single cell technologies has rapidly advanced our comprehension of the human immune system, offering unprecedented insights into cellular heterogeneity and immune function. While cryopreserved peripheral blood mononuclear cell (PBMC) samples enable deep characterization of immune cells, challenges in clinical isolation and preservation limit their application in underserved communities with limited access to research facilities. We present CryoSCAPE (Cryopreservation for Scalable Cellular And Proteomic Exploration), a scalable method for immune studies of human PBMC with multi-omic single cell assays using direct cryopreservation of whole blood.

Results

Comparative analyses of matched human PBMC from cryopreserved whole blood and density gradient isolation demonstrate the efficacy of this methodology in capturing cell proportions and molecular features. The method was then optimized and verified for high sample throughput using fixed single cell RNA sequencing and liquid handling automation with a single batch of 60 cryopreserved whole blood samples. Additionally, cryopreserved whole blood was demonstrated to be compatible with functional assays, enabling this sample preservation method for clinical research.

Conclusions

The CryoSCAPE method, optimized for scalability and cost-effectiveness, allows for high-throughput single cell RNA sequencing and functional assays while minimizing sample handling challenges. Utilization of this method in the clinic has the potential to democratize access to single-cell assays and enhance our understanding of immune function across diverse populations.
Understanding responses to multi-electrode epiretinal stimulation using a biophysical model
Authors: Vilkhu Ramandeep S. , Vasireddy Praful K. , Kish Kathleen E. , Gogliettino Alex R. , Lotlikar Amrith , Hottowy Pawel , Dabrowski Wladyslaw , Sher Alexander , Litke Alan M. , Mitra Subhasish , Chichilnisky E.J.
Published: August 2024

Objective

Neural interfaces are designed to evoke specific patterns of electrical activity in populations of neurons by stimulating with many electrodes. However, currents passed simultaneously through multiple electrodes often combine nonlinearly to drive neural responses, making evoked responses difficult to predict and control. This response nonlinearity could arise from the interaction of many excitable sites in each cell, any of which can produce a spike. However, this multi-site activation hypothesis is difficult to verify experimentally.

Approach

We developed a biophysical model to study retinal ganglion cell (RGC) responses to multi-electrode stimulation and validated it using data collected fromex vivopreparations of the macaque retina using a microelectrode array (512 electrodes; 30µm pitch; 10µm diameter).

Results

First, the model was validated by using it to reproduce essential empirical findings from single-electrode recording and stimulation, including recorded spike voltage waveforms at multiple locations and sigmoidal responses to injected current. Then, stimulation with two electrodes was modeled to test how the positioning of the electrodes relative to the cell affected the degree of response nonlinearity. Currents passed through pairs of electrodes positioned near the cell body or far from the axon (>40 µm) exhibited approximately linear summation in evoking spikes. Currents passed through pairs of electrodes close to the axon summed linearly when their locations along the axon were similar, and nonlinearly otherwise. Over a range of electrode placements, several distinct, localized spike initiation sites were observed, and the number of these sites covaried with the degree of response nonlinearity. Similar trends were observed for three-electrode stimuli. All of these trends in the simulation were consistent with experimental observations.Significance. These findings support the multi-site activation hypothesis for nonlinear activation of neurons, providing a biophysical interpretation of previous experimental results and potentially enabling more efficient use of multi-electrode stimuli in future neural implants.
Phthalate exposure influences mating behavior and sperm morphology in an aquatic ecotoxicology model system
Authors: Guevara Bryan Lamberto , Patel Nadia , Tu Yi , Neiman Maurine
Published: August 2024

Phthalates are a group of chemicals used to make plastics more durable, found in applications from cosmetics, lubricating oils, and flooring to soap, shampoo, and hairspray (CDC, 2021). Phthalates are also now known to be endocrine disruptors with connections to adverse reproductive outcomes in animals, including humans. Here, we evaluate the potential effects of a widely used phthalate ester, dimethyl phthalate (DMP), on male reproduction in a freshwater snail. DMP is found in industrial applications like solid rocket propellant as well as consumer products such as insect repellents and plastics. While there is some evidence that DMP negatively affects reproduction, especially in females, we still know very little about potential DMP effects on males. We addressed this important knowledge gap by testing the effects of DMP onPotamopyrgus antipodarum, a prosobranch snail native to New Zealand. These snails are very sensitive to water conditions and environmental chemicals, including endocrine-disrupting compounds, and are thus rising in prominence as water-quality sentinels and ecotoxicology models. We exposed experimental groups of maleP. antipodarumto one of three different concentrations of DMP and characterized mating behavior and sperm morphology as a function of DMP exposure. Differences in these traits were primarily observed between the males in the control versus the High (10-6M) DMP concentration group. As DMP exposure levels increased, we found that mating frequency ultimately decreased by more than 69% and that sperm morphology was increasingly altered relative to control males. Altogether, study outcomes suggest DMP exposure in male animals could have negative effects on reproduction, with particular relevance in aquatic and marine environments that are especially likely to harbor leached endocrine-disrupting chemicals.
Optimising experimental designs for model selection of ion channel drug binding mechanisms
Authors: Patten-Elliott Frankie , Lei Chon Lok , Preston Simon P. , Wilkinson Richard D. , Mirams Gary R.
Published: August 2024

The rapid delayed rectifier current carried by the human Ether-à-go-go-Related Gene (hERG) channel is susceptible to drug-induced reduction which can lead to an increased risk of cardiac arrhythmia. Establishing the mechanism by which a specific drug compound binds to hERG can help to reduce uncertainty when quantifying pro-arrhythmic risk. In this study, we introduce a methodology for optimising experimental voltage protocols to produce data that enable different proposed models for the drug-binding mechanism to be distinguished. We demonstrate the performance of this methodology via a synthetic data study. If the underlying model of hERG current is known exactly, then the optimised protocols generated show noticeable improvements in our ability to select the true model when compared to a simple protocol used in previous studies. However, if the model is not known exactly, and we assume a discrepancy between the data-generating hERG model and the hERG model used in fitting the models, then the optimised protocols become less effective in determining the ‘true’ binding dynamics. While the introduced methodology shows promise, we must be careful to ensure that, if applied in a real data study, we have a well-calibrated model of hERG current gating.
Widespread environment-specific causal effects detected in the UK Biobank
Authors: Knüsel Leona , Man Alice , Paré Guillaume , Kutalik Zoltán
Published: August 2024

Background

Mendelian Randomization (MR) is a widely used tool to infer causal relationships. Yet, little research has been conducted on the elucidation of environment specific causal effects, despite mounting evidence for the relevance of causal effect modifying environmental variables.

Methods

To investigate potential modifications of causal effects, we extended two-stage-least-squares MR to investigate interaction effects (2SLS-I). We first tested 2SLS-I in a wide range of realistic simulation settings including quadratic and environment-dependent causal effects. Next, we applied 2SLS-I to investigate how environmental variables such as age, socioeconomic deprivation, and smoking modulate causal effects between a range of epidemiologically relevant exposure (such as systolic blood pressure, education, and body fat percentage) - outcome (e.g. forced expiratory volume (FEV1), CRP, and LDL cholesterol) pairs (in up to 337’392 individuals of the UK biobank).

Results

In simulations, 2SLS-I yielded unbiased interaction estimates, even in presence of non-linear causal effects. Applied to real data, 2SLS-I allowed for the detection of 182 interactions (P<0.001), with age, socioeconomic deprivation, and smoking being identified as important modifiers of many clinically relevant causal effects. For example, the positive causal effect of Triglycerides on systolic blood pressure was significantly attenuated in the elderly whilst the positive causal effect of Gamma-glutamyl transferase on CRP was intensified in smokers.

Conclusion

We present 2SLS-I, a method to simultaneously investigate environment-specific and non-linear causal effects. Our results highlight the importance of environmental variables in modifying well-established causal effects.