bluuebunny/crossref_metadata_2025 huggingface dataset:
Tariffs and the Macroeconomy
Authors: Meng Xiangtao , Russ Katheryn N. , Singh Sanjay R.
Published: July 2023

For hundreds of years, policymakers and academics have puzzled over how to add up the effects of trade and trade barriers on economic activity. The literature is vast. Trade theory generally focuses on the question of whether trade or trade barriers, like tariffs, make people and firms better off using models of the real economy operating at full employment and a net-zero trade balance. They yield powerful fundamental intuition but are not well equipped to address issues such as capital accumulation, the role of exchange rate depreciation, monetary policy, intertemporal optimization by consumers, or current account deficits, which permeate policy debates over tariffs. The literature on open-economy macroeconomics provides additional tools to address some of these issues, but neither literature has yet been able to answer definitively the question of what impact tariffs have on infant industries, current account deficits, unemployment, or inequality, which remain open empirical questions. Trade economists have only begun to understand how multiproduct retailers affect who ultimately pays tariffs and still are struggling to meaningfully model unemployment in a tractable way conducive to fast or uniform application to policy analysis, while macro approaches overlook sectoral complexity. The field’s understanding of the importance of endogenous capital investment is growing, but it has not internalized the importance of the same intertemporal trade-offs between savings and consumption for assessing the distributional impacts of trade on households. Dispersion across assessments of the impacts of the U.S.–China trade war illustrates the frontiers that economists face assessing the macroeconomic impacts of tariffs.
Newborn Mortality
Authors: Liu Li , Hug Lucia , Yeung Diana , You Danzhen
Published: July 2023

As under-5 mortality declines globally, newborn or neonatal mortality is becoming increasingly important. Depending on measurement and empirical data sources, calculation of the magnitude and trend of all-cause and cause-specific neonatal mortality ranges from direct methods to model-based estimates. From 1990 to 2019, the global neonatal mortality rate decreased by 52%, though wide regional variations persist, with sub-Saharan Africa (SSA) consistently experiencing the highest neonatal mortality rates, followed by Southern Asia, accounting for 79% of the 2.4 million total newborn deaths in 2019. Globally, most deaths in 2019 are due to preterm birth complications (36%), intrapartum-related events (24%), congenital abnormalities (10%), pneumonia (8%), and sepsis (7%). Since 2000, in low- and middle-income regions like Central Asia and South Asia and SSA, most deaths were avoided through declines in intrapartum-related events (3.4% and 1.9% AARR [average annual rate of reduction from 2000 to 2019], respectively) and preterm birth complications (2.9% and 1.9% AARR, respectively); whereas high-income regions like Europe, Northern America, Eastern Asia and South-Eastern Asia were more rapidly able to reduce deaths due to congenital abnormalities (2.8% and 3.2% AARR, respectively). More investment is urgently required to improve data collection and data quality, as well as to leverage supporting empirical data with statistical modeling to improve the validity of neonatal mortality and cause-of-death estimates.
Islamic Bioethics: Biobanking
Authors: Ahram Mamoun , Ahmad Khalid Bani
Published: July 2023

Biobanks are biomedical research facilities that aim to collect biological specimens and relevant information for future research initiatives. Examples of biospecimens include blood, saliva, and urine, as well as tissue biopsies. Biobanks collate information that includes the personal and clinical data of individuals and provide researchers with high-quality samples in order, for example, to discover causes of diseases and identify the various factors that are associated with certain diseases. It can be argued that biobanks are permissible in Islam, but they should be under strict control by qualified authorities. In addition, since the effects of biobanks go beyond the domain of medicine and since they can influence society as a whole, their governance must be regulated by an independent body comprising experts in different fields, including Islamic jurisprudents.
Islam and Pop Culture in North America
Authors: Arjana Sophia Rose
Published: July 2023

Islam and popular culture constitute an area of scholarship that explores how Muslims are represented in popular culture. Historically, in the European and North American contexts, products attached to Islam and Muslims have often reflected Orientalist and Islamophobic themes. The study of these items has often focused on negative imagery and pejorative themes attached to Islam and Muslims. In the 21st century, scholars have shifted their attention to more nuanced portrayals of Islam, including those produced by Muslim writers, artists, and musicians engaged with forms of popular culture, such as music, literature, television, and film, through their own creative expressions. In North America, Islamic popular culture features a rich mosaic of music, art, literature, and other forms of expression that challenge the negative portrayals associated with Orientalist and Islamophobic discourse.
Intention in the Pali Suttas and Abhidharma
Authors: Meyers Karin
Published: July 2023

In common usage, “intention” refers to the mental determination, purpose, or plan to engage in an action or to bring about a particular result through action. In contemporary Anglo-American philosophy, it often refers to the mental representation of that determination, purpose, or plan and, in phenomenology, to the “aboutness” of consciousness, or the characteristic of having an object in mind. There is no Pali or Sanskrit Buddhist term that corresponds precisely with this range of meanings, but two terms come close and are often translated as “intention,” namely, saṅkappa (saṅkalpa in Sanskrit) and cetanā (the same in Pali and Sanskrit).

Generally speaking, saṅkappa (also translated as “resolve” or “thought”) refers to a thought that informs goal-oriented action and cetanā (also translated as “volition”) to an impulse toward an object or goal. Although Buddhist commentators commonly individuate cetanās in respect to specific actions with first-person thoughts (e.g., “I will give alms to the monk”), cetanā is more conative in nature, and saṅkappa, more cognitive. Saṅkappa and cetanā can thus be distinguished as something like “purposive thought” and “purposive impulse,” respectively.

Despite a significant degree of semantic overlap, the two terms tend to be used in different contexts. Saṅkappa is the preferred term for intention in relation to the practice of the path and occurs more frequently in the Pali suttas than cetanā. Cetanā is closely connected to moral action or karma and more basic to consciousness than saṅkappa. It figures more prominently in Buddhist psychology (in both the Pali and Sanskrit Abhidharma traditions), where it is understood to be present in every moment of consciousness (citta) and exert a strong influence over other mental factors and is also at the center of scholastic debates regarding the nature and dynamics of karma.

Contrary to what some scholars have suggested, the Buddhist emphasis on intention as essential or even equal to karma does not amount to a conviction in free will (or an argument against it), nor does it imply an intentionalist ethics (the view that the moral quality of an action or moral responsibility is determined exclusively or even primarily by the agent’s intention). Whereas Western philosophers often focus on intentions as reasons for action and their role in voluntary action, Buddhists focus on intentions (in the case of both saṅkappa and cetanā) as causal factors or conditions that play critical roles in the performance of an action and, in the case of cetanā, generate a karmic result. In sum, rather than viewing intentions in terms of an agent’s sovereign will, autonomy, or rational choice to act, Buddhists view them in terms of complex causal processes (including other mental factors, habits, precepts, social relationships, communal practices) that issue in action and shape experience in this and future lives.
Ecological Ideas and Historical Construction of the Brazilian Cerrado
Authors: Dutra e Silva Sandro
Published: July 2023

Brazil’s national territory has traditionally been analyzed in terms of large biogeographical regions. The most current and widely used classification for both planning and environmental conservation purposes in Brazil divides the country into six large biomes: the Amazon, the Caatinga, the Cerrado, the Pantanal, the Atlantic Coast Forest, and the Pampa. All the biomes have faced threats to the preservation of their natural resources from various causes. Despite its rich biodiversity, the Cerrado has historically been affected by these threats, especially by the rapid expansion of the agricultural frontier over the past fifty years.

An important issue for the environmental history of the Cerrado and for Brazilian biomes in general is the context of the ecological ideas used to construct the paradigms by which Brazil’s biogeographical formations are defined. This context involves ecological assumptions incorporated over the years that are crucial to understanding the historical construction of the Cerrado and other biomes. The ecological ideas that have historically constituted the Cerrado help to reflect on the historical distribution of phytogeographies, their specific features and the processes by which both human and nonhuman elements of the Brazilian biomes interact. The Cerrado is, therefore, a historical construction, the product of ecological metaphors and environmental paradigms adopted since the 19th century. Since 2004, the demarcations and territorial definitions of the Cerrado have been largely guided by the concept of biomes, which has also guided the country’s environmental policies. Similarly, the cartographic representation of the biomes is also a historical construction that reflects the prioritization of floristic compositions, especially in the distinction between forests and campos (grasslands) in Brazil.

Due to its geographic location, the Cerrado shares a border with almost all the biomes, with the exception of the Pampas in the far south of Brazil. In addition to its floristic complexity, the adaptive integration of its fauna and flora, and the ways in which humans have adapted to the environment, the environmental history of the Cerrado offers an important insight into the asymmetries and strategies by which the environment is used and protected in Brazil.
Inferior and Medially Based Breast Parenchymal Rotation Flap: A New Mastopexy Technique for Replacing Breast Volume After Breast Implant Explantation
Authors: Sözer Sadri Ozan , Sibar Serhat
Published: July 2023

Background

Recently, a growing number of patients have been opting for the removal of breast implants. This often results in a degree of volume loss that can vary from mild to substantial, contingent on the size of the implant, with many patients requiring a mastopexy. Although autoaugmentation mastopexy serves as the primary surgical approach to restore shape and fill the void left by the implant, the fullness attained with the implant cannot be replicated through autoaugmentation.

Objectives

Our goal was to present the technical details and utilization of an inferomedial pedicle–based breast parenchymal flap, without rotational restriction from the parenchyma, for autoaugmentation after explantation.

Methods

A retrospective chart review was performed of 12 patients who underwent surgery with this technique between the years of 2019 to 2022, with emphasis on reasons for explantation, early and late complications, and satisfaction scores on a Likert scale.

Results

Capsular contracture was the most common reason for explantation, and only 2 patients experienced minor wound dehiscence in the early postoperative period. With a mean follow-up of nearly 2 years, no bottoming out was encountered in any of the patients, and satisfactory breast shape was obtained. Further, postoperative satisfaction was significantly higher than preoperative satisfaction.

Conclusions

The inferomedial-based parenchymal rotation flap is a new procedure that can be applied in this patient group because of its wide rotation arc and reliable vascularity. It is also an effective option for creating the desired conical breast shape in patients who do not want breast implants over the long term.

Level of Evidence: 4
Signatures of kin selection in a natural population of the bacteria Bacillus subtilis
Authors: Belcher Laurence J , Dewar Anna E , Hao Chunhui , Ghoul Melanie , West Stuart A
Published: July 2023

Laboratory experiments have suggested that bacteria perform a range of cooperative behaviors, which are favored because they are directed toward relatives (kin selection). However, there is a lack of evidence for cooperation and kin selection in natural bacterial populations. Molecular population genetics offers a promising method to study natural populations because the theory predicts that kin selection will lead to relaxed selection, which will result in increased polymorphism and divergence at cooperative genes. Examining a natural population of Bacillus subtilis, we found consistent evidence that putatively cooperative traits have higher polymorphism and greater divergence than putatively private traits expressed at the same rate. In addition, we were able to eliminate alternative explanations for these patterns and found more deleterious mutations in genes controlling putatively cooperative traits. Overall, our results suggest that cooperation is favored by kin selection, with an average relatedness of r = .79 between interacting individuals.
Evaluation of three sets of advanced backcrosses of eggplant with wild relatives from different gene pools under low N fertilization conditions
Authors: Villanueva Gloria , Plazas Mariola , Gramazio Pietro , Moya Reyes D , Prohens Jaime , Vilanova Santiago
Published: July 2023

The development of new cultivars with improved nitrogen use efficiency (NUE) is key for implementing sustainable agriculture practices. Crop wild relatives (CWRs) provide valuable genetic resources for breeding programs aimed at achieving this goal. In this study, three eggplant (Solanum melongena) accessions together with their advanced backcrosses (ABs; BC3 to BC5 generations) were evaluated for 22 morpho-agronomic, physiological, and NUE traits under low nitrogen (LN) fertilization conditions. The ABs were developed with introgressions from the wild relatives Solanum insanum, Solanum dasyphyllum, and Solanum elaeagnifolium. The AB population comprised a total of 25, 59, and 59 genotypes, respectively, with overall donor wild relative genome coverage percentages of 58.8%, 46.3%, and 99.2%. The three S. melongena recurrent parents were also evaluated under control (normal) N fertilization. Reduction of N fertilization in the parents resulted in decreased chlorophyll content-related traits, aerial biomass, stem diameter, and yield and increased NUE, nitrogen uptake efficiency (NUpE), and nitrogen utilization efficiency (NUtE). However, the decrease in yield was moderate, ranging between 62.6% and 72.6%. A high phenotypic variation was observed within each of the three sets of ABs under LN conditions, with some individuals displaying improved transgressive characteristics over the recurrent parents. Using the single primer enrichment technology 5 k probes platform for high-throughput genotyping, we observed a variable but high degree of recurrent parent genome recovery in the ABs attributable to the lines recombination, allowing the successful identification of 16 quantitative trait loci (QTL). Different allelic effects were observed for the introgressed QTL alleles. Several candidate genes were identified in the QTL regions associated with plant growth, yield, fruit size, and NUE-related parameters. Our results show that eggplant materials with introgressions from CWRs can result in a dramatic impact in eggplant breeding for a more sustainable agriculture.
The Dynamics and Perception of Pain During Self-Injury
Authors: Selby Edward A. , Hughes Christopher
Published: July 2023

This chapter looks into the dynamics and perception of pain during nonsuicidal self-injury (NSSI). It cites that the dynamics of pain are essential for understanding the NSSI’s etiology and adaptation of treatment. One of the key issues in the field of self-injury research is the presence, nature, and stability of pain experiences during NSSI. Thus, etiological relevance, research relevance, treatment relevance, and public health policy are four primary ways to understand the role of pain during NSSI improves overall NSSI research and treatment. The chapter covers methodological approaches to research the role of pain in NSSI while considering some theoretical motivations for self-injury such as self-punishment motivation and pain analgesia.
Effects of evocalcet on parathyroid calcium‐sensing receptor and vitamin D receptor expression in uremic rats
Authors: Saito Tomohiro , Mizobuchi Masahide , Sakai Mariko , Kawata Takehisa , Kitayama Tetsuya , Kato Tadashi , Suzuki Taihei , Ogata Hiroaki , Koiwa Fumihiko , Honda Hirokazu
Published: July 2023

Little is known about the effect of the recently developed calcimimetic evocalcet (Evo) on parathyroid calcium‐sensing receptor (CaSR) and vitamin D receptor (VDR) expression. We examined the effects of Evo and cinacalcet (Cina) on CaSR and VDR expression in 5/6 nephrectomized Sprague–Dawley rats fed a high‐phosphorus diet for 4 weeks to develop secondary hyperparathyroidism (SHPT). These uremic rats were divided into 4 groups—baseline control (Nx4W) and groups with additional treatment with either the Vehicle, Evo, or Cina for 2 weeks; normal rats were used as normal controls (NC). Blood parameters and parathyroid tissue were analyzed. CaSR and VDR expression levels were determined using immunohistochemistry. The degree of kidney injury and hyperphosphatemia was similar in the uremic groups (Nx4W, Vehicle, Cina, and Evo). Serum parathyroid hormone levels were significantly higher in the Nx4W and Vehicle groups than in the NC group. This increase was significantly suppressed in the Cina and Evo groups compared with that in the Vehicle group. Serum calcium levels were significantly and equally lower in the Cina and Evo groups relative to those in the Vehicle group. CaSR expression was significantly lower in the Nx4W and Vehicle groups than in the NC group. This downregulation was of an equally lesser magnitude in the Cina and Evo groups. A similar trend was observed for VDR expression. These results indicate that Evo and Cina treatment can increase parathyroid CaSR and VDR expression in uremic rats with SHPT, which could provide better control of mineral and bone disorder markers.
Lethal eosinophilic crystalline pneumonia in mice expressing a stabilized Csf2mRNA
Authors: Arao Yukitomo , Stumpo Deborah J. , Hoenerhoff Mark J. , Tighe Robert M. , Yu Yen‐Rei , Sutton Deloris , Kashyap Amogh , Beerman Isabel , Blackshear Perry J.
Published: July 2023

Granulocyte–macrophage colony‐stimulating factor (GM‐CSF) is a cytokine that stimulates the proliferation and differentiation of granulocyte and macrophage precursors. The mouse gene‐encoding GM‐CSF, Csf2, is regulated at both transcriptional and post‐transcriptional levels. An adenine–uridine‐rich element (ARE) within the 3′‐untranslated region of Csf2 mRNA was shown in cell transfection studies to confer instability on this transcript. To explore the physiological importance of this element in an intact animal, we generated mice with a knock‐in deletion of the 75‐nucleotide ARE. Mice heterozygous for this ARE deletion developed severe respiratory distress and death within about 12 weeks of age. There was dense infiltration of lung alveolar spaces by crystal‐containing macrophages. Increased stability of Csf2 mRNA was confirmed in bone marrow‐derived macrophages, and elevated GM‐CSF levels were observed in serum and lung. These mice did not exhibit notable abnormalities in blood or bone marrow, and transplantation of bone marrow from mutant mice into lethally irradiated WT mice did not confer the pulmonary phenotype. Mice with a conditional deletion of the ARE restricted to lung type II alveolar cells exhibited an essentially identical lethal lung phenotype at the same ages as the mice with the whole‐body deletion. In contrast, mice with the same conditional ARE deletion in myeloid cells, including macrophages, exhibited lesser degrees of macrophage infiltration into alveolar spaces much later in life, at approximately 9 months of age. Post‐transcriptional Csf2 mRNA stability regulation in pulmonary alveolar epithelial cells appears to be essential for normal physiological GM‐CSF secretion and pulmonary macrophage homeostasis.
GRK specificity and Gβγ dependency determines a GPCR’s potential in biased agonism
Authors: Matthees Edda S. F. , Filor Jenny C. , Jaiswal Natasha , Reichel Mona , Youssef Noureldine , Drube Julia , Godbole Amod , Hoffmann Carsten
Published: July 2023

G protein-coupled receptors (GPCRs) are mainly regulated by GPCR kinase (GRK) phosphorylation and subsequent β-arrestin recruitment. Recently, it was shown that GPCRs differentially depend on GRK2/3, GRK2/3/5/6 or GRK5/6 for their regulation. The four ubiquitously expressed GRKs are classified into the cytosolic GRK2/3 and the membrane-tethered GRK5/6 subfamily. In vitro studies revealed that GRK2/3 interact with the membrane-localized G protein βγ-subunits. Yet, the role of this interaction as crosslink between G protein activation and β-arrestin binding to GPCRs remained strongly underappreciated. Here we systematically show that the Gβγ–GRK2/3 interaction is key for these GRKs to mediate β-arrestin2 binding to Gs-, Gi- and Gq-coupled GPCRs. In our GRK2/3/5/6 knockout cells, without endogenous GRK background, the utilized GRK2/3 mutants devoid of the Gβγ interaction site significantly diminished β-arrestin2 recruitment to the beta-2 adrenergic receptor (b2AR), muscarinic M2 and M5 acetylcholine receptors (M2R, M5R). This effect was overwritten by artificially tethering GRK2/3 via a CAAX motif to the plasma membrane independently of free Gβγ. Hence, the membrane recruitment is crucial for GRK2/3-mediated β-arrestin2 binding to GPCRs, which is naturally induced via the Gβγ interaction. This connects the β-arrestin interaction for GRK2/3-regulated receptors inseparably with the associated G protein activation. We outline a theoretical framework of how GRK dependence on free Gβγ can determine a GPCR’s potential in biased agonism. Due to this inherent cellular mechanism for GRK2/3 recruitment and receptor phosphorylation, we propose that it will likely be mechanistically unattainable to create β-arrestin-biased ligands for the subgroup of GRK2/3-regulated GPCRs, while GRK5/6-mediated receptor regulation is independent from Gβγ availability. Accordingly, one should first determine the GRK specificity of a GPCR to ultimately assess the receptor’s potential for the development of biased ligands.
Carbonate dissolution without acid: carbonate hydrolysis, catalyzed by photosynthetic microorganisms, in deteriorating stone monuments
Authors: Sun Henry J. , Zhang Gaosen , Jibrin Zakaria
Published: July 2023

Rapidly deteriorating stone (marble) monuments are generally blamed on acid rain. We suggest an alternative, not necessarily exclusive, culprit: rock-inhabiting cyanobacteria and microalgae, which may enter via fissures and dissolve carbonates as they propagate under the translucent stone surface. Cyanobacteria and algae absorb CO2and HCO−and, in so doing, catalyze the reaction between carbonates and water itself. The resultant calcium hydroxide is expected to react with atmospheric CO2and with adhered dust on its way out. We tested this hypothesis at the Forbidden City in Beijing, China, by inspecting stone monuments (dolomitic marble) for telltale signs of colonization and by studying an exfoliation crust with molecular and imaging techniques. The results, reported here, are consistent. Deterioration began in, and spread from, stone joints, cracks, and shattered stone edges. A cyanobacterial biofilm visible to the naked eye was present under the deteriorating stone surface. Colonized mineral grains were dissolved in a surface-controlled manner, i.e. along crystallographic and twinning planes. Secondary calcite, as well as clay minerals, were detected in the crust.
Mathematical analysis of light-sensitivity related challenges in assessment of the intrinsic period of the human circadian pacemaker
Authors: Usmani Imran M. , Dijk Derk-Jan , Skeldon Anne C.
Published: July 2023

Accurate assessment of the intrinsic period of the human circadian pacemaker is essential for a quantitative understanding of how our circadian rhythms are synchronised to exposure to natural and man-made light-dark cycles. The gold standard method for assessing intrinsic period in humans is forced desynchrony (FD) which assumes that the confounding effect of light on assessment of intrinsic period is removed by scheduling sleep-wake and associated dim light-dark (LD) cycles to periods outside the range of entrainment of the circadian pacemaker. However, the observation that the mean period of free-running blind people is longer than the mean period of sighted people assessed by FD (24.50±0.17 h versus 24.15±0.20 h, p<0.001) appears inconsistent with this assertion. Here, we present a mathematical analysis using a simple parametric model of the circadian pacemaker with a sinusoidal velocity response curve (VRC) describing the effect of light on the speed of the oscillator. The analysis shows that the shorter period in FD may be explained by exquisite sensitivity of the human circadian pacemaker to low light intensities and a VRC with a larger advance region than delay region. The main implication of this analysis, which generates new and testable predictions, is that current quantitative models for predicting how light exposure affects entrainment of the human circadian system may not accurately capture the effect of dim light. The mathematical analysis generates new predictions which can be tested in laboratory experiments. These findings have implications for managing healthy entrainment of human circadian clocks in societies with abundant access to light sources with powerful biological effects.
A Pilot Study Using AI for Genetic Effects on Personality: ABO Blood Type in Japan/Korea
Authors: Kanazawa Masayuki
Published: July 2023

It is estimated that genetic factors contribute to approximately 50% of an individual’s personality. However, despite this estimate, statistical analyses have yet to establish a significant and consistent relationship between personality tests and genetic factors. Conversely, a large number of individuals in Japan, South Korea, and Taiwan believe in a connection between genetically determined ABO blood type and personality traits. This pilot study aimed to investigate this relationship by analyzing data from a Japanese survey (N=1,827) and a South Korean survey (N=482) using a combination of traditional statistical methods and AI. The findings demonstrated a relationship between ABO blood type and self-reported personality traits, as assessed through several single-question items, consistent with the anticipated outcomes. The findings of this study imply that the relationship between blood type and personality may extend the ABO blood type to other heritable personality traits. Additionally, this study also explores the influence of the level of interest on personality and the potential role of evolutionary psychology.
Biomimetic computer-to-brain communication restoring naturalistic touch sensations via peripheral nerve stimulation
Authors: Valle Giacomo , Secerovic Natalija Katic , Eggemann Dominic , Gorskii Oleg , Pavlova Natalia , Cvancara Paul , Stieglitz Thomas , Musienko Pavel , Bumbasirevic Marko , Raspopovic Stanisa
Published: July 2023

Artificial communication with the brain through peripheral nerve stimulation recently showed promising results in people with sensorimotor deficits. However, these efforts fall short in delivering close-to-natural rich sensory experience, resulting in the necessity to propose novel venues for converting sensory information into neural stimulation patterns, which would possibly enable intuitive and natural sensations. To this aim, we designed and tested a biomimetic neurostimulation framework inspired by nature, able “to write” physiologically plausible information back into the residual healthy nervous system. Starting from the in-silico model of mechanoreceptors, we designed biomimetic policies of stimulation, emulating the activity of different afferent units. Then, we experimentally assessed these novel paradigms, alongside mechanical touch and commonly used, linear neuromodulations. We explored the somatosensory neuroaxis by stimulating the nerve while recording the neural responses at the dorsal root ganglion and spinal cord of decerebrated cats. Biomimetic stimulation resulted in a neural activity that travels consistently along the neuroaxis, producing the spatio-temporal neural dynamic more like the naturally evoked one. Finally, we then implemented these paradigms within the bionic device and tested it with patients. Biomimetic neurostimulations resulted in higher mobility and decreased mental effort compared to traditional approaches. The results of this neuroscience-driven technology inspired by the human body could be a model for the development of novel assistive neurotechnologies.
Active vision in binocular depth estimation: a top-down perspective
Authors: Priorelli Matteo , Pezzulo Giovanni , Stoianov Ivilin Peev
Published: July 2023

Abstract

Depth estimation is an ill-posed problem: objects of different shapes or dimensions, even if at different distances, may project to the same image on the retina. Our brain uses several cues for depth estimation, including monocular cues such as motion parallax and binocular cues like diplopia. However, it is still unclear how the computations required for depth estimation are implemented in biologically plausible ways. State-of-the-art approaches to depth estimation based on deep neural networks implicitly describe the brain as a hierarchical feature detector. Instead, we propose an alternative approach that casts depth estimation as a problem of active inference. We show that depth can be inferred by inverting a hierarchical generative model that simultaneously predicts the eyes projections from a 2D belief over an object. Model inversion consists of a series of biologically plausible, homogeneous transformations based on Predictive Coding principles. Under the plausible assumption of a nonuniform fovea resolution, depth estimation favors an active vision strategy that fixates the object with the eyes, rendering the depth belief more accurate. This strategy is not realized by first fixating on a target and then estimating the depth, but by combining the two processes through action-perception cycles, with a similar mechanism of the saccades during object recognition. The proposed approach requires only local (top-down and bottom-up) message passing that can be implemented in biologically plausible neural circuits.
Pre-existing interferon gamma conditions the lung to mediate early control of SARS-CoV-2
Authors: Hilligan Kerry L. , Namasivayam Sivaranjani , Clancy Chad S. , Baker Paul J. , Old Samuel I. , Peluf Victoria , Amaral Eduardo P. , Oland Sandra D. , O’Mard Danielle , Laux Julie , Cohen Melanie , Garza Nicole L. , Lafont Bernard A. P. , Johnson Reed F. , Feng Carl G. , Jankovic Dragana , Lamiable Olivier , Mayer-Barber Katrin D. , Sher Alan
Published: July 2023

Interferons (IFNs) are critical for anti-viral host defence. Type-1 and type-3 IFNs are typically associated with early control of viral replication and promotion of inflammatory immune responses; however, less is known about the role of IFNγ in anti-viral immunity, particularly in the context of SARS-CoV-2. We have previously observed that lung infection with attenuated bacteriaMycobacterium bovisBCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 (SCV2) infection and disease in two mouse models. Assessment of the pulmonary cytokine milieu revealed thativBCG induces a robust IFNγ response and low levels of IFNβ. Here we examined the role of ongoing IFNγ responses due to pre-established bacterial infection on SCV2 disease outcomes in two murine models. We report that IFNγ is required forivBCG induced reduction in pulmonary viral loads and that this outcome is dependent on IFNγ receptor expression by non-hematopoietic cells. Further analysis revealed that BCG infection promotes the upregulation of interferon-stimulated genes (ISGs) with reported anti-viral activity by pneumocytes and bronchial epithelial cells in an IFNγ-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirmed the importance of IFNγ in these anti-viral effects by demonstrating that the recombinant cytokine itself provides strong protection against SCV2 challenge when administered intranasally. Together, our data show that a pre-established IFNγ response within the lung is protective against SCV2 infection, suggesting that concurrent or recent infections that drive IFNγ may limit the pathogenesis of SCV2 and supporting possible prophylactic uses of IFNγ in COVID-19 management.
Tumor-intrinsic LKB1-LIF signaling axis establishes a myeloid niche to promote immune evasion and tumor growth
Authors: Rashidfarrokhi Ali , Pillai Ray , Hao Yuan , Wu Warren L. , Karadal-Ferrena Burcu , Dimitriadoy Sofia G. , Cross Michael , Yeaton Anna H. , Huang Shih Ming , Bhutkar Arjun J. , Herrera Alberto , Rajalingam Sahith , Hayashi Makiko , Huang Kuan-lin , Bartnicki Eric , Zavitsanou Anastasia-Maria , Wohlhieter Corrin A. , Leboeuf Sarah E. , Chen Ting , Loomis Cynthia , Mezzano Valeria , Kulicke Ruth , Davis Fred P. , Stransky Nicolas , Smolen Gromoslaw A. , Rudin Charles M. , Moreira Andre L. , Khanna Kamal M. , Pass Harvey I. , Wong Kwok-Kin , Koide Shohei , Tsirigos Aristotelis , Koralov Sergei B. , Papagiannakopoulos Thales
Published: July 2023

Tumor mutations can influence the surrounding microenvironment leading to suppression of anti-tumor immune responses and thereby contributing to tumor progression and failure of cancer therapies. Here we use genetically engineered lung cancer mouse models and patient samples to dissect howLKB1mutations accelerate tumor growth by reshaping the immune microenvironment. Comprehensive immune profiling ofLKB1-mutant vs wildtype tumors revealed dramatic changes in myeloid cells, specifically enrichment of Arg1+interstitial macrophages and SiglecFHineutrophils. We discovered a novel mechanism whereby autocrine LIF signaling inLkb1-mutant tumors drives tumorigenesis by reprogramming myeloid cells in the immune microenvironment. Inhibiting LIF signaling inLkb1-mutant tumors, via gene targeting or with a neutralizing antibody, resulted in a striking reduction in Arg1+interstitial macrophages and SiglecFHineutrophils, expansion of antigen specific T cells, and inhibition of tumor progression. Thus, targeting LIF signaling provides a new therapeutic approach to reverse the immunosuppressive microenvironment ofLKB1-mutant tumors.
Tar patties are hotspots of hydrocarbon turnover and nitrogen fixation during a nearshore pollution event in the oligotrophic southeastern Mediterranean Sea
Authors: Rubin-Blum Maxim , Yudkovsky Yana , Marmen Sophi , Raveh Ofrat , Amrani Alon , Kutuzov Ilya , Guy-Haim Tamar , Rahav Eyal
Published: July 2023

Weathered oil, that is, tar, forms hotspots of hydrocarbon degradation by complex biota in marine environment. Here, we used marker gene sequencing and metagenomics to characterize the communities of bacteria, archaea and eukaryotes that colonized tar patties and control samples (wood, plastic), collected in the littoral following an offshore spill in the warm, oligotrophic southeastern Mediterranean Sea (SEMS). We show aerobic and anaerobic hydrocarbon catabolism niches on tar interior and exterior, linking carbon, sulfur and nitrogen cycles. Alongside aromatics and larger alkanes, short-chain alkanes appear to fuel dominant populations, both the aerobic clade UBA5335 (Macondimonas), anaerobic Syntropharchaeales, and facultative Mycobacteriales. Most key organisms, including the hydrocarbon degraders and cyanobacteria, have the potential to fix dinitrogen, potentially alleviating the nitrogen limitation of hydrocarbon degradation in the SEMS. We highlight the complexity of these tar-associated communities, where bacteria, archaea and eukaryotes co-exist, exchanging metabolites and competing for resources and space.
Using big sequencing data to identify chronic SARS-Coronavirus-2 infections
Authors: Harari Sheri , Miller Danielle , Fleishon Shay , Burstein David , Stern Adi
Published: July 2023

The evolution of SARS-Coronavirus-2 (SARS-CoV-2) has been characterized by the periodic emergence of highly divergent variants, many of which may have arisen during chronic infections of immunocompromised individuals. Here, we harness a global phylogeny of ∼11.7 million SARS-CoV-2 genomes and search for clades composed of sequences with identical metadata (location, age, and sex) spanning more than 21 days. We postulate that such clades represent repeated sampling from the same chronically infected individual. A set of 271 such chronic-like clades was inferred, and displayed signatures of an elevated rate of adaptive evolution, in line with validated chronic infections. More than 70% of adaptive mutations present in currently circulating variants are found in BA.1 chronic-like clades that predate the circulating variants by months, demonstrating the predictive nature of such clades. We find that in chronic-like clades the probability of observing adaptive mutations is approximately 10-20 higher than that in global transmission chains. We next employ language models to find mutations most predictive of chronic infections and use them to infer hundreds of additional chronic-like clades in the absence of metadata and phylogenetic information. Our proposed approach presents an innovative method for mining extensive sequencing data and providing valuable insights into future evolutionary patterns.
Altered TFEB subcellular localization in nigral dopaminergic neurons of subjects with prodromal, sporadic andGBA-related Parkinson’s disease and Dementia with Lewy bodies
Authors: Moors Tim E , Morella Martino L , Bertran-Cobo Cesc , Geut Hanneke , Udayar Vinod , Timmermans-Huisman Evelien , Ingrassia Angela MT , Brevé John JP , Bol John GJM , Bonifati Vincenzo , Jagasia Ravi , van de Berg Wilma DJ
Published: July 2023

Transcription factor EB is a master regulator of genes involved in the maintenance of autophagic and lysosomal homeostasis, processes which have been implicated in the pathogenesis ofGBA-related and sporadic Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). TFEB activation at the lysosomal level results in its translocation from the cytosol to the nucleus. Here, we aimed at investigating whether TFEB subcellular localization is altered in post-mortem human brain of aged individuals with either prodromal PD/DLB (incidental Lewy body disease, iLBD, N=3),GBA-related PD/DLB (N=9) or sPD/DLB (N=9), compared to control subjects (N=12). We scanned nigral dopaminergic neurons using high-resolution confocal and stimulated emission depletion (STED) microscopy and semi-quantitatively scored the observed TFEB subcellular localization patterns. In line with previous studies, we observed reduced nuclear TFEB immunoreactivity in PD/DLB patients compared to controls, both sporadic andGBA-related cases, as well as in iLBD cases. Nuclear depletion of TFEB was more pronounced in neurons with Ser129-phosphorylated (pSer129) aSyn cytopathology and in cases carrying pathogenicGBAvariants. Interestingly, we further observed previously unidentified TFEB-immunopositive somatic clusters in human brain dopaminergic neurons and in human embryonic stem cell (hESC)-derived neurons, which localized at the Golgi apparatus. The TFEB clustering was more frequently observed and more severe in iLBD, sPD/DLB andGBA-PD/DLB compared to controls, particularly in pSer129 aSyn-positive neurons but also in neurons without apparent cytopathology. Notably, increased frequency of cytoplasmic TFEB clusters in aSyn-negative cells correlated with reduced totalGBAenzymatic activity and higher Braak LB stage. In the studied patient population, altered TFEB distribution was accompanied by a reduction in overall mRNA expression levels of selected CLEAR genes, indicating a possible early dysfunction of lysosomal regulation. Overall, these findings suggest the early cytoplasmic TFEB retention and accumulation at the Golgi prior pSer129 aSyn accumulation in incidental,GBA-related and sporadic PD/DLB and indicate TFEB as potential as early therapeutic target for synucleinopathies
Inherited retinal degeneration: T-type voltage-gated channels, Na+/Ca2+-exchanger and calpain-2 promote photoreceptor cell death
Authors: Yan Jie , Wang Lan , Yang Qian-Lu , Yang Qian-Xi , He Xinyi , Dong Yujie , Hu Zhulin , Jiao Kangwei , Paquet-Durand François
Published: July 2023

Inherited retinal degeneration (IRD) refers to a group of untreatable blinding diseases characterized by a progressive loss of photoreceptors. IRD pathology is often linked to an excessive activation of cyclic nucleotide-gated channels (CNGC) leading to Na+– and Ca2+-influx, subsequent activation of voltage-gated Ca2+-channels (VGCC), and further Ca2+influx. However, whether and how exactly intracellular Ca2+overload contributes to photoreceptor degeneration is still controversial.

Here, we used whole-retina and single-cell RNA-sequencing to compare gene expression between therd1mouse model for IRD and wild-type (wt) mice. Differentially expressed genes were linked to several Ca2+–signalling related pathways. To explore this further, organotypic retinal explant cultures derived fromrd1andwtmice were treated with the intracellular Ca2+-chelator BAPTA-AM and with inhibitors for different Ca2+-permeable channels, including CNGC, L-type VGCC, T-type VGCC, Ca2+-release-activated channel (CRAC), and Na+/Ca2+exchanger (NCX). Moreover, we employed the compound NA-184 to selectively inhibit the Ca2+-dependent protease calpain-2. The overall activity of poly(ADP-ribose) polymerases (PARPs), sirtuin-type histone-deacetylases, calpains, as well as the activation of calpain-1, and –2 were analysedin situon retinal tissue sections. Cell viability was assessedviathe TUNEL assay.

Whilerd1photoreceptor cell death was reduced by BAPTA-AM, the effects of Ca2+-channel blockers were ambiguous, with T-type VGCC and NCX inhibition showing protection, while blocking CNGC and CRAC was detrimental. Activity of calpains and PARPs generally followed similar trends as cell death. Remarkably, sirtuin activity and calpain-1 activation was associated with photoreceptor protection, while calpain-2 activity was linked to degeneration. Accordingly, the calpain-2 inhibitor NA-184 protectedrd1photoreceptors.

Together, these results indicate that Ca2+overload inrd1photoreceptors may be triggered by T-type VGCC in conjunction with NCX. High Ca2+-levels likely suppress the protective activity of calpain-1 and promote neurodegeneration via activation of calpain-2. Our study details the complexity of Ca2+-signalling in photoreceptors and emphasizes the importance of identifying and targeting degenerative processes to achieve a therapeutic benefit for IRD.
Brightest path tracing: A Python package to trace the brightest path in 2D and 3D images
Authors: Jha Vasudha , Cudmore Robert H.
Published: July 2023

Brightest path tracing is a widely used image processing technique in several fields including biology, geography, and geology. However, despite the availability of many image processing libraries in Python, few offer an out-of-the-box implementation of a bright-est path tracing algorithm. This paper presents a Python package,brightest-path-lib, that efficiently finds the path with maximum brightness between points in a 2D or 3D image. An example graphical user interface is provided as a Napari plugin. Taken together, the package and plugin provide a powerful and extensible tool for users to efficiently trace structures of interest in 2D or 3D images, regardless of the type of structure being analyzed.
The expression landscape and pangenome of long non-coding RNA in the fungal wheat pathogenZymoseptoria tritici
Authors: Glad Hanna M. , Tralamazza Sabina Moser , Croll Daniel
Published: July 2023

Long non-coding RNAs (lncRNAs) are regulatory molecules interacting in a wide array of biological processes. LncRNAs in fungal pathogens can be responsive to stress and play roles in regulating growth and nutrient acquisition. Recent evidence suggests that lncRNAs may also play roles in virulence, such as regulating pathogenicity-associated enzymes and on-host reproductive cycles. Despite the importance of lncRNAs, only few model fungi have well-documented inventories of lncRNA. In this study, we apply a machine-learning based pipeline to predict high-confidence lncRNA candidates inZymoseptoria tritici,an important global pathogen of wheat impacting global food production. We analyzed genomic features of lncRNAs and the most likely associated processes through analyses of expression over a host infection cycle. We find that lncRNAs are frequently expressed during early infection, before the switch to necrotrophic growth. They are mostly located in facultative heterochromatic regions, which are known to contain many genes associated with pathogenicity. Furthermore, we find that lncRNAs are frequently co-expressed with genes that may be involved in responding to host signals, such as those responses to oxidative stress. Finally, we assess pangenome features of lncRNAs using four additional reference-quality genomes. We find evidence that the repertoire of expressed lncRNAs varies substantially between individuals, even though lncRNA loci tend to be shared at the genomic level. Overall, this study provides a repertoire and putative functions of lncRNAs inZ. triticienabling molecular genetics and functional analyses in an important pathogen.

Impact statement

Long non-coding RNAs (lncRNAs) serve distinct roles from messenger RNA. Despite not encoding proteins, lncRNAs can control important cellular processes such as growth and response to stress. In fungal pathogens, lncRNAs are particularly interesting because they can influence how pathogens infect and harm their hosts. Yet, only very few fungal pathogens have high-quality repertoires of lncRNA established. Here, we used machine learning to identify lncRNA in the major wheat pathogenZymoseptoria tritici.We found that lncRNAs are highly active during the early stages of infection, before the pathogen switches to necrotrophic growth. These lncRNAs are mainly located in regions of the genome associated with pathogenicity. The repertoire of expressed lncRNAs varies substantially among individuals highlighting the potential for pathogen adaptation based on variation in lncRNAs. By expanding our knowledge of lncRNAs in important pathogen models, we enable research to comprehensively investigating their roles across fungi.