bluuebunny/crossref_metadata_2025 huggingface dataset:
Henderson on Meta-Induction and the Problem of Induction
Authors: Schurz Gerhard
Published: August 2023

This note presents a short reply to Henderson’s critical discussion of Schurz’s approach to the problem of induction based on the optimality of meta-induction. Henderson objects that the meta-inductive a posteriori justification of object-induction rests on a certain premise—namely, an approximation condition—that she reveals as untenable. I reply that Henderson’s approximation condition is indeed too strong to be plausible, but it is not needed by the meta-inductive approach; a much weaker and highly plausible approximation condition is sufficient.
The Principle of Dynamic Holism: Guiding Methodology for Investigating Cognition in Nonneuronal Organisms
Authors: Sims Matthew
Published: August 2023

Basal cognition investigates cognition working upward from nonneuronal organisms. Because basal cognition is committed to empirically testable hypotheses, a methodological challenge arises: how can experiments avoid using zoocentric assumptions that ignore the ecological contexts that might elicit cognitively driven behavior in nonneuronal organisms? To meet this challenge, I articulate the principle of dynamic holism (PDH), a methodological principle for guiding research on nonneuronal cognition. I describe PDH’s relation to holistic research programs in human-focused cognitive science and psychology then present an argument from analogy based on holistic developmental biology. Last, I examine two experiments exemplifying the need for PDH.
The Dilemma of Ahistorical Teleosemantics
Authors: Hundertmark Fabian
Published: August 2023

Teleosemantic theories aim to naturalize mental representation through the use of functions, typically based on past selection processes. However, the historical dependence of these theories has faced severe criticism, leading some philosophers to develop ahistorical alternatives. This article presents a new dilemma for all ahistorical teleosemantic theories, focusing in particular on the theories proposed by Timothy Schroeder and Bence Nanay. These theories require certain dispositions in the producers or consumers of mental representations, but the appeal to dispositions puts the proponents in an undesirable position: mental content is either overly dependent on current circumstances or ultimately dependent on historical factors.
The rhyme and reason of rebel support: exploring European voters’ attitudes toward dissident MPs
Authors: Duell Dominik , Kaftan Lea , Proksch Sven-Oliver , Slapin Jonathan , Wratil Christopher
Published: August 2023

Citizens often support politicians who vote against their parties in parliament. They view rebels as offering better representation, appreciate expressive acts, take rebellion as a signal of standing up for constituents, or see rebels as defending their moral convictions. Each explanation has different implications for representation, but they have not yet been tested systematically against one another. We implement survey experiments on nationally representative samples in the UK, Germany, France, and Italy to assess whether voters treat rebellion as a cue for better representation or infer positive character traits implying a valence advantage. Policy congruence does not drive voters’ preference for rebels. However, voters do associate positive traits with rebel MPs, even if they do not feel better represented by them.
Communal sin, atonement, and group non-agential moral responsibility
Authors: Cawdron Harvey
Published: August 2023

In analytic theology, corporate and/or communal accounts of moral responsibility are gaining recognition as a useful resource in numerous debates. One of the areas to which they have been applied is the atonement. It is thought that when Christ is atoning for the human community, one evades concerns about justice because it seems permissible for a member of a group to suffer punishment for the group's actions even if they are not morally responsible for these themselves. To establish the moral responsibility of the human community, one can either adopt group agency or utilize a non-agential form of group moral responsibility. I shall explore the latter option here and shall outline the understanding of communal sin undergirding the model.
Trade, literacy and documentary histories of the northern Black Sea
Authors: Lamont Jessica L.
Published: August 2023

The northern coast of the Black Sea has produced an abundance of documentary texts dating from the sixth through fourth centuries BC. Of great value to the epigraphist and historian are dozens of Greek letters, receipts and curses inscribed on lead and ceramic media. When placed in dialogue with one another, these texts yield new insights into daily life and literacy in communities for which literary sources are scant or absent. They document the bustling trade in saltfish, enslaved persons and textiles, and the web of relations between Greek and non-Greek individuals in north Pontic cities, from marriage to commercial ties with indigenous groups of the Pontic interior. This article demonstrates how trade could drive literacy in non-elite communities of the northern Black Sea. Literacy and mercantile activity were very much entwined, and developed in parallel with one another and with other civic and social institutions within these port communities.
“SUBJECT GENERALITY” AND DISTRIBUTION IN MEDIEVAL ARABIC SYLLOGISTIC
Authors: El-Rouayheb Khaled
Published: August 2023

A relatively well-known medieval Latin innovation is the doctrine of distributive supposition. This notion came to be used in syllogistic theory in the late medieval and early modern periods, as Latin logicians sought to establish general rules for syllogistic productivity across the various figures. It is much less well-known that some logicians in the medieval Arabic tradition also attempted to establish general rules for the syllogism, appealing to what they called “subject generality.” In the present article, I introduce this use of “subject generality” in some influential Arabic works on logic from the thirteenth century to the sixteenth, specifically Al-ǧumal by Afḍal al-Dīn al-Ḫūnaǧī (d. 1248) and Tahḏīb al-manṭiq by Saʿd al-Dīn al-Taftāzānī (d. 1390) and some of their commentators. I also compare this concept of “subject generality” to the Latin concept of “distribution.”
African Americans, World War I, and the Awakening of a “Colored” Manifest Destiny
Authors: Destenay Emmanuel
Published: August 2023

Different aspects of the African American experience during World War One have been covered since the release in 1974 of Florette Henri’s and Arthur E. Barbeau’s The Unknown Soldiers: African American Troops in World War I. All these studies concur in their assumptions that World War One opened up a new quest for full citizenships and galvanized soldiers and officers alike. A new era started right in the middle of the conflict fueling African American units with hope of change. World War One turned into the matrix for a new form of militancy. However, perhaps World War One did not only trigger a new form of militancy among African Americans. Something else might have snapped in African American (and perhaps African) leaders of the time. What if World War One had nurtured the awakening of a “colored manifest destiny”?
Traumatic stress symptoms among Spanish healthcare workers during the COVID-19 pandemic: a prospective study
Authors: Portillo-Van Diest Ana , Vilagut Gemma , Alayo Itxaso , Ferrer Montse , Amigo Franco , Amann Benedikt L. , Aragón-Peña Andrés , Aragonès Enric , Asúnsolo Del Barco Ángel , Campos Mireia , Del Cura-González Isabel , Espuga Meritxell , González-Pinto Ana , Haro Josep M. , Larrauri Amparo , López-Fresneña Nieves , Martínez de Salázar Alma , Molina Juan D. , Ortí-Lucas Rafael M. , Parellada Mara , Pelayo-Terán José M. , Pérez-Zapata Aurora , Pijoan José I. , Plana Nieves , Puig Teresa , Rius Cristina , Rodríguez-Blázquez Carmen , Sanz Ferran , Serra Consol , Urreta-Barallobre Iratxe , Kessler Ronald C. , Bruffaerts Ronny , Vieta Eduard , Pérez-Solá Víctor , Alonso Jordi , Mortier Philippe ,   MINDCOVID Working Group
Published: August 2023

Aim

To investigate the occurrence of traumatic stress symptoms (TSS) among healthcare workers active during the COVID-19 pandemic and to obtain insight as to which pandemic-related stressful experiences are associated with onset and persistence of traumatic stress.

Methods

This is a multicenter prospective cohort study. Spanish healthcare workers (N = 4,809) participated at an initial assessment (i.e., just after the first wave of the Spain COVID-19 pandemic) and at a 4-month follow-up assessment using web-based surveys. Logistic regression investigated associations of 19 pandemic-related stressful experiences across four domains (infection-related, work-related, health-related and financial) with TSS prevalence, incidence and persistence, including simulations of population attributable risk proportions (PARP).

Results

Thirty-day TSS prevalence at T1 was 22.1%. Four-month incidence and persistence were 11.6% and 54.2%, respectively. Auxiliary nurses had highest rates of TSS prevalence (35.1%) and incidence (16.1%). All 19 pandemic-related stressful experiences under study were associated with TSS prevalence or incidence, especially experiences from the domains of health-related (PARP range 88.4–95.6%) and work-related stressful experiences (PARP range 76.8–86.5%). Nine stressful experiences were also associated with TSS persistence, of which having patient(s) in care who died from COVID-19 had the strongest association. This association remained significant after adjusting for co-occurring depression and anxiety.

Conclusions

TSSs among Spanish healthcare workers active during the COVID-19 pandemic are common and associated with various pandemic-related stressful experiences. Future research should investigate if these stressful experiences represent truly traumatic experiences and carry risk for the development of post-traumatic stress disorder.
Magnetosheath Jets Over Solar Cycle 24: An Empirical Model
Authors: Vuorinen Laura , LaMoury Adrian T. , Hietala Heli , Koller Florian
Published: August 2023

Time History of Events and Macroscale Interactions during Substorms (THEMIS) spacecraft have been sampling the subsolar magnetosheath since the first dayside science phase in 2008, and we finally have observations over a solar cycle. However, we show that the solar wind coverage during these magnetosheath intervals is not always consistent with the solar wind conditions throughout the same year. This has implications for studying phenomena whose occurrence depends strongly on solar wind parameters. We demonstrate this with magnetosheath jets—flows of enhanced earthward dynamic pressure in the magnetosheath. Jets emerge from the bow shock, and some of them can go on and collide into the magnetopause. Their occurrence is highly linked to solar wind conditions, particularly the orientation of the interplanetary magnetic field, as jets are mostly observed downstream of the quasi‐parallel shock. We study the yearly occurrence rates of jets recorded by THEMIS over solar cycle 24 (2008–2019) and find that they are biased due to differences in spacecraft orbits and uneven sampling of solar wind conditions during the different years. Thus, we instead use the THEMIS observations and their corresponding solar wind conditions to develop a model of how jet occurrence varies as a function of solar wind conditions. We then use OMNI data of the whole solar cycle to estimate the unbiased yearly jet occurrence rates. For comparison, we also estimate jet occurrence rates during solar cycle 23 (1996–2008). Our results suggest that there is no strong solar cycle dependency in jet formation.
Quantifying the Impacts of the Angle of Attack on the Morphology of Atmospheric von Kármán Vortex Streets
Authors: Annis Stefano , Badas Maria Grazia , Horváth Ákos , Basu Sukanta
Published: August 2023

A mesoscale model is used to systematically investigate how the incoming flow incidence angle affects the development of atmospheric von Kármán vortex streets for non‐axisymmetric islands. The analysis is focused on an event observed on the leeward side of Guadalupe Island. By keeping the synoptic conditions the same, several simulations are performed for rotated orientations of the island topography, which correspond to a change in the angle of attack (AoA) relative to the upstream flow. The asymmetry of the vortex shedding and the role of the leading and trailing edge are in line with what was observed in laboratory von Kármán vortex streets past a flat plate. The eddies become larger with increasing AoA while the shedding frequency decreases, and the asymmetry between cyclonic and anticyclonic eddies weakens. Cyclonic vortices are more developed and stronger under typical conditions when they are shed from the trailing edge. We also demonstrate that the wake asymmetry is fundamentally between trailing‐edge and leading‐edge eddies rather than between cyclonic and anticyclonic eddies.
Planetary Impacts: Scaling of Crater Depth From Subsonic to Supersonic Conditions
Authors: Allibert L. , Landeau M. , Röhlen R. , Maller A. , Nakajima M. , Wünnemann K.
Published: August 2023

Planetary impacts have shaped the surfaces and interiors of planets. They were particularly critical in the last stage of planetary accretion, as they have eventually formed terrestrial planets. During these large supersonic collisions, shock waves melted the impactor and the target, and formed silicate magma oceans. Because the propagation of shock waves and the melting is faster than the excavation of an impact crater, the cratering stage can be considered as a purely hydrodynamic process. Here, we use both laboratory impact experiments in water and numerical simulations to investigate the crater dimensions resulting from the impact of a liquid impactor onto a liquid target. We show that our numerical models reproduce the laboratory experiments at subsonic impact velocities. We then explore the effect of both the Froude number, which is the ratio of the impactor kinetic energy to gravity, and the Mach number, which is the ratio of the impact speed to the sound speed. We vary these two parameters independently in impact simulations, going from subsonic to supersonic conditions. We obtain a new scaling law for the crater dimensions that describes the transition from subsonic to supersonic impacts. Our results indicate that the transition between these two regimes results from a change in the partitioning of the impactor kinetic energy into potential energy in the crater and internal energy. Finally, our scaling suggests that, in the limit of large Mach numbers, the crater depth depends only on the sound velocity and gravity, and is independent of the impact speed.
Observation of nonlinear disclination states
Authors: Ren Boquan , Arkhipova Antonina A. , Zhang Yiqi , Kartashov Yaroslav V. , Wang Hongguang , Zhuravitskii Sergei A. , Skryabin Nikolay N. , Dyakonov Ivan V. , Kalinkin Alexander A. , Kulik Sergei P. , Kompanets Victor O. , Chekalin Sergey V. , Zadkov Victor N.
Published: August 2023

Introduction of controllable deformations into periodic materials that lead to disclinations in their structure opens novel routes for construction of higher-order topological insulators hosting topological states at disclinations. Appearance of these topological states is consistent with the bulk-disclination correspondence principle, and is due to the filling anomaly that results in fractional charges to the boundary unit cells. So far, topological disclination states were observed only in the linear regime, while the interplay between nonlinearity and topology in the systems with disclinations has been never studied experimentally. We report here on the experimental observation of the nonlinear photonic disclination states in waveguide arrays with pentagonal or heptagonal disclination cores inscribed in transparent optical medium using the fs-laser writing technique. The transition between nontopological and topological phases in such structures is controlled by the Kekulé distortion coefficient r with topological phase hosting simultaneously disclination states at the inner disclination core and spatially separated from them corner-I, corner-II, and extended edge states at the outer edge of the structure. We show that the robust nonlinear disclination states bifurcate from their linear counterparts and that location of their propagation constants in the gap and, hence, their spatial localization can be controlled by their power. Nonlinear disclination states can be efficiently excited by Gaussian input beams, but only if they are focused into the waveguides belonging to the disclination core, where such topological states reside. Our results open new prospects for investigation of nonlinear effects in topological systems with disclinations and are relevant for different areas of science, including Bose-Einstein and polariton condensates, where potentials with the disclinations can be created.
Value of including loupes in prosthodontic and endodontic components of dental degrees: a systematic review
Authors: Abasseri Tarek , Ha William
Published: August 2023

Background It is crucial dental students graduate with sound knowledge of endodontics and prosthodontics. The use of loupes is important for these due to their intricate nature, but there is currently no standardisation of curricula.

Objective This systematic review investigates the value of including loupes in completing dental degrees and their benefits to dental students.

Methods Literature was searched from inception to February 2022 in PubMed, Embase and Scopus. Articles included were primary studies of dental students studying endodontics or prosthodontics, which had outcomes related to the value of utilising loupes in learning, clinical application and ergonomics.

Results A total of 1,489 articles were retrieved, of which 14 relevant articles were identified. These articles discussed student perceptions and the impact on visual acuity, ergonomic practices and dental procedures. Overall, students perceived that loupes increased self-confidence and allowed a greater operative view but were initially difficult to use. Using loupes resulted in greater visual acuity than no magnification and improved ergonomic practices by reducing neck angulation and improving posture. Students also received better grades when using loupes during cavity access preparation or root canal therapy.

Conclusion The use of loupes by dental students can be beneficial if there is initial teaching on their use.
Exploring dental academics' perceptions of and experience with discrimination in the UK and Ireland: a qualitative study
Authors: Freeman Zoe , Penlington Chris , Fathi Hawa , Shazada Khaleel , Waterhouse Paula
Published: August 2023

Introduction Diversity is known to be important but diversity of dental school academics in the UK and Ireland is low in comparison with the dental profession and the overall population. The aims were to explore whether UK and Ireland dental school academics are satisfied with their career progression, whether they believe that there are barriers to career progression in dental schools based on protected characteristics, and experience of discrimination at work.

Methods An online survey, including four free-text questions related to the study aims, was circulated by the Dental Schools Council to dental academics at all UK and Ireland dental schools. Qualitative content analysis was used to analyse free-text comments.

Results and discussion There were 192 responses from 20 dental schools. Five data categories were constructed which highlight the impact of discrimination in dental academia, the importance of opportunities and support, different perspectives of diversity and discrimination, and academic and institutional culture.

Conclusion Staff perceived and experienced barriers to career progression. Many were satisfied with their career progression, but a proportion of staff expressed dissatisfaction and attributed this to discrimination based upon protected characteristics. The culture in dental schools is beginning to change to address factors contributing to inequality in dental academia.
3-Bromopyruvate overcomes cetuximab resistance in human colorectal cancer cells by inducing autophagy-dependent ferroptosis
Authors: Mu Mingchao , Zhang Qin , Zhao Chenye , Li Xiaopeng , Chen Zilu , Sun Xuejun , Yu Junhui
Published: August 2023

Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide. Cetuximab, in combination with chemotherapy, is effective for treating patients with wild-type KRAS/BRAF metastatic CRC (mCRC). However, intrinsic or acquired drug resistance often limits the use of cetuximab. In this study, we investigated the potential of co-treatment with 3-Bromopyruvate (3-BP) and cetuximab to overcome cetuximab resistance in CRC, both in vitro and in vivo. Our results demonstrated that the co-treatment of 3-BP and cetuximab synergistically induced an antiproliferative effect in both CRC cell lines with intrinsic cetuximab resistance (DLD-1 (KRASG13D/-) and HT29 (BRAFV600E)) and in a cetuximab-resistant cell line derived from Caco-2 with acquired resistance (Caco-2-CR). Further analysis revealed that co-treatment induced ferroptosis, autophagy, and apoptosis. Mechanistically, co-treatment inhibited FOXO3a phosphorylation and degradation and activated the FOXO3a/AMPKα/pBeclin1 and FOXO3a/PUMA pathways, leading to the promotion of ferroptosis, autophagy, and apoptosis in DLD-1 (KRASG13D/-), HT29 (BRAFV600E), and Caco-2-CR cells. In conclusion, our findings suggest that co-treatment with 3-BP and cetuximab could be a promising strategy to overcome cetuximab resistance in human CRC.
Polymerase iota (POLI) confers radioresistance of esophageal squamous cell carcinoma by regulating RAD51 stability and facilitating homologous recombination
Authors: Li Xiaoqing , Gao Dexuan , Shen Fei , Chen Hengrui , Zhang Zhuqiang , He Chao , Gao Aidi , Lang Yue , Zhu Xiaozhong , Zhou Jundong , Shang Zeng-Fu , Ding Wei-Qun , Zhu Ji
Published: August 2023

Radiotherapy resistance is an important and urgent challenge in the clinical management of esophageal squamous carcinoma (ESCC). However, the factors mediating the ESCC resistance to radiotherapy and its underlying molecular mechanisms are not fully clarified. Our previous studies have demonstrated the critical role of DNA polymerase iota (POLI) in ESCC development and progression, here, we aimed to investigate the involvement of POLI in ESCC radiotherapy resistance and elucidate the underlying molecular mechanism. We found that highly expressed POLI was correlated with shorter overall survival of ESCC patients received radiotherapy. Down-regulation of POLI sensitized ESCC to IR, prolonged γH2AX foci in nuclei and comet tails after IR. HR but not NHEJ repair is inhibited in POLI-deficient ESCC cells. POLI stabilizes RAD51 protein via competitively binding with and blocking the interaction between RAD51 and E3 ligase XIAP and XIAP-mediated ubiquitination. Furthermore, loss of POLI leads to the activation of GAS signaling. Our findings provide novel insight into the role of POLI in the development of radioresistance mediated by stabilizing RAD51 protein in ESCC.
Nogo-A antibody delivery through the olfactory mucosa mitigates experimental autoimmune encephalomyelitis in the mouse CNS
Authors: Pernet Vincent , Joly Sandrine , Spiegel Sebastian , Meli Ivo , Idriss Sherif , Maigler Frank , Mdzomba Julius Baya , Roenneke Anna K. , Franceschini Alessandra , Silvestri Ludovico , Pavone Francesco S. , Calamai Martino , Schindowski Katharina , Chan Andrew
Published: August 2023

Systemic administration of Nogo-A-neutralizing antibody ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, the blood-brain barrier (BBB) is a major obstacle limiting the passage of systemically applied antibody to the CNS. To bypass the BBB, in the present study we tested the intranasal route of administration by targeting the olfactory mucosa with the Nogo-A-blocking antibody 11C7 mAb in myelin oligodendrocyte glycoprotein-induced EAE. Antibodies were specifically administered onto the olfactory mucosa using a microcatheter. Antibody distribution was examined in the CNS by ELISA and light-sheet microscopy. The effects of 11C7 mAb on Nogo-A signaling were assessed by Western blotting. EAE-induced deficits were monitored daily. Demyelination was observed on spinal cord histological sections. Gene expression changes were followed by trancriptomic analyses. A sensitive capture ELISA revealed a rapid and widespread distribution of 11C7 mAb in the CNS, including the olfactory bulb, the cerebellum and the lumbar spinal cord, but not in the CSF. Light-sheet microscopy allowed to observe antibody accumulation in the parenchyma, thus demonstrating nose-to-brain transfer of IgG. At the functional level, the widespread penetration of 11C7 mAb in the CNS, including the thoracolumbar spinal cord, resulted in the improvement of motor symptoms and in the preservation of myelin in the spinal cord of EAE mice. This was accompanied by Nogo-A signaling downregulation, as reflected by the decreased level of phosphorylated cofilin observed by Western blotting in the cerebellum. In the brain of EAE score-matched animals, 11C7 modified the expression of genes that can influence neurotransmission and cognitive functions, independently of the demyelination phenotype in the spinal cord. In conclusion, our data show the feasibility of olfactory mucosa-directed administration for the delivery of therapeutic antibodies targeting CNS antigens in EAE mice.
Targeted shock-and-kill HIV-1 gene therapy approach combining CRISPR activation, suicide gene tBid and retargeted adenovirus delivery
Authors: Klinnert Sarah , Schenkel Corinne D. , Freitag Patrick C. , Günthard Huldrych F. , Plückthun Andreas , Metzner Karin J.
Published: August 2023

Infections with the human immunodeficiency virus type 1 (HIV-1) are incurable due the long-lasting, latent viral reservoir. The shock-and-kill cure approach aims to activate latent proviruses in HIV-1 infected cells and subsequently kill these cells with strategies such as therapeutic vaccines or immune enhancement. Here, we combined the dCas9-VPR CRISPR activation (CRISPRa) system with gRNA-V, the truncated Bid (tBid)-based suicide gene strategy and CD3-retargeted adenovirus (Ad) delivery vectors, in an all-in-one targeted shock-and-kill gene therapy approach to achieve specific elimination of latently HIV-1 infected cells. Simultaneous transduction of latently HIV-1 infected J-Lat 10.6 cells with a CD3-retargeted Ad-CRISPRa-V and Ad-tBid led to a 57.7 ± 17.0% reduction of productively HIV-1 infected cells and 2.4-fold ± 0.25 increase in cell death. The effective activation of latent HIV-1 provirus by Ad-CRISPRa-V was similar to the activation control TNF-α. The strictly HIV-1 dependent and non-leaky killing by tBid could be demonstrated. Furthermore, the high transduction efficiencies of up to 70.8 ± 0.4% by the CD3-retargeting technology in HIV-1 latently infected cell lines was the basis of successful shock-and-kill. This novel targeted shock-and-kill all-in-one gene therapy approach has the potential to safely and effectively eliminate HIV-1 infected cells in a highly HIV-1 and T cell specific manner.
Dissecting human population variation in single-cell responses to SARS-CoV-2
Authors: Aquino Yann , Bisiaux Aurélie , Li Zhi , O’Neill Mary , Mendoza-Revilla Javier , Merkling Sarah Hélène , Kerner Gaspard , Hasan Milena , Libri Valentina , Bondet Vincent , Smith Nikaïa , de Cevins Camille , Ménager Mickaël , Luca Francesca , Pique-Regi Roger , Barba-Spaeth Giovanna , Pietropaoli Stefano , Schwartz Olivier , Leroux-Roels Geert , Lee Cheuk-Kwong , Leung Kathy , Wu Joseph T. , Peiris Malik , Bruzzone Roberto , Abel Laurent , Casanova Jean-Laurent , Valkenburg Sophie A. , Duffy Darragh , Patin Etienne , Rotival Maxime , Quintana-Murci Lluis
Published: August 2023

Humans display substantial interindividual clinical variability after SARS-CoV-2 infection1–3, the genetic and immunological basis of which has begun to be deciphered4. However, the extent and drivers of population differences in immune responses to SARS-CoV-2 remain unclear. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells—from 222 healthy donors of diverse ancestries—that were stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces weaker, but more heterogeneous, interferon-stimulated gene activity compared with influenza A virus, and a unique pro-inflammatory signature in myeloid cells. Transcriptional responses to viruses display marked population differences, primarily driven by changes in cell abundance including increased lymphoid differentiation associated with latent cytomegalovirus infection. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell composition on population disparities in immune responses, with genetic variants exerting a strong effect on specific loci. Furthermore, we show that natural selection has increased population differences in immune responses, particularly for variants associated with SARS-CoV-2 response in East Asians, and document the cellular and molecular mechanisms by which Neanderthal introgression has altered immune functions, such as the response of myeloid cells to viruses. Finally, colocalization and transcriptome-wide association analyses reveal an overlap between the genetic basis of immune responses to SARS-CoV-2 and COVID-19 severity, providing insights into the factors contributing to current disparities in COVID-19 risk.
Dopamine and glutamate regulate striatal acetylcholine in decision-making
Authors: Chantranupong Lynne , Beron Celia C. , Zimmer Joshua A. , Wen Michelle J. , Wang Wengang , Sabatini Bernardo L.
Published: August 2023

Striatal dopamine and acetylcholine are essential for the selection and reinforcement of motor actions and decision-making1. In vitro studies have revealed an intrastriatal circuit in which acetylcholine, released by cholinergic interneurons (CINs), drives the release of dopamine, and dopamine, in turn, inhibits the activity of CINs through dopamine D2 receptors (D2Rs). Whether and how this circuit contributes to striatal function in vivo is largely unknown. Here, to define the role of this circuit in a living system, we monitored acetylcholine and dopamine signals in the ventrolateral striatum of mice performing a reward-based decision-making task. We establish that dopamine and acetylcholine exhibit multiphasic and anticorrelated transients that are modulated by decision history and reward outcome. Dopamine dynamics and reward encoding do not require the release of acetylcholine by CINs. However, dopamine inhibits acetylcholine transients in a D2R-dependent manner, and loss of this regulation impairs decision-making. To determine how other striatal inputs shape acetylcholine signals, we assessed the contribution of cortical and thalamic projections, and found that glutamate release from both sources is required for acetylcholine release. Altogether, we uncover a dynamic relationship between dopamine and acetylcholine during decision-making, and reveal multiple modes of CIN regulation. These findings deepen our understanding of the neurochemical basis of decision-making and behaviour.
R-loop-dependent promoter-proximal termination ensures genome stability
Authors: Xu Congling , Li Chengyu , Chen Jiwei , Xiong Yan , Qiao Zhibin , Fan Pengyu , Li Conghui , Ma Shuangyu , Liu Jin , Song Aixia , Tao Bolin , Xu Tao , Xu Wei , Chi Yayun , Xue Jingyan , Wang Pu , Ye Dan , Gu Hongzhou , Zhang Peng , Wang Qiong , Xiao Ruijing , Cheng Jingdong , Zheng Hai , Yu Xiaoli , Zhang Zhen , Wu Jiong , Liang Kaiwei , Liu Yan-Jun , Lu Huasong , Chen Fei Xavier
Published: August 2023

The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions1,2. Here we identify a stable association between the genome-stability regulator sensor of single-stranded DNA (SOSS)3 and the transcription regulator Integrator-PP2A (INTAC)4–6. Through SSB1-mediated recognition of single-stranded DNA, SOSS–INTAC stimulates promoter-proximal termination of transcription and attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced genome instability. SOSS–INTAC-dependent attenuation of R-loops is enhanced by the ability of SSB1 to form liquid-like condensates. Deletion of NABP2 (encoding SSB1) or introduction of cancer-associated mutations into its intrinsically disordered region leads to a pervasive accumulation of R-loops, highlighting a genome surveillance function of SOSS–INTAC that enables timely termination of transcription at promoters to constrain R-loop accumulation and ensure genome stability.
Lactobacillus oris improves non-alcoholic fatty liver in mice and inhibits endogenous cholesterol biosynthesis
Authors: Zhao Yiming , Li Congyong , Luan Zhe , Chen Jun , Wang Cong , Jing Yujia , Qi Shirui , Zhao Zhizhuang , Zhang Hanwen , Wu Junling , Chen Yi , Li Zhuanyu , Zhao Bowen , Wang Shufang , Yang Yunsheng , Sun Gang
Published: August 2023

We previously confirmed that a strain of Lactobacillus oris isolated from the fecal samples of healthy Hainan centenarian having potent lipid-lowering ability in HepG2 cells; and this study was to investigate the effect of the stain on non-alcoholic fatty liver in mice in vivio. The Lactobacillus oris strain isolated from Hainan centenarian fecal samples were frozen stored in our laboratory. Thirty ob/ob mice (10 in each group) were orally gavaged with Lactobacillus oris (Lactobacillus, 5 × 109 cfu), mixed probiotics (Mixed, 5 × 109 cfu, a mixture with known lipid-lowering ability), or culture medium (Control) respectively. Lactobacillus oris isolated from fecal samples of Hainan centenarians showed significantly in vivo lipid lowering ability compared with the controls, and the ability was comparable with mixed probiotics strains in mice The possible mechanisms of lipid-lowering of probiotics and Lactobacillus oris may be associated with HMGR inhibition to suppress the synthesis of endogenous cholesterol; bile acids reabsorption, and intestinal FXR-FGF15 signaling pathways promoting the cholesterol conversion into bile acids secretion.
Foreign DNA detection in genome-edited potatoes by high-throughput sequencing
Authors: Yasumoto Shuhei , Muranaka Toshiya
Published: August 2023

Genome editing is a powerful breeding technique that introduces mutations into specific gene sequences in genomes. For genome editing in higher plants, nucleotides for artificial nuclease (e.g. TALEN or CRISPR-Cas9) are transiently or stably introduced into the plant cells. After the introduction of mutations by artificial nucleases, it is necessary to select lines that do not contain the foreign nucleotides to overcome GMO regulation; however, there is still no widely legally authorized and approved method for detecting foreign genes in genome-edited crops. Recently, k-mer analysis based on next-generation sequencing (NGS) was proposed as a new method for detecting foreign DNA in genome-edited agricultural products. Compared to conventional methods, such as PCR and Southern hybridization, in principle, this method can detect short DNA fragments with high accuracy. However, this method has not yet been applied to genome-edited potatoes. In this study, we evaluated the feasibility of k-mer analysis in tetraploid potatoes by computer simulation, and also evaluated whether the k-mer method can detect foreign genes with high accuracy by analyzing samples of genome-edited potatoes. We show that when NGS data (at a depth of × 30 the genome size) are used, the k-mer method can correctly detect foreign genes in the potato genome even with the insertion of DNA fragments of 20 nt in length. Based on these findings, we expect that k-mer analysis will be one of the main methods for detecting foreign genes in genome-edited potatoes.
Long- and short-term history effects in a spiking network model of statistical learning
Authors: Maes Amadeus , Barahona Mauricio , Clopath Claudia
Published: August 2023

The statistical structure of the environment is often important when making decisions. There are multiple theories of how the brain represents statistical structure. One such theory states that neural activity spontaneously samples from probability distributions. In other words, the network spends more time in states which encode high-probability stimuli. Starting from the neural assembly, increasingly thought of to be the building block for computation in the brain, we focus on how arbitrary prior knowledge about the external world can both be learned and spontaneously recollected. We present a model based upon learning the inverse of the cumulative distribution function. Learning is entirely unsupervised using biophysical neurons and biologically plausible learning rules. We show how this prior knowledge can then be accessed to compute expectations and signal surprise in downstream networks. Sensory history effects emerge from the model as a consequence of ongoing learning.
An analysis of interactions between three structurally diverse anthocyanidins, as well as their glucosides, and model biological membranes, albumin, and plasmid DNA
Authors: Dudek Anita , Strugała-Danak Paulina , Kral Teresa , Hof Martin , Pruchnik Hanna
Published: August 2023

The aim of the study is to investigate the differences in the interaction of three structurally diverse anthocyanidins, namely peonidin, petunidin, and delphinidin, as well as their glucosides with model biological membranes, human albumin, and plasmid DNA in order to look into their structure–activity relationships. Fluorimetric studies, as well as ATR-FTIR analyses, were jointly used in order to determine the changes observed in both the hydrophilic and hydrophobic layers of cell-mimic membranes (MM) which reflected the membrane lipid composition of tumour cells and red blood cell membranes (RBCM). Our results showed that anthocyanins and anthocyanidins can cause an increase in the packing order of the polar heads of lipids, as well as interact with their deeper layers by reducing the fluidity of lipid chains. The results presented here indicate that all compounds tested here possessed the ability to bind to human serum albumin (HSA) and the presence of a glucose molecule within the structures formed by anthocyanidin reduces their ability to bind to proteins. Using fluorescence correlation spectroscopy, it was demonstrated that the compounds tested here were capable of forming stable complexes with plasmid DNA and, particularly, strong DNA conformational changes were observed in the presence of petunidin and corresponding glucoside, as well as delphinidin. The results we obtained can be useful in comprehending the anthocyanins therapeutic action as molecular antioxidants and provide a valuable insight into their mechanism of action.
RNase E biomolecular condensates stimulate PNPase activity
Authors: Collins Michael J. , Tomares Dylan T. , Nandana Vidhyadhar , Schrader Jared M. , Childers W. Seth
Published: August 2023

Bacterial Ribonucleoprotein bodies (BR-bodies) play an essential role in organizing RNA degradation via phase separation in the cytoplasm of bacteria. BR-bodies mediate multi-step mRNA decay through the concerted activity of the endoribonuclease RNase E coupled with the 3′-5′ exoribonuclease Polynucleotide Phosphorylase (PNPase). In vivo, studies indicated that the loss of PNPase recruitment into BR-bodies led to a significant build-up of RNA decay intermediates in Caulobacter crescentus. However, it remained unclear whether this is due to a lack of colocalized PNPase and RNase E within BR-bodies or whether PNPase’s activity is stimulated within the BR-body. We reconstituted RNase E’s C-terminal domain with PNPase towards a minimal BR-body in vitro to distinguish these possibilities. We found that PNPase’s catalytic activity is accelerated when colocalized within the RNase E biomolecular condensates, partly due to scaffolding and mass action effects. In contrast, disruption of the RNase E-PNPase protein–protein interaction led to a loss of PNPase recruitment into the RNase E condensates and a loss of ribonuclease rate enhancement. We also found that RNase E’s unique biomolecular condensate environment tuned PNPase’s substrate specificity for poly(A) over poly(U). Intriguingly, a critical PNPase reactant, phosphate, reduces RNase E phase separation both in vitro and in vivo. This regulatory feedback ensures that under limited phosphate resources, PNPase activity is enhanced by recruitment into RNase E’s biomolecular condensates.
Associations between fatty acid intake and diabetic retinopathy in a Japanese population
Authors: Sasaki Mariko , Yuki Kenya , Hanyuda Akiko , Yamagishi Kazumasa , Motomura Kaoru , Kurihara Toshihide , Tomita Yohei , Mori Kiwako , Ozawa Nobuhiro , Ozawa Yoko , Sawada Norie , Negishi Kazuno , Tsubota Kazuo , Tsugane Shoichiro , Iso Hiroyasu
Published: August 2023

Residents of Chikusei City, aged 40–74 years, underwent systemic and ophthalmological screening, and participants with diabetes were included in this analysis. Dietary intake was assessed using a food frequency questionnaire and calculated as a percentage of the total energy. The presence of diabetic retinopathy (DR) was defined as Early Treatment Diabetic Retinopathy Study levels ≥ 20 in either eye. The association between dietary fatty acid intake and DR has been examined in a cross-sectional study. Among the 647 diabetic participants, 100 had DR. The mean total fat and saturated fatty acid (SFA) intakes were 22.0% and 7.3% of the total energy intake, respectively. After adjusting for potential confounders, the highest quartiles of total fat and SFA intake were positively associated with the presence of DR compared with the lowest quartiles (odds ratios (95% confidence intervals), 2.61 (1.07–6.39), p for trend = 0.025, and 2.40 (1.12–5.17), p for trend = 0.013, respectively). No significant associations were found between DR prevalence and monounsaturated or unsaturated fatty acid intake. These results suggest that a high intake of fat and SFA may affect the development of DR, even in individuals whose total fat intake is generally much lower than that of Westerners.
Development and validation of a disease-specific quality of life measure QLICD-HY (V2.0) for patients with hypertension
Authors: Liu Yuxi , Chang Yue , Wan Dandan , Li Weiqiang , Xu Chuanzhi , Wan Chonghua
Published: August 2023

The purpose of the present study is to develop and validate the hypertension scale of the Quality of Life Instruments (QoL) for Chronic Diseases system, QLICD-HY (V2.0). The QLICD-HY (V2.0) was developed via a programmed decision method with several focus groups, nominal discussions and pilot testing. The data was collected from 370 hypertensive inpatients and measured their QoL three times before and after treatment. Using correlation, factor analyses, as well as t-tests, the psychometric properties of the scale were assessed with regard to validity, reliability and responsiveness. Correlation and factor analysis supported good construct validity and criterion-related validity when using Short Form 36 as a criterion. Test–retest reliability coefficients for the overall scale score and all domains, with the exception of the psychological and social domain (0.77, 0.78), were greater than 0.80, with a range of 0.77–0.92. The internal consistency for all domains was higher than 0.70. With the exception of the psychological domain and social domain, the overall score and scores for the majority of aspects within each domain underwent statistically significant changes (t-tests) after the treatment. The QLICD-HY (V2.0) has good validity, reliability and responsiveness and can be used as a QoL measure for hypertensive patients.
Disease-associated astrocytes and microglia markers are upregulated in mice fed high fat diet
Authors: Lin Li , Basu Rashmita , Chatterjee Debolina , Templin Andrew T. , Flak Jonathan N. , Johnson Travis S.
Published: August 2023

High-fat diet (HFD) is associated with Alzheimer’s disease (AD) and type 2 diabetes risk, which share features such as insulin resistance and amylin deposition. We examined gene expression associated with astrocytes and microglia since dysfunction of these cell types is implicated in AD pathogenesis. We hypothesize gene expression changes in disease-associated astrocytes (DAA), disease-associated microglia and human Alzheimer’s microglia exist in diabetic and obese individuals before AD development. By analyzing bulk RNA-sequencing (RNA-seq) data generated from brains of mice fed HFD and humans with AD, 11 overlapping AD-associated differentially expressed genes were identified, including Kcnj2, C4b and Ddr1, which are upregulated in response to both HFD and AD. Analysis of single cell RNA-seq (scRNA-seq) data indicated C4b is astrocyte specific. Spatial transcriptomics (ST) revealed C4b colocalizes with Gfad, a known astrocyte marker, and the colocalization of C4b expressing cells with Gad2 expressing cells, i.e., GABAergic neurons, in mouse brain. There also exists a positive correlation between C4b and Gad2 expression in ST indicating a potential interaction between DAA and GABAergic neurons. These findings provide novel links between the pathogenesis of obesity, diabetes and AD and identify C4b as a potential early marker for AD in obese or diabetic individuals.
Intrathecal [64Cu]Cu-albumin PET reveals age-related decline of lymphatic drainage of cerebrospinal fluid
Authors: Sarker Azmal , Suh Minseok , Choi Yoori , Park Ji Yong , Lee Yun-Sang , Lee Dong Soo
Published: August 2023

Age-related cognitive decline is associated with dysfunctional lymphatic drainage of cerebrospinal fluid (CSF) through meningeal lymphatic vessels. In this study, intrathecal [64Cu]Cu-albumin positron emission tomography (PET) was applied in mice to evaluate lymphatic drainage of CSF and its variation with age. [64Cu]Cu-albumin PET was performed at multiple time points after intrathecal injection of [64Cu]Cu-albumin at an infusion rate of 700 nl/min in adult and aged mice (15–25 months old). CSF clearance and paravertebral lymph nodes were quantified after injection and during the stationary phase. Stationary phase of the next day followed the initial perturbed state by injection of 6 ul (1/7 of total CSF volume) and CSF clearance half-time from the subarachnoid space was 93.4 ± 19.7 and 123.3 ± 15.6 min in adult and aged mice (p = 0.01), respectively. While the % injected dose of CSF space were higher, the activity of the paravertebral lymph nodes were lower in the aged mice on the next day. [64Cu]Cu-albumin PET enabled us to quantify CSF-lymphatic drainage across all levels of brain spinal cords and to visualize and quantify lymph node activity due to CSF drainage. [64Cu]Cu-albumin PET revealed the age-related decrease of the lymphatic drainage of CSF due to this decreased drainage from the subarachnoid space, especially during the stationary phase, in aged mice.