bluuebunny/crossref_metadata_2025 huggingface dataset:
Extensive evaluation of a new LC–MS-MS method to quantify monofluoroacetate toxin in the kidney
Authors: Langston James , Stump Samuel , Filigenzi Michael , Tkachenko Andriy , Guag Jake , Poppenga Robert , Rumbeiha Wilson K
Published: April 2024

Monofluoroacetate is a highly lethal toxin that causes death by inhibiting cellular adenosine triphosphate (ATP) production. The heart and brain are the primary target organs. Acute death is attributed to cardiac fibrillation and/or convulsions. Although it occurs naturally in some plants, a major source of animal intoxication is access to sodium monofluoroacetate (NaMFA) pesticide, which continues to be a concern in the USA and around the world despite restricted use in some countries including the USA. There are also concerns about misuse of this pesticide for malicious poisoning. Currently, a tissue-based diagnostic method for NaMFA intoxication in animals is lacking. There is a critical need by the veterinary diagnostic community for a simple, sensitive and reliable tissue-based diagnostic test to confirm NaMFA poisoning in animals. We have developed and extensively evaluated a sensitive novel liquid chromatography combined with tandem mass spectrometry method suitable for this purpose. The limits of detection and limits of quantitation are 1.7 and 5.0 ng/g, respectively. The accuracy and precision met or exceeded expectations. The method performance was verified using the incurred kidney obtained from animal diagnostic cases. This novel kidney-based method is now available for clinical use and can help with diagnostic purposes, including detecting potential issues related to animal foods.
The Cumulative Effects of Marketized Care
Authors: Chatzidakis Andreas , Eckhardt Giana M , Husemann Katharina C
Published: April 2024

Care is increasingly marketized. Previous marketing and consumer research has focused on specific tensions underlying marketized care provision and the ways in which consumers navigate them. In contrast, this conceptual article draws on interdisciplinary research on care to develop a cumulative understanding of marketized care, that is, based on those effects that build up over time when a critical mass of consumers routinely addresses care needs via markets. Defining marketized care as attending to the welfare needs of human and nonhuman others through the market, we identify four negative cumulative effects: individuating effects on consumer subjectivities, alienating effects on care relationships, responsibilizing effects on consumers as opposed to other institutional actors of care provision, and exploitative effects generated in global care and supply chains. We also outline four principles that can mitigate these effects: interdependent consumer autonomy, affective reconnections, proportionate responsibilization, and market reconfiguration. Our conceptualization moves the literature on marketized care forward by outlining its cumulative nature as well as offering potential solutions that are neither demonizing nor celebratory of markets. In doing so, we offer a series of generative insights for research on marketized care that contribute to addressing collective human and nonhuman flourishing.
Price Partitioning of Socio-Moral Surcharges
Authors: Goenka Shreyans , Bagchi Rajesh
Published: April 2024

Many companies are levying mandatory surcharges on products to raise funds for socio-moral causes (e.g., carbon-offset, living-wage, fair-trade, and sustainability surcharges). Should these surcharges be presented separately from the product price (i.e., partitioned pricing) or combined with the product price (i.e., all-inclusive pricing)? This research argues that partitioned pricing for socio-moral surcharges can backfire. When socio-moral surcharges are partitioned, consumers feel that the company is avoiding its own responsibility toward the cause, reducing intrinsic corporate social responsibility attributions and consequently leading to adverse consumer reactions. This theorization is specific to surcharges attached to socio-moral causes; the effects reverse for non-socio-moral surcharges. Further, we document three ways via which firms can alter consumer beliefs and attenuate negative reactions. These include approaches that signal that the firm is not seeking reputational benefits, that the firm is not avoiding responsibility, and by shifting consumers’ focus from the costs they have to bear to the benefits they accrue. Hence, this research presents implications for managers and policymakers seeking to incorporate socio-moral surcharges into product prices while mitigating consumer backlash.
Machine learning for electric energy consumption forecasting: Application to the Paraguayan system
Authors: Morales-Mareco Félix , García-Torres Miguel , Divina Federico , Stalder Diego H , Sauer Carlos
Published: April 2024

In this paper we address the problem of short-term electric energy prediction using a time series forecasting approach applied to data generated by a Paraguayan electricity distribution provider. The dataset used in this work contains data collected over a three-year period. This is the first time that these data have been used; therefore, a preprocessing phase of the data was also performed. In particular, we propose a comparative study of various machine learning and statistical strategies with the objective of predicting the electric energy consumption for a given prediction horizon, in our case seven days, using historical data. In this paper we have tested the effectiveness of the techniques with different historical window sizes. Specifically, we considered two ensemble strategies, a neural network, a deep learning technique and linear regression. Moreover, in this study, we tested whether the inclusion of meteorological data can help achieve better predictions. In particular, we considered data regarding temperature, humidity, wind speed and atmospheric pressure registered during the three-year period of data collection. The results show that, in general, the deep learning approach obtains the best results and that such results are obtained when meteorological data are also considered. Moreover, when meteorological data is used, a smaller historical window size is required to obtain precise predictions.
PhrasIS: Phrase Inference and Similarity benchmark
Authors: Lopez-Gazpio I , Gaviria J , García P , Sanjurjo-González H , Sanz B , Zarranz A , Maritxalar M , Agirre E
Published: April 2024

We present PhrasIS, a benchmark dataset composed of natural occurring Phrase pairs with Inference and Similarity annotations for the evaluation of semantic representations. The described dataset fills the gap between word and sentence-level datasets, allowing to evaluate compositional models at a finer granularity than sentences. Contrary to other datasets, the phrase pairs are extracted from naturally occurring text in image captions and news headlines. All the text fragments have been annotated by experts following a rigorous process also described in the manuscript achieving high inter annotator agreement. In this work we analyse the dataset, showing the relation between inference labels and similarity scores. With 10K phrase pairs split in development and test, the dataset is an excellent benchmark for testing meaning representation systems.
Gaussian process-based analysis of the nitrogen dioxide at Madrid Central Low Emission Zone
Authors: Gómez-González Juan Luis , Cárdenas-Montes Miguel
Published: April 2024

Concern about air-quality in urban areas has led to the implementation of Low Emission Zones as one of many other initiatives to control it. Recently in Spain, the enactment of a law made this mandatory for cities with a population larger than 50k inhabitants. The delimitation of these areas is not without controversy because of possible negative economic and social impacts. Therefore, clear assessments of how these initiatives decrease pollutant concentrations are to be provided. Madrid Central is a major initiative of Madrid city council for reducing motor traffic and the associated air pollution in the city centre. This Low Emission Zone starts at the end of 2018, but the first fully-operational period corresponds to the second quarter of 2019. In this work, a methodology based on the Gaussian Process to analyse the evolution of Nitrogen Dioxide inside Madrid Central is undertaken. A Gaussian Process is a stochastic process suitable for interpretable model selection and predictions. Due to its probabilistic nature it provides error estimation at predictions. After the activation of Madrid Central, a relevant reduction of Nitrogen Dioxide has been observed. However, the role of the meteorology during this period must be ascertained to correctly evaluate the role of the activation of the Low Emission Zone against a prone weather. In this work, a model based on the Gaussian Process is trained with meteorological information to predict the concentration of Nitrogen Dioxide at Madrid Central, $[NO_{2}]$. This probabilistic description allows extracting statistical information on the reduction affected by the meteorological scenario and separately by the Madrid Central activation.
Characterizing diurnal roosts of male Little Brown Myotis (Myotis lucifugus) during summer
Authors: Hilty Shannon L , Litt Andrea R , Maxell Bryce A , Gower Claire N , Garrott Robert A , Hanauska-Brown Lauri
Published: April 2024

Shelter is one critical aspect of an animal’s habitat, providing refuge from predators and weather, protection for offspring, and aiding in physiological homeostasis. During the day, bats find shelter in roosts—spaces created under tree bark, in tree cavities, or between rocks—after spending the night searching for food. Finding a roost with a microclimate that enables bats to remain in their thermoneutral zone could reduce energetic demands or allow bats to allocate energy to other activities such as reproduction and fighting disease. We aimed to characterize the structural features and microclimate (i.e., temperature) of roosts used by male Little Brown Myotis (Myotis lucifugus) during the summer and determine whether bats select certain characteristics disproportionally to what is available at different spatial scales. During the summers of 2017 and 2018, we radio-tracked 34 male M. lucifugus in Lodgepole Pine-dominated forests. We located at least 1 roost for 20 individuals (average = 2.85 roosts/bat, range = 1 to 6). Although snags were available, most of the roosts were in rock features (86% in rocks, 14% in trees or snags). Male M. lucifugus were more likely to select rock roosts with less canopy closure that were closer to water compared to available roosts on the landscape. They also selected roosts in rock features occurring within larger areas of rock cover that had wider entrances and access to crevices that faced the sky; these roosts also had warmer microclimates relative to other locations available on the landscape. Crevices that allow the bat to bask in the sun and change locations within a roost, minimizing energy needed for active thermoregulation, could be very beneficial for individuals recovering from diseases such as white-nose syndrome. Our work indicates that rock features provide habitat for male M. lucifugus during summer; other studies have shown that bats roost in these features during autumn and winter, further supporting their importance. By protecting these important rock structures, managers can help bats meet their habitat needs throughout the year.
Biotic and abiotic factors drive multi-trophic interactions among spiders at different spatial scales in urban greenspaces
Authors: Delgado de la flor Yvan A , Perry Kayla I , Collis Lyndsie M , Phelan P Larry , Gardiner Mary M
Published: April 2024

Urbanization is often detrimental to biodiversity, yet urban greenspaces can be managed to provide habitat for many arthropods. Understanding how anthropogenic filters influence processes of community assembly in urban ecosystems will inform conservation of species such as spiders, which provide natural pest control. Spiders are abundant in urban areas, but the relative importance of biotic and abiotic factors for structuring spider communities in urban greenspaces is unclear. We initiated the Cleveland Pocket Prairie Project in the legacy city of Cleveland, Ohio, where vacant lots and urban prairies were established across eight inner-city neighborhoods. In each greenspace, spiders were collected along with landscape and local environmental data in July 2017. Using a path analysis approach, we investigated the relative importance and strength of landscape and local environmental filters for influencing the structure of spider communities during mid-summer within this system. We found that spider community assembly was influenced by multiple abiotic and biotic drivers across spatial scales related to landscape composition, soil texture and quality, prey breadth, and habitat management designs. Web-building and active hunting spiders responded differently to these landscape and local drivers, highlighting the need to incorporate a functional perspective when studying community assembly. These findings suggest that a multi-scale approach to conservation management is needed to support biodiversity and associated biological control services in urban ecosystems.
Patient characteristics, diagnostic testing, and initial treatment profiles of patients with connective tissue disease-associated pulmonary arterial hypertension using a Japanese claims database
Authors: Tokushige Natsuko , Hayashi Yasuhiro , Omura Junichi , Jinnai Tatsunori , Atsumi Tatsuya
Published: April 2024

Objectives

To investigate the diagnostic and therapeutic landscape for patients with connective tissue disease (CTD) and CTD-associated pulmonary arterial hypertension (CTD-PAH) in acute-care general hospitals in Japan.

Methods

We conducted a retrospective cohort study by analysing the Medical Data Vision (MDV) database from April 2008 to September 2020. CTD patients who prescribed immunosuppressants were included in cohort 1, and CTD-PAH patients extracted from cohort 1 were included in cohort 2. Patient characteristics, diagnostic screening frequencies for PAH, and initial PAH-specific treatment patterns were assessed.

Results

Overall, 16,648 patients with CTD and 81 patients with CTD-PAH were included in cohorts 1 and 2, respectively. The frequencies of screening tests for PAH, including brain natriuretic peptide (BNP), transthoracic echocardiogram (TTE), and ‘diffusing capacity’ of the ‘lungs for carbon monoxide’ (DLCO), among CTD patients were 0.7, 0.3, and 0.1 tests/person-year, respectively. The most common initial PAH-specific treatment therapy was monotherapy (87.7%), followed by dual therapy (7.4%) and triple therapy (2.5%).

Conclusion

This is the first study to describe the patient flow from PAH diagnosis to initial PAH-specific treatment for real-world patients who were followed regularly due to CTD in Japanese clinical practice.
Social learning and the acquisition of information and knowledge—a network approach for the case of technology adoption
Authors: Abdul Mumin Yazeed , Goetz Renan
Published: April 2024

The complexity of agricultural innovations and heterogeneity of circumstances of technology application, outcomes, and social network structures have often led to obstacles in social learning and suboptimal adoption. In this article, we examine technology diffusion by focusing on the roles of peer adoption decision, peer experience, and network structures, using survey data from 500 farm households in Northern Ghana to generate social network contacts. Our results reveal that learning from peer experiences matter more in the diffusion process than just peer adoption decisions alone. We also find that social learning and the likelihood of adoption are higher when peers are central nodes, and particularly when they belong to cohesive subgroups, but lower when they are in highly segregated networks. Our results shed new light on the role of central agents, since highly cohesive neighbourhoods seem to promote diffusion more in high-modularity networks than central nodes.
Tumor Response Predicts Survival Time of Nivolumab Monotherapy for Advanced Gastric Cancer: A Subgroup Analysis of the DELIVER Trial (JACCRO GC-08)
Authors: Sunakawa Yu , Sakamoto Yasuhiro , Kawabata Ryohei , Ishiguro Atsushi , Akamaru Yusuke , Kito Yosuke , Takahashi Masazumi , Matsuyama Jin , Yabusaki Hiroshi , Makiyama Akitaka , Suzuki Takahisa , Tsuda Masahiro , Yasui Hisateru , Hihara Jun , Takeno Atsushi , Inoue Eisuke , Ichikawa Wataru , Fujii Masashi
Published: April 2024

Background

This prospective observational study evaluated the real-world effectiveness of nivolumab monotherapy in previously treated advanced gastric cancer (GC). A preplanned 2-year final analysis was performed to confirm survival and tumor behavior with nivolumab monotherapy.

Patients and Methods

The primary endpoint was overall survival (OS). The data regarding tumor size were prospectively collected and evaluated using the RECIST criteria. Exploratory analyses were performed for survival according to the tumor response and depth of response (DpR) in patients with measurable lesions who were receiving nivolumab monotherapy as third- or later-line therapy.

Results

In 487 patients, the median OS and progression-free survival (PFS) were 5.8 (95% CI 5.3-6.9) months and 1.8 (95% CI 1.7-2.0) months, respectively. The response rate (RR) was 14.5% in 282 patients with measurable lesions. In 234 patients treated with third- or later-line, the DpR was found to be associated with PFS and OS in the Spearman analysis (r = 0.55 and 0.44, respectively) as well as using a discrete variable. When the DpR was divided into 5 groups (−20%≥DpR; −20%<DpR ≤ 0%; 0%<DpR ≤ 30%; 30%<DpR ≤ 50%; 50%<DpR) according to tumor shrinkage, clinically meaningful differences in PFS, and OS were noted. Patients with DpR of ≥30% had favorable survival time in nivolumab monotherapy as a later-line treatment.

Conclusion

The final analysis confirmed the efficacy of nivolumab monotherapy for patients with advanced GC in routine clinical practice. The exploratory analysis indicated that increasing DpR was associated with longer median PFS and OS in nivolumab treatment at a later-line setting.
Clinical outcomes of etoposide and cytarabine as consolidation in elderly patients with primary CNS lymphoma
Authors: Kim Yu Ri , Cho Hyunsoo , Kim Soo-Jeong , Chung Haerim , Kook Hye Won , Jang Ji Eun , Cheong June-Won , Kim Jin Seok
Published: April 2024

Background

A consolidation strategy has not been established for transplant-ineligible elderly patients with primary central nervous system lymphoma (PCNSL). In this study, we aimed to retrospectively evaluate the clinical outcomes of etoposide and cytarabine (EA) as consolidation chemotherapy for transplant-ineligible patients with PCNSL following high-dose methotrexate (MTX)-based induction chemotherapy.

Materials and Methods

Between 2015 and 2021, newly diagnosed transplant-ineligible patients with PCNSL with diffuse large B-cell lymphoma were consecutively enrolled. All enrolled patients were over 60 years old and received EA consolidation after achieving a complete or partial response following induction chemotherapy.

Results

Of the 85 patients who achieved a complete or partial response to MTX-based induction chemotherapy, 51 received EA consolidation chemotherapy. Among the 25 (49.0%, 25/51) patients in partial remission before EA consolidation, 56% (n = 14) achieved complete remission after EA consolidation. The median overall survival and progression-free survival were 43 and 13 months, respectively. Hematological toxicities were most common, and all patients experienced grade 4 neutropenia and thrombocytopenia. Forty-eight patients experienced febrile neutropenia during consolidation chemotherapy, and 4 patients died owing to treatment-related complications.

Conclusion

EA consolidation chemotherapy for transplant-ineligible, elderly patients with PCNSL improved response rates but showed a high relapse rate and short progression-free survival. The incidences of treatment-related mortality caused by hematologic toxicities and severe infections were very high, even after dose modification. Therefore, the use of EA consolidation should be reconsidered in elderly patients with PCNSL.
Arabidopsis transcription factor TCP4 controls the identity of the apical gynoecium
Authors: Wang Yutao , Wang Ning , Lan Jingqiu , Pan Yige , Jiang Yidan , Wu Yongqi , Chen Xuemei , Feng Xianzhong , Qin Genji
Published: April 2024

The style and stigma at the apical gynoecium are crucial for flowering plant reproduction. However, the mechanisms underlying specification of the apical gynoecium remain unclear. Here, we demonstrate that Class II TEOSINTE BRANCHED 1/CYCLOIDEA/PCF (TCP) transcription factors are critical for apical gynoecium specification in Arabidopsis (Arabidopsis thaliana). The septuple tcp2 tcp3 tcp4 tcp5 tcp10 tcp13 tcp17 (tcpSEP) and duodecuple tcp2 tcp3 tcp4 tcp5 tcp10 tcp13 tcp17 tcp24 tcp1 tcp12 tcp18 tcp16 (tcpDUO) mutants produce narrower and longer styles, while disruption of TCPs and CRABS CLAW (CRC) or NGATHAs (NGAs) in tcpDUO crc or tcpDUO nga1 nga2 nga4 causes the apical gynoecium to be replaced by lamellar structures with indeterminate growth. TCPs are predominantly expressed in the apex of the gynoecium. TCP4 interacts with CRC to synergistically upregulate the expression level of NGAs, and NGAs further form high-order complexes to control the expression of auxin-related genes in the apical gynoecium by directly interacting with TCP4. Our findings demonstrate that TCP4 physically associates with CRC and NGAs to control auxin biosynthesis in forming fine structures of the apical gynoecium.
Children betrayed: The unseen victims of domestic violence and how law enforcement can better protect them
Authors: Glick Saul , Spearman Kathryn J
Published: April 2024

Domestic violence is a commonplace and serious societal problem with vast public health and economic consequences. Childhood exposure to domestic violence can blight children’s biological and social development. Often, local police departments are first responders to domestic violence. This is because danger is associated with these events, which requires police presence. Yet, children are often unseen victims of domestic violence. In general, law enforcement agencies (i) are ill-equipped to identify the risks experienced by children; (ii) struggle to find alternative outcomes for children at risk other than removal or criminalization; (iii) do not use scientifically informed assessment tools which might improve their interactions with children; and (iv) inconsistently share data with other agencies in a timely manner. Moreover, gaps in criminal legal, child welfare, and family court responses to violence in the family create circumstances where children may fall through the cracks. Positive interventions in relation to domestic violence and children who suffer as a result of it should be viewed as a public priority. Improving responses to these issues should be reframed as (i) a way to reduce the amount of future violent crimes committed, and (ii) reduce the resource burden felt by public services. This commentary discusses the scope and scale of children’s exposure to domestic violence and child maltreatment and discusses international best practices that can serve as models to improve law enforcement’s response to children.
Keats’s Unwritten Epic
Authors: O’Halloran Meiko
Published: April 2024

When Keats told friends he had ‘given up’ his epic project, ‘Hyperion’, in September 1819, he expressed dissatisfaction with its artful ‘Miltonic inversions’. While sailing to Italy in the autumn of 1820 and in the months before he died, however, Keats told Joseph Severn about an epic he wanted to write—on Sabrina, the river goddess in Milton’s Comus. This essay offers the first critical investigation of Keats’s projected poem. I pursue Keats’s unwritten epic, using Severn’s accounts, a selection of Keats’s letters and poems, and the source text to reveal what may have interested him about Milton’s rendering of Sabrina’s story and what it can tell us. Far from putting Milton behind him, Keats continued to draw inspiration from his poetry, returning to a work he had previously dismissed and finding fresh pleasure in a masque that Milton had composed in his mid-twenties, long before Paradise Lost. I suggest that in Sabrina, the tutelary spirit of the Severn, Keats found a figure of transformation, survival, and healing—a young goddess whose liminal existence on the Welsh border and whose partially told story appealed to his imagination and his belief in poetry’s enduring power to transcend mortal limits.
Adverse Events Reporting in Digital Interventions Evaluations for Psychosis: A Systematic Literature Search and Individual Level Content Analysis of Adverse Event Reports
Authors: Allan Stephanie , Ward Thomas , Eisner Emily , Bell Imogen H , Cella Matteo , Chaudhry Imran B , Torous John , Kiran Tayyeba , Kabir Thomas , Priyam Aansha , Richardson Cara , Reininghaus Ulrich , Schick Anita , Schwannauer Matthias , Syrett Suzy , Zhang Xiaolong , Bucci Sandra
Published: April 2024

Background

Digital health interventions (DHIs) have significant potential to upscale treatment access to people experiencing psychosis but raise questions around patient safety. Adverse event (AE) monitoring is used to identify, record, and manage safety issues in clinical trials, but little is known about the specific content and context contained within extant AE reports. This study aimed to assess current AE reporting in DHIs.

Study Design

A systematic literature search was conducted by the iCharts network (representing academic, clinical, and experts by experience) to identify trials of DHIs in psychosis. Authors were invited to share AE reports recorded in their trials. A content analysis was conducted on the shared reports.

Study Results

We identified 593 AE reports from 18 DHI evaluations, yielding 19 codes. Only 29 AEs (4.9% of total) were preidentified by those who shared AEs as being related to the intervention or trial procedures. While overall results support the safety of DHIs, DHIs were linked to mood problems and psychosis exacerbation in a few cases. Additionally, 27% of studies did not report information on relatedness for all or at least some AEs; 9.6% of AE reports were coded as unclear because it could not be determined what had happened to participants.

Conclusions

The results support the safety of DHIs, but AEs must be routinely monitored and evaluated according to best practice. Individual-level analyses of AEs have merit to understand safety in this emerging field. Recommendations for best practice reporting in future studies are provided.
First evaluation of the impact of a targeted subunit vaccine against bovine viral diarrhea virus in feedlot cattle
Authors: Bellido Demian , Gumina Emanuel R , Rodríguez Senes Gonzalo J , Chiariotti Franco M , Audrito Maximiliano , Sueldo Pedro M , Sueldo Gustavo M , Wigdorovitz Andrés
Published: April 2024

Bovine respiratory disease (BRD) is a serious health and economic problem in the beef industry, which is often associated with transportation and caused by different pathogens. In this study, we evaluated the effect of a novel subunit targeted vaccine against bovine viral diarrhea virus (BVDV) in feedlot cattle, a major viral agent of BRD. The core of this novel vaccine is the fusion of the BVDV structural glycoprotein, E2, to a single-chain antibody, APCH, together termed, APCH-E2. The APCH antibody targets the E2 antigen to the major histocompatibility type II molecule (MHC-II) present in antigen-presenting cells. To evaluate the vaccine, 2,992 animals were randomly allocated into two groups, control group (N = 1,491) and treatment group (N = 1,501). Animals of both groups received the routine sanitary plan: two doses of clostridial, respiratory, and rabies vaccines. Animals within the treatment group also received two doses of a targeted subunit vaccine against BVDV. Serum samples were taken on the day of the first inoculation (T0) and 90 d later (T90). Viral circulation was monitored using an anti-P80 ELISA (virus-specific) and immune response was evaluated by anti-E2 ELISA (detects virus and vaccine immune responses). Only animals treated for respiratory disease were considered positive cases of BRD. Results demonstrate that the control group had significantly more animals treated for BRD cases compared to the treatment group (5.9% vs. 3.7%, P = 0.02). The control group had a greater number of animals positive for anti-P80 antibodies and significantly fewer animals positive for anti-E2 antibodies compared to the treatment group (69% vs. 61% and 71% vs. 99%, respectively, P = 0.003), consistent with natural viral circulation within this group. The treatment group, conversely, had fewer animals positive for anti-P80 antibodies and a greater number of animals positive for anti-E2 antibodies, consistent with a robust vaccine-induced antibody response and a reduction of the BVDV circulation within this group. The data indicate the new subunit targeted vaccine induced greater anti-E2 antibodies and reduced the amount of BVD virus circulation within the treatment group leading to a fewer number of animals needing to be treated for BRD.
Dimethyl itaconate inhibits antigen‐specific Th17 cell responses and autoimmune inflammation via modulating NRF2/STAT3 signaling
Authors: Wang Ying , Yang Chao , Hou Yubiao , Wang Jiali , Zhang Kailang , Wang Lihua , Sun Deming , Li Xiaorong , Wei Ruihua , Nian Hong
Published: April 2024

Pathogenic Th17 cells play a crucial role in autoimmune diseases like uveitis and its animal model, experimental autoimmune uveitis (EAU). Dimethyl itaconate (DMI) possesses potent anti‐inflammatory effects. However, there is still a lack of knowledge about the role of DMI in regulating pathogenic Th17 cells and EAU. Here, we reported that intraperitoneal administration of DMI significantly inhibited the severity of EAU via selectively suppressing Th17 cell responses. In vitro antigen stimulation studies revealed that DMI dramatically decreased the frequencies and function of antigen‐specific Th17, but not Th1, cells. Moreover, DMI hampered the differentiation of naive CD4+ T cells toward pathogenic Th17 cells. DMI‐treated DCs produced less IL‐1β, IL‐6, and IL‐23, and displayed an impaired ability to stimulate antigen‐specific Th17 activation. Mechanistically, DMI activated the NRF2/HO‐1 pathway and suppressed STAT3 signaling, which subsequently restrains p‐STAT3 nuclear translocation, leading to decreased pathogenic Th17 cell responses. Thus, we have identified an important role for DMI in regulating pathogenic Th17 cells, supporting DMI as a promising therapy in Th17 cell‐driven autoimmune diseases including uveitis.
Oxidized phospholipid POVPC contributes to vascular calcification by triggering ferroptosis of vascular smooth muscle cells
Authors: Lu Lihe , Ye Yuanzhi , Chen Yajun , Feng Liyun , Huang Jiali , Liang Qingchun , Lan Zirong , Dong Qianqian , Liu Xiaoyu , Li Yining , Zhang Xiuli , Ou Jing‐Song , Chen An , Yan Jianyun
Published: April 2024

Vascular calcification is an actively regulated biological process resembling bone formation, and osteogenic differentiation of vascular smooth muscle cells (VSMCs) plays a crucial role in this process. 1‐Palmitoyl‐2‐(5′‐oxo‐valeroyl)‐sn‐glycero‐3‐phosphocholine (POVPC), an oxidized phospholipid, is found in atherosclerotic plaques and has been shown to induce oxidative stress. However, the effects of POVPC on osteogenic differentiation and calcification of VSMCs have yet to be studied. In the present study, we investigated the role of POVPC in vascular calcification using in vitro and ex vivo models. POVPC increased mineralization of VSMCs and arterial rings, as shown by alizarin red staining. In addition, POVPC treatment increased expression of osteogenic markers Runx2 and BMP2, indicating that POVPC promotes osteogenic transition of VSMCs. Moreover, POVPC increased oxidative stress and impaired mitochondria function of VSMCs, as shown by increased ROS levels, impairment of mitochondrial membrane potential, and decreased ATP levels. Notably, ferroptosis triggered by POVPC was confirmed by increased levels of intracellular ROS, lipid ROS, and MDA, which were decreased by ferrostatin‐1, a ferroptosis inhibitor. Furthermore, ferrostatin‐1 attenuated POVPC‐induced calcification of VSMCs. Taken together, our study for the first time demonstrates that POVPC promotes vascular calcification via activation of VSMC ferroptosis. Reducing the levels of POVPC or inhibiting ferroptosis might provide a novel strategy to treat vascular calcification.
Neurotensin modulates ovarian vascular permeability via adherens junctions
Authors: Pearson Andrew C. , Shrestha Ketan , Curry Thomas E. , Duffy Diane M.
Published: April 2024

Neurotensin (NTS) is a 13‐amino acid peptide which is highly expressed in the mammalian ovary in response to the luteinizing hormone surge. Antibody neutralization of NTS in the ovulatory follicle of the cynomolgus macaque impairs ovulation and induces follicular vascular dysregulation, with excessive pooling of red blood cells in the follicle antrum. We hypothesize that NTS is an essential intrafollicular regulator of vascular permeability. In the present study, follicle injection of the NTS receptor antagonist SR142948 also resulted in vascular dysregulation. To measure vascular permeability changes in vitro, primary macaque ovarian microvascular endothelial cells (mOMECs) were enriched from follicle aspirates and studied in vitro. When treated with NTS, permeability of mOMECs decreased. RNA sequencing (RNA‐Seq) of mOMECs revealed high mRNA expression of the permeability‐regulating adherens junction proteins N‐cadherin (CDH2) and K‐cadherin (CDH6). Immunofluorescent detection of CDH2 and CDH6 confirmed expression and localized these cadherins to the cell–cell boundaries, consistent with function as components of adherens junctions. mOMECs did not express detectable levels of the typical vascular endothelial cadherin, VE‐cadherin (CDH5) as determined by RNA‐Seq, qPCR, western blot, and immunofluorescence. Knockdown of CDH2 or CDH6 via siRNA abrogated the NTS effect on mOMEC permeability. Collectively, these data suggest that NTS plays an ovulation‐critical role in vascular permeability maintenance, and that CDH2 and CDH6 are involved in the permeability modulating effect of NTS on the ovarian microvasculature. NTS can be added to a growing number of angiogenic regulators which are critical for successful ovulation.
Two founder variants account for over 90% of pathogenic BRCA alleles in Orkney and Shetland
Authors: Kerr Shona M. , Klaric Lucija , Muckian Marisa D. , Cowan Emma , Snadden Lesley , Tzoneva Gannie , Shuldiner Alan R. , Miedzybrodzka Zosia , Wilson James F.
Published: April 2024

For breast and ovarian cancer risk assessment in the isolated populations of the Northern Isles of Orkney and Shetland (in Scotland, UK) and their diasporas, quantifying genetically driftedBRCA1andBRCA2pathogenic variants is important. Two actionable variants in these genes have reached much higher frequencies than in cosmopolitan UK populations. Here, we report aBRCA2splice acceptor variant, c.517-2A>G, found in breast and ovarian cancer families from Shetland. We investigated the frequency and origin of this variant in a population-based research cohort of people of Shetland ancestry, VIKING I. The variant segregates with female breast and ovarian cancer in diagnosed cases and is classified as pathogenic. Exome sequence data from 2,108 participants with three or more Shetlandic grandparents in VIKING I was used to estimate the population prevalence of c.517-2A>G in Shetlanders. Nine VIKING I research volunteers carry this variant, on a shared haplotype (carrier frequency 0.4%). This frequency is ∼130-fold higher than in UK Biobank, where the small group of carriers has a different haplotype. Records of birth, marriage and death indicate genealogical linkage of VIKING I carriers to a founder from the Isle of Whalsay, Shetland, similar to our observations for theBRCA1founder variant from Westray, Orkney. In total, 93.5% of pathogenic BRCA variant carriers in Northern Isles exomes are accounted for by these two drifted variants. We thus provide the scientific evidence of an opportunity for screening people of Orcadian and Shetlandic origins for each drifted pathogenic variant, particularly women with Westray or Whalsay ancestry.
Prominent involvement of acetylcholine in shaping stable olfactory representation across the Drosophila brain
Authors: Fan Jiaqi , Wang Yuling , Li Lingbo , He Jing , Zhao Zhifeng , Deng Fei , Li Guochuan , Li Xinyang , Zhou Yiliang , Zhao Jiayin , Li Yulong , Wu Jiamin , Fang Lu , Dai Qionghai
Published: April 2024

Despite the vital role of neuromodulation in the neural system, the specific spatiotemporal dynamics of neuromodulators and their interactions with neuronal activities in vivo are still unclear, hampering our understanding of their information representation and functional contributions systemically. To address this problem, we employed two-photon synthetic aperture microscopy (2pSAM) to record long-term neuronal and neuromodulatory olfactory responses across the Drosophila brain at high speed. Our results revealed distinct response properties, global information propagation, functional connectivity, and odor identity representation among neuronal, cholinergic, and serotoninergic dynamics across multiple brain regions. We discovered the compensation between neuronal activity and cholinergic dynamics, both in the odor identity representation across the brain and the functional connectivity network structures of specific brain regions. Moreover, employing low-dimensional manifold and functional connectivity network analyses, we characterized the stable representation of cholinergic dynamics over a long term. Collectively, our unbiased and comprehensive investigation unveiled the prominent involvement of acetylcholine (ACh) in shaping olfactory representation across the brain, underscoring the inadequacy of solely considering neuronal activities when examining information representation of the brain.
The genome sequence of the Violet Carpenter Bee, Xylocopa violacea (Linnaeus, 1785): a hymenopteran species undergoing range expansion.
Authors: Nash Will , Man Angela , McTaggart Seanna , Baker Kendall , Barker Tom , Catchpole Leah , Durrant Alex , Gharbi Karim , Irish Naomi , Kaithakottil Gemy , Ku Debby , Providence Aaliyah , Shaw Felix , Swarbreck David , Watkins Chris , Mc Cartney Ann , Formenti Giulio , Mouton Alice , Vella Noel , von Reumont Bjoern Marcus , Vella Adriana , Haerty Wilfried
Published: April 2024

We present a reference genome assembly from an individual male Violet Carpenter Bee (Xylocopa violacea, Linnaeus, 1758). The assembly is 1.02 gigabases in span. 48% of the assembly is scaffolded into 17 pseudo-chromosomal units. The mitochondrial genome has also been assembled and is 21.8 kilobases in length. The genome is highly repetitive, likely representing a highly heterochromatic architecture expected of bees from the genus Xylocopa. We also use an evidence-based methodology to annotate 10,152 high confidence coding genes. This genome was sequenced as part of the pilot project of the European Reference Genome Atlas (ERGA) and represents an important addition to the genomic resources available for Hymenoptera.
Spatially heterogeneous selection and inter-varietal differentiation maintain population structure and local adaptation in a widespread conifer
Authors: Peláez Pablo , Lorenzana Gustavo P. , Baesen Kailey , Montes Jose Ruben , De La Torre Amanda R.
Published: April 2024

Douglas-fir (Pseudotsuga menziesii) plays a critical role in the ecology and economy of Western North America. This conifer species comprises two distinct varieties: the coastal variety (var.menziesii) along the Pacific coast, and the interior variety (var.glauca) spanning the Rocky Mountains into Mexico, with instances of inter-varietal hybridization in Washington and British Columbia. Recent investigations have focused on assessing environmental pressures shaping Douglas-fir’s genomic variation for a better understanding of its evolutionary and adaptive responses. Here, we characterize range-wide population structure, estimate inter-varietal hybridization levels, identify candidate loci for climate adaptation, and forecast shifts in species and variety distribution under future climates.

Using a custom SNP-array, we genotyped 540 trees revealing four distinct clusters with asymmetric admixture patterns in the hybridization zone. Higher genetic diversity observed in coastal and hybrid populations contrasts with lower diversity in inland populations of the southern Rockies and Mexico, exhibiting a significant isolation by distance pattern, with less marked but still significant isolation by environment. For both varieties, we identified candidate loci associated with local adaptation, with hundreds of genes linked to processes such as stimulus response, reactions to chemical compounds, and metabolic functions. Ecological niche modeling showed contrasting potential distribution shifts among varieties in the coming decades.

Overall, our findings provide crucial insights into the population structure and adaptive potential of Douglas-fir, with the coastal variety being the most likely to preserve its evolutionary path throughout the present century, which carry implications for the conservation and management of this species across their range.
Weighting of sensory cues reflect changing patterns of visual investment during ecological divergence inHeliconiusbutterflies
Authors: Borrero José , Perez Elisa Mogollon , Wright Daniel Shane , Lozano Daniela , Rueda-Muñoz Geraldine , Pardo-Diaz Carolina , Salazar Camilo , Montgomery Stephen H. , Merrill Richard M.
Published: April 2024

Integrating information across sensory modalities enables animals to orchestrate a wide range of complex behaviours. The relative importance placed on one sensory modality over another reflects the reliability of cues in a particular environment and corresponding differences in neural investment. As populations diverge across environmental gradients, the reliability of sensory cues may shift, favouring divergence in neural investment and the weight given to different sensory modalities. During their divergence across closed-forest and forest-edge habitats, closely related butterfliesHeliconius cydnoandH. melpomeneevolved distinct brain morphologies, with the former investing more in vision. Quantitative genetic analyses suggest selection drove these changes, but their behavioural effects remain uncertain. We hypothesised that divergent neural investment may alter sensory weighting. We trained individuals in an associative learning experiment using multimodal colour and odour cues. When positively rewarded stimuli were presented in conflict pairing positively trained colour with negatively trained odour, andvice-versa,H. cydnofavoured visual cues more strongly thanH. melpomene. Hence, differences in sensory weighting may evolve early during divergence and are predicted by patterns of neural investment. These findings, alongside other examples, imply that differences in sensory weighting stem from divergent investment as adaptations to local sensory environments.
MODERATE ALCOHOL CONSUMPTION INDUCES LASTING IMPACTS ON PREFRONTAL CORTICAL SIGNALING IN MICE
Authors: Smith Grace C. , Griffith Keith R. , Sicher Avery R. , Brockway Dakota F. , Proctor Elizabeth A. , Crowley Nicole A.
Published: April 2024

Both alcohol use disorder (AUD) and Alzheimer’s Disease and Related Dementias (ADRD) appear to include disruption in the balance of excitation and inhibition in the cortex, but their potential interactions are unclear. We examined the effect of moderate voluntary binge alcohol consumption on the aged, pre-disease neuronal environment by measuring intrinsic excitability and spontaneous neurotransmission on prefrontal cortical pyramidal (excitatory, glutamatergic) and non-pyramidal (inhibitory, GABAergic) neurons following a prolonged period of abstinence from alcohol in mice. Results highlight that binge alcohol consumption has lasting impacts on the electrophysiological properties of prefrontal cortical neurons. A profound increase in excitatory events onto layer 2/3 non-pyramidal neurons following alcohol consumption was seen, along with altered intrinsic excitability of pyramidal neurons, which could have a range of effects on Alzheimer’s Disease progression in humans. These results indicate that moderate voluntary alcohol influences the pre-disease environment in aging and highlight the need for further mechanistic investigation into this risk factor.

HIGHLIGHTS

Moderate voluntary alcohol consumption leads to disruption of prefrontal cortical signaling at protracted ages in both male and female mice

Excitatory glutamatergic events onto prelimbic cortex GABAergic neurons, but not pyramidal neurons, are increased 6 months following alcohol exposure

Both pyramidal neurons and GABAergic neurons show altered intrinsic excitability 6 months following alcohol exposure
Afrothismia ugandensissp. nov. (Afrothismiaceae), Critically Endangered and endemic to Budongo Central Forest Reserve, Uganda
Authors: Cheek Martin , Gereau Roy E. , Kalema James
Published: April 2024

The fully mycotrophicAfrothismia ugandensis(Afrothismiaceae), formerly described asA. winklerivar.budongensisCowley, is renamed, redescribed and illustrated from the Budongo Forest in Western Uganda. This change in status is supported by eight newly elucidated qualitative morphological diagnostic characters despite the overall similarity withA. winkleri, a species restricted to Cameroon and Gabon.Afrothismia ugandensisis remarkable in the genus for occurring in semi-deciduous (not evergreen) forest and for having ellipsoid or ovoid (vs. globose) root bulbils. It has only been recorded twice, first in August 1940, and most recently in June 1998, despite targeted searches in recent years. In both 1940 and 1998, only single individuals appear to have been detected. A single site for the species is known with certainty. It is here assessed as Critically Endangered (CR B2ab (iii); D1) using the IUCN 2012 categories and criteria.Afrothismia ugandensisis threatened by forest degradation and clearance due to illegal selective small-holder logging for firewood and charcoal, timber and limited agriculture.