bluuebunny/crossref_metadata_2025 huggingface dataset:
A Custom’s Nine Lives: Decolonial Continuities of Opinio Juris in Customary International Law
Authors: Singh Prabhakar
Published: December 2024

“Old” customs stress upon State practice while the “new” on opinio juris. The Right of Passage over Indian Territory case (1960) started a debate from the bench to the bar on the coexistence of general, local, and special customs in the postcolonial law of territory. Although key to, first, the Asian and, then, the African self-determination, the relationship of opinio juris and decolonization remains unexamined. In the Question of the Delimitation of the Continental Shelf between Nicaragua and Colombia case (2023), the International Court of Justice has enriched opinio juris by accepting “considerations other than a sense of legal obligation”. Having lived overland occasionally decoupled from State practices since the Military and Paramilitary Activities in Nicaragua case (1986), the conceptually amphibious opinio juris enters the sea today. Historically, Asian opinio juris (1940s) first normatively fractured colonialism to, subsequently, fertilize the customary law on African decolonization (1950s).
Investigating an ELT community of practice in India
Authors: Mukherjee Kuheli
Published: December 2024

The study reports on the genesis of an Indian ELT Community of Practice (CoP) and its impact on its members during and after the Covid pandemic. Quantitative and qualitative data collected through a questionnaire, reflective narratives, and observations explored how the participant teachers evaluated the impact of community participation on their professional learning, consistent with the concept of situated learning through legitimate peripheral participation in a CoP. Participants’ reflections testified how members’ journeys from peripheral to full and intensified participation through involvement in CoP activities offered opportunities for learning and legitimising their role as community practitioners. The insights offered might be relevant for utilising informal bottom-up CoPs for teachers’ continuous professional development in general and also provide ideas for making such CoPs run effectively for teacher development. It argues that bottom-up Communities of Practice can become an integral part of in-service teacher education in India and similar challenging contexts.
Using an SMS to improve bowel cancer screening: the acceptability and feasibility of a multifaceted intervention
Authors: McIntosh Jennifer G , Wood Anna , Jenkins Mark , Onwuka Shakira , Chondros Patty , Campbell Tina , Wenkart Edweana , O’Reilly Clare , Dixon Ian , Toner Julie , Martinez Gutierrez Javiera , Govan Linda , Emery Jon D
Published: December 2024

Background

The Australian National Bowel Cancer Screening Program sends an immunochemical faecal occult blood test to Australians aged 50–74 years to screen for bowel cancer, but uptake is low (40.9%). The SMARTscreen trial demonstrated that sending a short messaging services (SMS) prompt from the participant’s general practitioner (GP) increased the proportion of kit returns by 16.5%. This research aimed to determine the acceptability and feasibility of implementing SMARTscreen.

Method

SMARTscreen was a cluster randomized controlled trial set in 21 Australian general practices in regional Australia. Participants and general practice staff involved in the trial were included in this study. Acceptability and feasibility were measured quantitatively by calculating proportions of the SMS received, viewed, or opted out of, and qualitatively by interviewing people who sent and received the SMS.

Results

Of 2914 SMS sent, 2645 SMS (91%) were received by participants, 1128 (43%) people opened the weblink, and 59 (2%) people opted out of receiving future SMS. Interviews with general practice staff (n = 17) and participants (n = 18) found that sending and receiving the SMS was acceptable and feasible. The SMS was considered a low-burden activity that easily integrated into the clinic’s workflow without impacting clinicians’ time. Participants reported an increased intention to participate in screening, but some people worried the weblink was spam, and some suggested sending it out of working hours.

Conclusion

The SMS-based intervention was widely accepted by GP staff and participants. Future research should test the SMS with and without the weblink, and send the SMS at a more convenient time of the day/week.
Mindfulness interventions in older adults for mental health and well-being: A meta-analysis
Authors: Verhaeghen Paul , Aikman Shelley N , Mirabito Grazia
Published: December 2024

Objectives

Mindfulness interventions are consistently associated with beneficial effects in younger adults. In this meta-analysis, we seek to quantify the effectiveness of mindfulness interventions for the mental health and well-being of older adults.

Method

We include 46 studies that implemented a mindfulness intervention (MBSR = 20; MBCT = 9; ad hoc protocol = 17) with older adults (samples with an average age of 60 or older; healthy adults = 20; adults with underlying symptoms = 26), examining a wide range of outcome measures (e.g., stress, quality of life, sleep).

Results

Mindfulness interventions in older adults yielded an estimated Hedges’ g of 0.25. Moderator analyses revealed three significant effects. Type of intervention mattered, with the effect size for MBSR not significantly different from zero (Hedges’ g = 0.12) while the effect sizes for MBCT (Hedges’ g = 0.33) and “other” interventions (Hedges’ g = 0.36) were. Outcome measure mattered, with significant beneficial effect sizes for mental functioning (Hedges’ g = 0.59), depression (Hedges’ g = 0.35), sleep (Hedges’ g = 0.39), anxiety (Hedges’ g = 0.32), “other” (Hedges’ g = 0.24), stress (Hedges’ g = 0.22) and mindfulness (Hedges’ g = 0.23). Finally, whether the outcome was targeted (e.g., measures of depression in a population suffering from major depressive disorder) mattered: variables that measured targeted outcomes yielded stronger effects (Hedges’ g = 0.30).

Discussion

Mindfulness interventions with older adults are effective, but modestly so. The extant literature is limited by reliance on modified interventions that have not been evaluated for effectiveness.
The law of digital afterlife: the Chinese experience of AI ‘resurrection’ and ‘grief tech’
Authors: Cheng Kwan Yiu
Published: December 2024

This article considers the prominent private law and regulatory problems relating to the practice of AI ‘resurrection’ where a digital replica with the appearance, voice, and personality of the deceased is created to interact with the real world. The intention is to offer solace and comfort to the bereaved by interacting with a digital representation of their loved one, providing a semblance of continued presence as if the departed had never left this world. This article first considers the industry of AI ‘resurrection’ in the context of ‘grief tech’. It uses the Chinese experience for discussion as to date the practice is most prevalent in China but the legal considerations are applicable to other jurisdictions. It then discusses whether and how the practice may constitute the infringement of the deceased’s portrait right as a personality interest protected under the Civil Code and its remedies. It finally considers the regulatory aspects of AI ‘resurrection’ with respect to personal information, deep synthesis and AI generative technology.
Associations between Growth Differentiation Factor 15, Cardiac Troponin T, and N-terminal pro-B-type Natriuretic Peptide, and Future Myocardial Fibrosis Assessed by Cardiac Magnetic Resonance Imaging: Data from the Akershus Cardiac Examination 1950 Study
Authors: Wimalanathan Thakshani , Paus Michael Fredrik , Brox Skranes Julia , Berge Trygve , Tveit Arnljot , Røsjø Helge , Omland Torbjørn , Nakrem Lyngbakken Magnus , Heck Siri Lagethon
Published: December 2024

Background

Myocardial fibrosis is associated with a poor outcome for patients with cardiovascular disease (CVD). Growth differentiation factor 15 (GDF-15) concentrations predict the risk of death in patients with CVD, but the underlying pathophysiological mechanisms are poorly understood. We aimed to assess the associations between biomarkers of cellular stress and inflammation (GDF-15), cardiac injury (cardiac troponin T [cTnT]), and stretch (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), and subsequent focal and diffuse myocardial fibrosis assessed by cardiac magnetic resonance (CMR) imaging.

Methods

We measured GDF-15, cTnT, and NT-proBNP in 200 study participants without known coronary artery disease or renal dysfunction from the population-based Akershus Cardiac Examination 1950 Study at baseline in 2012 to 2015. Focal myocardial scars and diffuse fibrosis were assessed by late gadolinium enhancement imaging and septal extracellular volume fraction (ECV) by CMR 4 to 7 years later. The relationships between cardiac biomarkers and CMR parameters were assessed by logistic regression analysis adjusted for common cardiovascular risk factors.

Results

The median age was 63.9 (interquartile range 63.4–64.5) years and 49% were women. GDF-15 (adjusted odds ratio [aOR] 4.40, 95% CI 1.09–17.72) and cTnT (aOR 1.59, 95% CI 1.01–2.50) were associated with nonischemic scars in the fully adjusted model. cTnT (aOR 2.45, 95% CI 1.41–4.25) and NT-proBNP (aOR 3.12, 95% CI 1.55–6.28) were associated with ischemic scars. None of the biomarkers were significantly associated with elevated ECV.

Conclusions

In a general population cohort, GDF-15, an emerging biomarker of cellular stress and inflammation, associates with nonischemic scars. Biomarkers of myocardial injury and stretch associate with ischemic scars, while no biomarker was associated with diffuse fibrosis as assessed by CMR.
Template of a climate sustainability plan for medical professional organizations: the Canadian Association of Gastroenterology example
Authors: Leddin Desmond , Sinclair Paul , Singh Harminder , Sherman Rachael
Published: December 2024

Environmental change is underway and has the potential to adversely affect digestive health. Professional medical organizations have an important role to play in addressing the challenge. An important initial response is the development of a sustainability plan for the medical organization. There are no standardized criteria as to what should be included in such a plan. We have proposed 12 key components that should be contained in sustainability plans for medical organizations. We describe how these were developed for the Canadian Association of Gastroenterology (CAG) and plans for future implementation. We hope that the CAG plan may serve as a template to assist peer medical organizations optimize their response to the climate crisis.
Reimagining Ethiopia: philosophy education as a tool for overcoming ethnic divisions
Authors: Merawi Fasil
Published: December 2024

This article explores the role that can be played by philosophy education in Ethiopia as a means to develop a shared meaning that is able to go beyond the ethnic polarization that is currently haunting the nation. It shows that through the introduction of a philosophy education that fosters a culture of critical reflection, dialogue, and reflection on the nature of human existence, human values, and a moral fabric that is able to bestow a sense of a common purpose on the lives of individuals, one can develop a shared conception of meaning in the Ethiopian context. This reflective exercise, made possible by philosophy education, can lead into the bridging of ethnic divisions and a process of intercultural understanding that is able to introduce commonly shared normative systems. In a nation like Ethiopia that is being plagued by ethnic divisions rooted in the system of ethnic federalism, philosophy education can provide a foundation for social cohesion and ethical deliberation that leads into the creation of an inclusive society grounded on the development of a shared sense of identity.
AGN flares as counterparts to LIGO/Virgo mergers: no confident causal connection in spatial correlation analysis
Authors: Veronesi Niccolò , van Velzen Sjoert , Rossi Elena Maria
Published: December 2024

The primary formation channel for the stellar-mass Binary Black Holes which have been detected merging by the LIGO–Virgo–KAGRA (LVK) collaboration is yet to be discerned. One of the main reason is that the detection of an Electromagnetic counterpart to such Gravitational Wave (GW) events, which could signpost their formation site, has so far been elusive. Recently, 20 Active Galactic Nuclei flaring activities detected by the Zwicky Transient Facility have been investigated as potential counterparts of GW events by Graham et al. We present the results of a spatial correlation analysis that involves such events and uses the up-to-date posterior samples of 78 mergers, detected during the third observing run of the LVK collaboration. We apply a likelihood method which takes into account the exact position of the flares within the 3D sky map of the GW events. We place an upper limit of 0.155 at a 90 per cent credibility level on the fraction of the detected coalescences that are physically related to an observed flare, whose posterior probability distribution peaks at a null value. Finally, we show that the typically larger values of the masses of the GW-events, which host at least one flare in their localization volume, are also consistent with the no-connection hypothesis. This is because of a positive correlation between binary masses and the size of the localization uncertainties.
The forest at EndEoR: the effect of Lyman limit systems on the end of reionization
Authors: Georgiev Ivelin , Mellema Garrelt , Giri Sambit K
Published: December 2024

The final stages of cosmic reionization (EndEoR) are expected to be strongly regulated by the residual neutral hydrogen in the already ionized regions of the Universe. Its presence limits the mean distance that ionizing photons can travel and hence the extent of the regions that sources of ionizing photons can affect. The structures containing most of this residual neutral hydrogen are typically unresolved in large-scale simulations of reionization. Here, we investigate and compare a range of approaches for including the effect of these small-scale absorbers, also known as Lyman limit systems (LLSs), in such simulations. We evaluate the impact of these different approaches on the reionization history, the evolution of the ultraviolet background, and its fluctuations. We also compare to observational results on the distribution of Lyman-$\alpha$ opacity towards the EndEoR and the measured mean free path of ionizing photons. We further consider their effect on the 21-cm power spectrum. We find that although each of the different approaches can match some of the observed probes of the final stages of reionization, only the use of a redshift-dependent and position-dependent LLS model is able to reproduce all of them. We therefore recommend that large-scale reionization simulations, which aim to describe both the state of the ionized and neutral intergalactic medium, use such an approach, although the other, simpler approaches are applicable depending on the science goal of the simulation.
Constraining a relativistic mean field model using neutron star mass–radius measurements II: hyperonic models
Authors: Huang Chun , Tolos Laura , Providência Constança , Watts Anna
Published: December 2024

We investigate whether measurements of the neutron star mass and radius or the tidal deformability can provide information about the presence of hyperons inside a neutron star. This is achieved by considering two inference models, with and without hyperons, based on a field theoretical approach. While current observations do not distinguish between the two scenarios, we have shown that data simulating expected observations from future large-area X-ray timing telescopes could provide some information through Bayes’ factors. Inference using simulated data generated from an equation of state containing hyperons decisively favours the hyperonic model over the nucleonic model. However, a 2 per cent uncertainty in the mass and radius determination may not be sufficient to constrain the parameters of the model when only six neutron star mass–radius measurements are considered.
VIRAC2: NIR astrometry and time series photometry for 500M+ stars from the VVV and VVVX surveys
Authors: Smith Leigh C , Lucas Philip W , Koposov Sergey E , Gonzalez-Fernandez Carlos , Alonso-García Javier , Minniti Dante , Sanders Jason L , Bedin Luigi R , Belokurov Vasily , Evans N Wyn , Hempel Maren , Ivanov Valentin D , Kurtev Radostin G , Saito Roberto K
Published: December 2024

We present VIRAC2, a catalogue of positions, proper motions, parallaxes and Z, Y, J, H, and $K_s$ near-infrared photometric time series of 545 346 537 unique stars. The catalogue is based on a point spread function fitting reduction of nearly a decade of VISTA VVV and VVVX images, which cover $560~{\rm deg}^2$ of the Southern Galactic plane and bulge. The catalogue is complete at the $\gt 90$ per cent level for $11\lt K_s~{\rm mag}\lt 16$ sources, but extends to $K_s\approx {}17.5$ mag in most fields. Astrometric performance for $11\lt K_s~{\rm mag}\lt 14$ sources is typically $\approx {}0.37~{\rm mas~yr}^{-1}$ per dimension for proper motion, and $1~{\rm mas}$ for parallax. At $K_s=16$ the equivalent values are around $1.5~{\rm mas~yr}^{-1}$ and $5~{\rm mas}$. These uncertainties are validated against Gaia DR3 and Hubble Space Telescope astrometry. The complete catalogues are available via the ESO archive. We perform an initial search of the catalogue for nearby ultracool dwarf candidates. In total, we find 26 new sources whose parallaxes place them within 50 parsecs of the Sun. Among them we find two high-confidence T dwarfs and a number of other sources that appear to lie close to the L/T transition.
NGTS-EB-7, an eccentric, long-period, low-mass eclipsing binary
Authors: Rodel Toby , Watson Christopher A , Ulmer-Moll Solène , Gill Samuel , Maxted Pierre F L , Casewell Sarah L , Brahm Rafael , Wilson Thomas G , Costes Jean C , Eschen Yoshi Nike Emilia , Doyle Lauren , Freckelton Alix V , Alves Douglas R , Apergis Ioannis , Bayliss Daniel , Bouchy Francois , Burleigh Matthew R , Dumusque Xavier , Eberhardt Jan , Fernández Jorge Fernández , Gillen Edward , Goad Michael R , Hawthorn Faith , Helled Ravit , Henning Thomas , Hobbs Katlyn L , Jenkins James S , Jordán Andrés , Kendall Alicia , Lendl Monika , McCormac James , de Mooij Ernst J W , O’Brien Sean M , Saha Suman , Pinto Marcelo Tala , Trifonov Trifon , Udry Stéphane , Wheatley Peter J
Published: December 2024

Despite being the most common types of stars in the Galaxy, the physical properties of late M dwarfs are often poorly constrained. A trend of radius inflation compared to evolutionary models has been observed for earlier type M dwarfs in eclipsing binaries, possibly caused by magnetic activity. It is currently unclear whether this trend also extends to later type M dwarfs below the convective boundary. This makes the discovery of lower mass, fully convective, M dwarfs in eclipsing binaries valuable for testing evolutionary models – especially in longer-period binaries where tidal interaction between the primary and secondary is negligible. With this context, we present the discovery of the NGTS-EB-7 AB system, an eclipsing binary containing a late M dwarf secondary and an evolved G-type primary star. The secondary star has a radius of $0.125\pm 0.006$ R$_{\odot }$, a mass of $0.096^{+0.003}_{-0.004}$ M$_{\odot }$ and follows a highly eccentric (e = $0.71436\pm 0.00085$) orbit every $193.35875\pm 0.00034$ d. This makes NGTS-EB-7 AB the third longest-period eclipsing binary system with a secondary smaller than 200 ${\rm M}_{\rm J}$ with the mass and radius constrained to better than 5 per cent. In addition, NGTS-EB-7 is situated near the centre of the proposed LOPS2 southern field of the upcoming PLATO mission, allowing for detection of the secondary eclipse and measurement of the companion’s temperature. With its long-period and well-constrained physical properties – NGTS-EB-7 B will make a valuable addition to the sample of M dwarfs in eclipsing binaries and help in determining accurate empirical mass/radius relations for later M dwarf stars.
Quantifying Molecular Changes in the Preeclamptic Rat Placenta with Targeted Contrast-Enhanced Ultrasound Imaging
Authors: Shi Lili , Alencar Allan K. N. , Swan Kenneth F. , Lawrence Dylan J. , Pridjian Gabriella , Bayer Carolyn L.
Published: December 2024

Purpose

Abnormal placental remodeling is linked to various pregnancy-related diseases, including preeclampsia (PE). This study applies a bicompartmental (BCM) model to quantify molecular expression changes in the placenta, indicative of abnormal placental remodeling, and evaluates the effectiveness of targeted contrast-enhanced ultrasound (T-CEUS) in detecting the abnormal placental vasculature. The BCM model provides high temporal resolution and differentiation of anatomical artery structures within the placenta by analyzing the distribution of contrast agents.

Methods

A targeted contrast agent (TCA) composed of gas-filled microbubbles (MB), with a surface-conjugated peptide to target ανβ3integrin, a biomarker for angiogenesis, was used for quantifying placental vascular development. CEUS images were acquired from timed pregnant Sprague Dawley rats with experimentally-induced reduced uterine perfusion pressure (RUPP) placental insufficiency. On gestational day (GD) 18 of a 21-day gestation, CEUS images were acquired from both Normal pregnant (NP; n=6) and RUPP (n=6) dams after injection of the TCA. The BCM model was used to estimate the binding dynamics of the TCA, providing a parametric map of the binding constant (Kb) of the placenta.

Results

The RUPP group showed a significant reduction in the value ofKbcompared to the NP group (p< 0.05). A histogram of the placentalKbwas compared to alternative analyses (differential target enhancement, dTE and late enhancement, LE) to demonstrate that it can differentiate between anatomical artery structures with a higher contrast-to-background ratio.

Conclusions

The BCM method differentiates molecular changes associated with the abnormal placental development associated with PE. It also reveals more intricate internal anatomical structures of the placenta in comparison to dTE and LE, suggesting that the BCM could enhance early detection and monitoring of PE.
mmVelo: A deep generative model for estimating cell state-dependent dynamics across multiple modalities
Authors: Nomura Satoshi , Kojima Yasuhiro , Minoura Kodai , Hayashi Shuto , Abe Ko , Hirose Haruka , Shimamura Teppei
Published: December 2024

Single-cell multiomics provides unique insight into the regulatory relationships across different biological layers such as the transcriptome and regulome. However, single-cell multiomics is limited by its ability to capture only static snapshots at the time of observation, restricting the reflection of dynamic state changes orchestrated across modalities. RNA velocity analysis of single cells allows for the prediction of temporal changes in the transcriptome; however, the inferred dynamics cannot be applied across all biological layers, specifically in the regulome. Therefore, to address this limitation, we developed multimodal velocity of single cells (mmVelo), a deep generative model designed to estimate cell state-dependent dynamics across multiple modalities. mmVelo estimates cell state dynamics based on spliced and unspliced mRNA expression, and uses multimodal representation learning to project these dynamics onto chromatin accessibility, inferring chromatin velocity at a single-peak resolution. We applied mmVelo to single-cell multiomics data from a developing mouse brain and validated the accuracy of the estimated chromatin accessibility dynamics. Furthermore, using the estimated dynamics, we identified the transcription factors that are crucial for chromatin accessibility regulation in mouse skin. Finally, using multiomics data as a bridge, we demonstrated that during human brain development, the dynamics of missing modalities can be inferred from single-modal data via cross-modal generation. Overall, mmVelo enhances our understanding of the dynamic interactions between modalities, offering insights into the regulatory relationships across molecular layers.
The cysteine-reactive covalent RNF4 ligand CCW16 induces ferroptosis in AML cells by activation of ROS signaling
Authors: Gotthardt Gina , Weckesser Janik , Tascher Georg , da Gama Sara Barros , Uckelmann Hannah J. , Schwalm Martin , Mosler Thorsten , Ferrario Giulio , Münch Christian , Knapp Stefan , Müller Stefan
Published: December 2024

The SUMO-targeted E3 ubiquitin ligase RNF4 plays an important role in safeguarding genome and proteome integrity. RNF4 recognizes polySUMO modified proteins and induces their proteolytic or non-proteolytic ubiquitylation. Given the key function of RNF4 in maintaining proteome and genome stability, we explored its role in cancer cell survival and as a potential cancer drug target. We found that RNF4 is overexpressed in acute myeloid leukemia and high expression levels correlate with poor survival of patients. Depletion of RNF4 exerts antiproliferative effects in AML cells and increased their sensitivity towards antileukemic drugs thus validating RNF4 as a potential vulnerability in AML. To develop PROTACs for targeted degradation of RNF4, we aimed to exploit the recently described cysteine-reactive RNF4 ligand CCW16, and synthesized a set of CCW16-derived degrader molecules using established VHL- and CRBN-E3 ligands. We validated covalent binding of CCW16 and CCW16-derived PROTACs to cysteine residues outside the RING domain of RNF4 using recombinant protein. However, none of the synthesized PROTACs were active in degrading RNF4 in a panel of different cell lines. Consistent with the high reactivity of the chosen electrophile, we detected in the cellular context covalent attachment of CCW16 to accessible cysteines in a large number of proteins including covalent linkage with the catalytic residues in members of the peroxiredoxin family. Furthermore, exposure of cells to CCW16-derived PROTACs induced upregulation of heme oxygenase 1, a ferroptosis marker and impaired cell viability in a distinct, RNF4-independent, ferroptotic cell death pathway.
Material matters: raw material influences stone tool performance in capuchin monkeys
Authors: O’Malley Theo D. R. , Reeves Jonathan S. , Slania Nora E. , Falótico Tiago , Proffitt Tomos , de la Torre Ignacio , Luncz Lydia V.
Published: December 2024

Identifying the conditions that facilitate tool use is a central focus in the field of human evolution and animal behavior. Particular interest lies in studying stone tool use by non-human primates, especially when stone hammers are used to open encased food sources. Percussive tool use is a rare and complex technological behavior which was also employed by our early hominin ancestors. It is widely theorized that environmental factors play a role in explaining the presence and absence of stone tool use across primate populations. Research to date has focused heavily on the quality and availability of tool-extractable foods, and how these compare to alternative food sources. There has been limited investigation into whether access to different types of raw tool material for hammerstones and anvils affects the efficiency of tool users when exploiting encased resources. Here, we quantitatively analyzed how percussive tools of different raw materials vary in their performance and durability. Wild capuchins (Sapajus libidinosus) in Brazil were provided with stones sourced globally from primate and hominin tool use sites. We measured the reliability with which monkeys could crack nuts when using different raw materials, the number of strikes required to open a nut or obtain a food reward, and how these metrics changed over time. We further reported variations in the durability of different raw materials which directly relates to how long a tool remains usable. Our results showed that differences in nut cracking reliability and efficiency were largely driven by the ability of the tool material to stabilize the nut. Furthermore, there was wide variation in tool durability, particularly for anvils. These results highlight the importance of considering raw materials among the ecological factors that can influence the selective benefits or costs of tool use behaviors.

HIGHLIGHTS

Raw material influences primate percussive stone tool durability and performance

Materials differ in their ability to stabilize food sources

Efficiency of hammer strikes differed across materials

Differences in material performance did not depend on their capacity to from pits

Material performance has consequences for food yield and energetic efficiency
Mouse Forebrain Region-specific Molecular Characteristics and Cholinergic Neurons Subtyping: An Integrated Analysis Based on Spatial Multi-omics
Authors: Chen Yujie , Han Mengyao , Meng Jiayue , Cao Dongjian , Cheng Nianhao , Luo Qingming , Yang Jie , Zhang Guoqing
Published: December 2024

The forebrain regions displays distinct yet under-characterized gene expression patterns. This study analyzed region-specific feature genes in forebrain regions and Isocortex sub-regions at both transcriptomic and proteomic levels. The key finding is the observation of low correlation but high functional similarity between mRNA and protein expression, which offers insights into the connection between gene expression forms in neuronal pathways and the neuronal activity state. Cholinergic neurons (CNs), play a vital role for the forebrain’s sensory and motor regulation. With Spatial-transcriptome and immunofluorescence joint analysis (STIF), which overcomes the limited resolution of the 10X Visium system, CNs- and CN-subtypes specific feature genes in the striatum and basal forebrain were identified, which providing crucial insights into the heterogeneity and functional diversity of these neuronal populations. The spatial distribution and expression pattern of the feature genes in this study were validated with either external datasets or rolling circle amplification-FISH, coincident results were revealed.
Single-Nucleus Neuronal Transcriptional Profiling of MaleC. elegansUncovers Regulators of Sex-Specific and Sex-Shared Behaviors
Authors: Morillo Katherine S. , St. Ange Jonathan , Weng Yifei , Kaletsky Rachel , Murphy Coleen T.
Published: December 2024

Sexual differentiation of the nervous system causes differences in neuroanatomy, synaptic connectivity, and physiology. These sexually-dimorphic phenotypes ultimately translate into profound behavioral differences.C. elegans’two sexes, XO males and XX hermaphrodites, demonstrate differences in neurobiology and behavior. However, the neuron class and sex-specific transcriptomic differences, particularly at the single-neuron level, that cause such phenotypic divergence remains understudied. Here, using single-nucleus RNA sequencing, we assessed and compared adult male and hermaphroditeC. elegansneuronal transcriptomes, identifying sex-specific neurons, including previously-unannotated male neurons. Sex-shared neurons displayed large expression differences, with some neuron classes clustering as distinct neurons between the sexes. Males express ∼100 male-specific GPCRs, largely limited to a subset of neurons. We identified the most highly-divergent neurons between the sexes, and functionally characterized a sex-shared target,vhp-1,in male-specific pheromone chemotaxis. Our data provide a resource for discovering nervous-system-wide sex transcriptomic differences and the molecular basis of sex-specific behaviors.
MCM2mediates post-MI cardioprotection by promoting the pro-angiogenic cardiosome signaling
Authors: Alam Perwez , Huang Wei , Adam Mike , Nieman Michelle , Stutenroth Spencer , Tranter Michael , Wang Yi-Gang , Kanisicak Onur
Published: December 2024

Abstract

Background

In the past decade, induced cardiac rejuvenation has emerged as a leading approach to repair cardiac injury. Recent studies demonstrate that promoting cell cycle reentry in adult cardiomyocytes (CM) enhances cardiac rejuvenation by influencing paracrine signaling. We previously demonstrated that the inhibition of two cell cycle inhibitors,Retinoblastoma 1(Rb1) andMeis homeobox 2(Meis2), in the adult CM enhances angiogenesis and cardiac function following ischemic injury, but the underlying mechanisms have yet to be elucidated. The goal of this study is to determine the mechanisms by which inhibition ofRb1andMeis2promotes cardiac rejuvenation in a mouse model of myocardial infarction.

Methods

Myocardial infarction was induced in adult C57/Bl6 mice via permanent LAD occlusion followed by direct injection of either control orRb1+Meis2siRNA cocktail to the ischemic myocardium.MCM2overexpression doneviadirect myocardial injection of anMCM2-plasmid DNA expression cassette. Cardiac function and LV wall motion was assessed via echocardiography, and fibrosis and CM hypertrophy were assessed via histology. RNA-sequencing was performed on isolated adult murine CMs with siRNA-mediatedRb1+Meis2knockdown to delineate the downstream mechanisms. Further identification ofRb1, Meis2,andMCM2-dependent mechanisms were done usingin vitrotechniques in isolated CMs and HUVEC cells.

Results

We show that siRNA-mediated knockdown ofRb1andMeis2 in vivoreduces pathological LV remodeling and preserves cardiac structure and function in adult mouse hearts post-MI. RNA-seq analyses revealedMCM2as a potential downstream target ofRb1/Meis2to enhance protective paracrine signaling in primary adult CMs. Indeed, re-expression ofMCM2,which is developmentally lost from neonatal to adult CM in the heart, improves cardiac function and LV wall motion while reducing myocyte hypertrophy and fibrotic scar size post-MI. Mechanistically, re-expression ofMCM2promotes the secretion of pro- angiogenic factors from adult CM, and transfer of conditioned media fromMCM2expressing CM induced vasculogenesis in HUVEC cells. Proteomic analysis of theMCM2interactome confirmed a significant enrichment of angiogenic mediators and suggests anMCM2-dependent protein packaging of pro- angiogenic factors in CM-derived small extracellular vesicles (cardiosomes).

Conclusion

Re-expression ofMCM2in adult CM promotes the secretion of pro-angiogenic cardiosomes that induce paracrine revascularization of endothelial cells and mitigates cardiac injury post-MI.

SUMMARY DIAGRAM
Epiboly in zebrafish requires reactive oxygen species produced by NADPH oxidases for the regulation of vesicular trafficking
Authors: Ramírez-Corona Arlen , Reza-Medina Brenda , Schnabel Denhi , Lomeli Hilda , Salas-Vidal Enrique
Published: December 2024

Epiboly is the first morphogenetic cell movement that occurs at the onset of gastrulation in zebrafish. During epiboly, the blastoderm thins out and spreads cells over the massive yolk cell. Epiboly progression is controlled by a complex regulatory network that involves diverse molecular effectors. Previously, we reported that reactive oxygen species (ROS) derived from NADPH oxidases (Nox) are required for normal epiboly progression, embryo survival, and early development. We also found that the inhibition of Nox activity during gastrulation downregulates E-cadherin abundance at the enveloping layer (EVL) cell margins. Since the dynamic localization of E-cadherin at the plasma membrane is highly regulated by endocytosis and vesicular trafficking during epiboly, in the present study, we investigated the effects of Nox inhibition and hydrogen peroxide (H2O2) on endocytosis and in the localization of different proteins important for endosomal trafficking in zebrafish embryos. We show that the simultaneous treatment with the Nox inhibitor VAS2870 and the dynamin 2 (Dnm2) inhibitor dynasore rescues the effects of VAS2870 on epiboly delay, embryo mortality and E-cadherin abundance at EVL cell margins. Furthermore, we found that H2O2impacts the endocytic rate of fluorescent fluid-phase markers at the EVL, as well as the localization and abundance of Rab11, a small GTPase protein involved in recycling endosomes. Our results suggest that Nox-derived ROS participate in the regulation of the initial steps of endocytosis and in the endosomal trafficking required for epiboly progression during early zebrafish development.

HIGHLIGHTS

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NADPH oxidase (Nox) activity is required for the epiboly and localization of E- cadherin.

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Dynamin inhibition rescues the developmental defects produced by the loss of Nox activity.

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Nox-derived reactive oxygen species (ROS) participate in the regulation of endosome and E-cadherin trafficking, which is required for epiboly.

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Nox inhibition increases the rate of fluorescent fluid-phase markers of endocytosis in EVL cells.

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H2O2decreases fluid-phase internalization in EVL cells.

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H2O2regulates Rab11 localization
A flow cytometric approach to identifying the relative abundance and functional capacities of hemocyte subsets in the American cockroach,Periplaneta americana(L.)
Authors: Boyer-Millander Faith J. , Martin Aaron T. , Hamm Chadwick A. , Appel Arthur G. , Hiltbold Schwartz Elizabeth
Published: December 2024

There is growing interest in insects as subjects for comparative immunological studies; however, very little has been done to wholistically characterize insect immune cells using modern techniques such as flow cytometry, and virtually no work of this kind has been done inPeriplaneta americana. Here, we use an array of general molecular probes including fluorescent lectins, lysosomal indicators, and functional assays to distinguish and characterize insect immune cells (hemocytes) based on cell markers and functions. We have utilized fluorescent tracers of lysosomal content, ROS production, and phagocytosis, as well as microscopic examination of morphology and melanization to distinguish hemocyte types based on these functions. Our findings support the use of lectins as an additional means of separating at least three populations of cockroach immune cells coupled with morphological measurements such as size and complexity. Our results indicate that many functions are enriched in the more granular hemocyte population as these are the cells that undergo phagocytosis and melanization.
Mutation inWdr45leads to early motor dysfunction and widespread aberrant axon terminals in a beta-propeller protein associated neurodegeneration (BPAN) patient-inspired mouse model
Authors: Meyerink Brandon L , Karia Krishna S , Rechtzigel Mitchell J , Patthi Prithvi R , Edwards Ariana C , Howard Jessica M , Aaseng Elizabeth R , Weimer Jill M , Pilaz Louis-Jan
Published: December 2024

Beta-propeller Protein Associated Neurodegeneration (BPAN) is a devastating neurodevelopmental and neurodegenerative disease linked to variants inWDR45. Currently, there is no cure or disease altering treatment for this disease. This is, in part, due to a lack of insight into early phenotypes of BPAN progression andWDR45’s role in establishing and maintaining neurological function. Here we generated and characterized a mouse model bearing a c52C>T BPAN patient variant inWdr45.We show this mutation ablates WDR45 protein expression and alters autophagy in the brain. Behavioral analysis of these mice revealed characteristic signs of BPAN including cognitive impairment, hyperactivity, and motor decline. We show these behaviors coincide with widespread neuroinflammation and development of axonal spheroids in multiple neuron subclasses throughout the brain. Several lines of evidence suggest these spheroids arise from axon terminals. Transcriptomic analysis uncovered multiple disrupted pathways in the cortex including genes associated with synapses, neurites, endosomes, endoplasmic reticulum, and ferroptosis. This is supported by accumulation of the iron regulating transferrin receptor 1 (TFRC) and the endoplasmic reticulum resident calreticulin (CALR) in the cortex as these animals age. CALR forms spheroid structures similar to the axonal spheroids seen in these animals. Taken together, our data demonstrate that WDR45 is necessary for healthy brain function and maintenance of axon terminals. This model opens the door to therapeutics targeting BPAN and further exploration of the role of WDR45 in neuronal function.
Quantifying the contribution of somatosensory afferent types and changes therein to pain sensitivity using transcutaneous optogenetic stimulation in behaving mice
Authors: Xie Yu-Feng , Dedek Christopher , Prescott Steven A.
Published: December 2024

Optogenetics provides an unprecedented opportunity to delineate how different somatosensory afferents contribute to sensation, including pain. By expressing channelrhodopsin-2 (ChR2) in certain afferents, those afferents can be selectively activated by transcutaneous photostimuli applied to behaving mice. Despite the great care taken to precisely target expression of ChR2, imprecise photostimulation has hindered quantitative behavioral testing. Here, using a robot to reproducibly photostimulate behaving mice and precisely measure their paw withdrawal, we show that selectively activating nociceptors with ramped photostimuli evokes faster withdrawal than co-activating nociceptive and non-nociceptive afferents, consistent with gate control. We also show that inflammation-induced hyperexcitability in nociceptors is sufficient to increase pain sensitivity. Electrophysiological testing confirmed that inflammation increases nociceptor excitability without affecting phototransduction. Data further suggest that withdrawal latency depends on the number of nociceptors activated rather than how strongly each nociceptor is activated. Consistent with changes described in nociceptor somata, the behavioral consequences of peripherally blocking different voltage-gated sodium (NaV) channels showed that nociceptor axons normally rely on NaV1.8 but upregulate NaV1.7 after inflammation, with important clinical implications for drug efficacy. Collectively, these results demonstrate the utility of optogenetic pain testing when reproducibly delivered and strategically designed photostimuli are used.

SIGNIFICANCE STATEMENT

Transcutaneous optogenetic stimulation was first applied to behaving mice to explore the neural basis for pain over a decade ago. Despite great care taken to control which afferents express optogenetic actuators, the sensitivity of such testing has been hindered by crude photostimulation methods and imprecise response measurement. Here, we demonstrate highly quantitative optogenetic pain testing using robotic stimulation and withdrawal detection. By comparing paw withdrawal to equivalent nociceptor activation with and without activation of non-nociceptive afferents, we demonstrate the antinociceptive effect of the latter input. We also demonstrate increased pain sensitivity due to inflammation-induced hyperexcitability in nociceptors and the associated change in NaVisoform expression. We also show that withdrawal from ramped optogenetic stimulation reflects how many nociceptors are recruited.
Proteomic analysis reveals complex interactions between PERK/ISR and MAPK1 in translational control in a phenotypic toxin model of Parkinson’s disease expressing PINTAC peptides
Authors: Nallur Girish N
Published: December 2024

In a proteomics investigation of a Parkinson’s disease [PD] cell model, a panel of 7 proprietary PINTAC peptides deployed in anin vitrophenotypic screen in SH-SY5Y cells treated with 6-OHDA identified 2 shorter variants of PERK protein kinase. One of the PERK variants, which is SUMOylated, associatesin vitrowith phosphorylated EIF2 alpha and its ubiquitinated isoforms, which also involves another PERK substrate. PINTACs revealed the presence of multiple post-translational modifications [PTMs] of MAPK1 in presence of OHDA. A fragment derived from MAPK1 protein sequence physically associated with multiple proteins from SH-SY5Y cellsin vitro, including some PERK substrates involved in translational control. Most associations were abolished by OHDA treatment, with concomitant appearance of new interactions of the MAPK1 peptide with RSK proteins. Some PINTACs promoted the potentiation of the function of RPS6viaRSK activation induced by OHDA. A model of the phenotypic effects of aggregator and degrader PINTAC peptides is presented. The significance of these findings for novel drug discovery in PD is discussed in the context of target discovery and therapeutic applications of PINTAC peptides or small molecule mimics.
A2A-positive neurons in the nucleus accumbens core regulate effort exertion
Authors: Shoemaker Charles T. , Friedman Alexander D. , Lu Bryan , Kim Jiwon , Ruan Shaolin , Yin Henry H.
Published: December 2024

Previous work has implicated the nucleus accumbens (NAc) in the regulation of effort, defined as the amount of work an animal is willing to perform for a given reward, but little is known about the specific contributions of neuronal populations within the NAc to effort regulation. In this study, we examined the contributions of direct pathway and indirect pathway neurons in the NAc core using an operant effort regulation task, in which the effort requirement is the number of lever presses needed for earning a food reward. Using optogenetics, we manipulated the activity of direct pathway spiny projection neurons (dSPNs, D1+) and indirect pathway SPNs (iSPNs, A2A+). Activating dSPNs reduced lever pressing regardless of the effort requirement, as it elicited gnawing, a competing consummatory behavior. On the other hand, activating iSPNs in the NAc core (but not in the shell) reduced lever pressing in an effort-dependent manner: stimulation-inducted reduction in performance was greater at higher press-to-reward ratio requirements. In contrast, optogenetically inhibiting NAc core iSPN output resulted in increased levels of effort exertion. Our results show that the indirect pathway output from the NAc core can bidirectionally regulate effort exertion.