bluuebunny/crossref_metadata_2025 huggingface dataset:
EXPERIMENTAL DESIGN ISSUES ASSOCIATED WITH CLASSIFICATIONS OF HYPERSPECTRAL IMAGING DATA
Authors: Nansen Christian , Lee Hyoseok , Mesgaran Mohsen B.
Published: August 2024

Hyperspectral imaging has emerged as a pivotal tool to classify plant materials (seeds, leaves, and whole plants), pharmaceutical products, food items, and many other objects. This communication addresses two issues, which appear to be over-looked or ignored in >99% of hyperspectral imaging studies: 1) the “small N, large P” problem, when number of spectral bands (explanatory variables, “P”) surpasses number of observations, (“N”) leading to potential model over-fitting, and 2) absence of independent validation data in performance assessments of classification models. Based on simulations of randomly generated data, we illustrate risks associated with these issues. We explore and discuss consequences of over-fitting and risks of misleadingly high accuracy that can result from having a large number of variables relative to observations. We highlight connections of these issues with radiometric repeatability (levels of stochastic noise). A method is proposed wherein a theoretical dataset is generated to mirror the structure of an actual dataset, with the classification of this theoretical dataset serving as a reference. By shedding light on important and common experimental design issues, we aim to enhance methodological rigor and transparency in classifications of hyperspectral imaging data and foster improved and effective applications across various science domains.
Genomic insights into the adaptive evolution of the memorial rose (Rosa lucieae; Rosaceae) in saline environments
Authors: Jeon Ji-Hyeon , Jung Myunghee , Shin Younhee , Kim Seung-Chul
Published: August 2024

Rosa lucieae(syn.Rosa wichuranaorR. wichuraiana; Rosaceae) is one of the major wild progenitors of modern rose cultivars. In breeding roses,R. lucieaehas contributed not only to white blooms and shiny leaves, but most of all, to succeed in various harsh conditions and high resistance to diseases and pests. The wildR. lucieaeinhabits littoral sand banks or rocks, where drought stress and high salinity inhibit plant growth. In this study, we assembled the chromosome-level genome sequence of a wild accession ofR. lucieaeand identified potential genes that may responsible for the evolution of salt tolerance. Within the 544.7 Mb-long genome ofR. lucieae, recent duplications and divergence of the genes responsible to stress tolerance were identified, including stress response, signaling, homeostasis, and detoxification. Additionally, the gene family evolution analyses elucidated rapid evolution of stress tolerant functions inR. lucieae. The first high-quality genome assembly of wildR. lucieaecontributes significantly to our understanding of the genomic evolution and adaptive mechanism ofR. lucieae, which promises the enhancement of our efforts in rose breeding programs.
Sld3CBD-Cdc45 structural insights into Cdc45 recruitment for CMG complex formation
Authors: Li Hao , Ishizaki Izumi , Kato Koji , Sun XiaoMei , Muramatsu Sachiko , Itou Hiroshi , Ose Toyoyuki , Araki Hiroyuki , Yao Min
Published: August 2024

DNA replication requires Cdc45 and GINS recruitment into the MCM duplex hexamer by initiation factors to form an active helicase, the Cdc45–MCM–GINS (CMG) complex, at the replication origins. The initiation factor Sld3 is a central regulator of Cdc45 and GINS recruitment worked with Sld7 together. However, the mechanism through which Sld3 regulates CMG complex formation remains unclear. Here, we present the structure of the Sld3 Cdc45-binding-domain in complex with Cdc45 (Sld3CBD–Cdc45), showing detailed interactions and conformational changes required for binding to each other. The mutant analysis indicated that the binding between Sld3CBD and Cdc45 could be broken easily. We also revealed that Sld3CBD, GINS, and MCM bind to different sites on Cdc45 in the Sld3CDB–CMG model, indicating that after recruitment of Cdc45, Sld7–Sld3 could remain in Cdc45–MCM until CMG formation. The consistency between the particle size of Sld7–Sld3–Cdc45 and the distance between Sld3CBDs in the Cdc45–MCM dimer indicated the binding manner of the Cdc45–Sld3–[Sld7]2–Sld3–Cdc45 off/on MCM duplex hexamer. A DNA-binding assay of Sld3 and its complexes with single-stranded ARS1 fragments revealed a relationship between the dissociation of Sld7–Sld3 from CMG and the unwound single-stranded DNA. These findings help to further our understanding of the molecular basis of regulation of CMG complex formation by Sld3.
A microendovascular system can record precise neural signals from cortical and deep vessels with minimal invasiveness
Authors: Iwata Takamitsu , Nakamura Hajime , Uemura Takafumi , Araki Teppei , Matsumura Takaki , Abe Takaaki , Nezu Toshikazu , Takagaki Masatoshi , Ozaki Tomohiko , Miura Shinpei , Fukuma Ryohei , John Sam E. , Grayden David B. , Kishima Haruhiko , Sekitani Tsuyoshi , Yanagisawa Takufumi
Published: August 2024

Minimally invasive intravascular electroencephalography (ivEEG) signals are a promising tool for developing clinically feasible brain–computer interfaces (BCIs) that restore communication and motor functions in paralyzed patients. However, current ivEEG techniques can only record signals from the superior sagittal sinus (SSS), making it challenging to record motor responses related to hand and mouth movements from brain regions distant from the SSS, despite their critical role in BCIs. Here, using micro intravascular electrodes, ivEEGs recorded from the cortical or deep veins of eight pigs could measure cortical activities with greater signal power and better spatial resolution than those recording in the SSS, thus allowing mapping of the sensorimotor and visual functional areas. Additionally, electrical stimulation in the cortical vein between the micro intravascular electrodes induced muscle contractions contralateral to the stimulated area in five anesthetized pigs. These results demonstrate that ivEEG using micro intravascular electrodes is a promising tool for developing BCIs.
RNA functional control by hydrolysis reversible acylation
Authors: Liu Kaizheng , Kietrys Anna M.
Published: August 2024

We present the hydrolysis reversible acylation of RNA 2′-OH for functional control. Compared with previously reported acylating reagents, our new moleculeEST1Aeliminated the need of toxic organic molecules in deacylation. Instead, the acylation was removed by biocompatible intracellular stimuli such as esterase and histidine. After validating the reversibility using oligonucleotides, we applied our acylating reagent on functional RNAs, including broccoli aptamer, eGFP mRNA, and eGFP siRNA, and gained activity control on them. Further inhibitory and enhancive assays in HepG2 and U87MG cells confirmed that both carboxylesterase and cholinesterase contributed to deacylationin cellulo. By taking advantage of differences in esterase expression among cell lines, our new strategy can benefit the development of cell-selective gene therapeutics.
Analysis and control of untemplated DNA polymerase activity for guided synthesis of kilobase-scale DNA sequences
Authors: Castle Simeon D. , Woolfson Adrian , Linshiz Gregory , Riley Blake T. , Samuel Ifor D.W. , Holliger Philipp , Oldfield Lauren , Hessel Andrew , Gorochowski Thomas E.
Published: August 2024

DNA polymerases are complex molecular machines able to replicate genetic material using a template-driven process. While the copying function of these enzymes is well established, their ability to perform untemplated DNA synthesis is less well characterized. Here, we explore the ability of DNA polymerases to synthesize DNA fragments in the absence of template. We use long-read nanopore sequencing and real-time PCR to observe the synthesis of pools of DNA products derived from a diverse set of natural and engineered DNA polymerases across varying temperatures and buffer compositions. We detail the features of the DNA fragments generated, enrichment of select sequence motifs, and demonstrate that the sequence composition of the synthesized DNA may be altered by modifying environmental conditions. This work provides an extensive data set to better discern the process of untemplated DNA polymerase activity and may support its potential repurposing as a technology for the guided synthesis of DNA sequences on the kilobase-scale and beyond.
Roles for the canonical polarity machinery in thede novoestablishment of polarity in budding yeast spores
Authors: Cooperman Benjamin , McMurray Michael
Published: August 2024

The yeastSaccharomyces cerevisiaebuds at sites pre-determined by cortical landmarks deposited during prior budding. During mating between haploid cells in the lab, external pheromone cues override the cortical landmarks to drive polarization and cell fusion. By contrast, in haploid gametes (called spores) produced by meiosis, a pre-determined polarity site drives initial polarized morphogenesis independent of mating partner location. Spore membranes are madede novoso existing cortical landmarks were unknown, as were the mechanisms by which the spore polarity site is made and how it works. We find that the landmark canonically required for distal budding, Bud8, stably marks the spore polarity site along with Bud5, a GEF for the GTPase Rsr1 that canonically links cortical landmarks to the conserved Cdc42 polarity machinery. Cdc42 and other GTPase regulators arrive at the site during its biogenesis, after spore membrane closure but apparently at the site where membrane synthesis began, and then these factors leave, pointing to the presence of discrete phases of maturation. Filamentous actin may be required for initial establishment of the site, but thereafter Bud8 accumulates independent of actin filaments. These results suggest a distinct polarization mechanism that may provide insights into gamete polarization in other organisms.

SIGNIFICANCE STATEMENT

Dormant budding yeast spores possess a single, stable cortical site that marks the location where polarized growth occurs upon dormancy exit. It was not known how the site forms or which molecules comprise it.

Using fluorescently tagged proteins in living cells undergoing sporulation, the authors found proteins canonically involved in polarization of non-spore cells arriving at the polarity site in a choreographed manner and required for site function.

These findings point to a distinct polarity mechanism from non-spore cells and raise new questions about polarity protein interactions with membranes that may be applicable to gametogenesis in other organisms.
Changes in hypothalamic subunits volume and their association with metabolic parameters and gastrointestinal appetite-regulating hormones following bariatric surgery
Authors: Lachance Amélie , Daoust Justine , Pelletier Mélissa , Caron Alexandre , Carpentier André C. , Biertho Laurent , Maranzano Josefina , Tchernof André , Dadar Mahsa , Michaud Andréanne
Published: August 2024

Background

Some nuclei of the hypothalamus are known for their important roles in maintaining energy homeostasis and regulating food intake. Moreover, obesity has been associated with hypothalamic inflammation and morphological alterations, as indicated by increased volume. However, the reversibility of these changes after bariatric surgery-induced weight loss remains underexplored.

Objective

The aim of this study was to characterize volume changes in hypothalamic subunits up to two years following bariatric surgery and to determine whether these differences were associated with changes in metabolic parameters and levels of gastrointestinal appetite-regulating hormone levels.

Methods

Participants with severe obesity undergoing bariatric surgery were recruited. They completed high-resolution T1-weighted brain magnetic resonance imaging (MRI) before bariatric surgery and at 4, 12 and 24 months post-surgery. Blood samples collected during the fasting and postprandial states were analyzed for glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin concentrations. The hypothalamus was segmented into 5 subunits per hemisphere using a publicly available automated tool. Linear mixed-effects models were employed to examine volume changes between visits and their associations with variables of interest.

Results

A total of 73 participants (mean age 44.5 ± 9.1 years, mean BMI 43.5 ± 4.1 kg/m2) were included at baseline. Significant volume reductions were observed in the whole left hypothalamus 24 months post-surgery. More specifically, decreases were noted in both the left anterior-superior and left posterior subunits at 12 and 24 months post-surgery (all p<0.05, after FDR correction). These reductions were significantly associated with the percentage of total weight loss (both subunits p<0.001), improvements in systolic blood pressure (both subunits p<0.05), and an increase in postprandial PYY (both subunits p<0.05).

Conclusion

These results suggest that some hypothalamic morphological alterations observed in the context of obesity could potentially be reversed with bariatric surgery induced-weight loss.
Inverse correlation between NLRP3 and TMEM176B as a possible tool for colorectal cancer progression
Authors: Cambui Raylane Adrielle Gonçalves , Roa Mariela Estefany Vera , Leal Vinicius Nunes Cordeiro , Yamada Suemy Melim , de Oliveira Leonardo Antônio Teixeira , Nadaf Izabel Nazira , Lelis Cleiton Ribeiro , da Cunha Pedroso Rafaela Cássia , do Nascimento Costa Rafaela Cardoso , Amorim Raquel Maria Neves , do Amaral Jefferson Rodrigues , Lemes Polyana Silva , Rizzo Leonardo Amorim , do Espírito Santo Gilmar Ferreira , Elias Rosa Maria , Cogliati Bruno , Hill Marcelo , Pontillo Alessandra
Published: August 2024

Purpose

TMEM176B has been recently identified as a novel player in anti-cancer immune responses by negatively modulating the NLRP3 inflammasome activation in colorectal cancer (CRC). Yet, the TMEM176B/NLRP3 axis in CRC needs to be deeply investigated.

Methods

TMEM176B and NLRP3 expression were evaluated in CRC patients by immunohistochemistry and RT-qPCR assays. The prognostic relevance of TMEM176B and NLRP3 was determined by in silico analysis. The NLRP3 inflammasome activation in the CRC microenvironment was assessed in a peripheral blood mononuclear cells (PBMC) and CRC cell line (HCT-116) spheroids co-culture assay.

Results

Reduced NLRP3 and increased TMEM176B expression correlates to CRC stages and poor survival. The in vitro assay showed HCT-116 cells activated NLRP3 inflammasome in PBMC.

Conclusion

These findings evidence the inverse correlation between NLRP3 and TMEM176B in CRC progression, suggesting them as a predictive tool.
“Dynamics of factors associated with neonatal death in Madagascar: a comparative analysis of the 2003, 2008, 2021 DHS”
Authors: Rakotondrasoa Sedera Radoniaina , Cissé Kadari , Millogo Tieba , Rabarisoa Hajalalaina , Alain Felix , Kouanda Seni , Rakotonirina Julio
Published: August 2024

Neonatal mortality remains a major public health challenge, as reductions have stagnated worldwide despite cost-effective interventions in recent years. The temporal evolution of its determinants is insufficiently studied. This study aimed to analyze the dynamics of factors associated with neonatal death in Madagascar between 2003 and 2021.

A secondary analysis was conducted using data from the 2003, 2008, and 2021 Demographic and Health Surveys (DHS) of Madagascar. The study population is focused on children under the age of 5 years at the time of these surveys. The death of a newborn within 30 days after birth constitutes the outcome variable. A multilevel binomial logistic regression was performed.

The number of children under 5 included in the analysis were 5,415 in 2003, 12,448 in 2008 and 12,399 in 2021. The prevalence of neonatal deaths was 3.05% in 2003, 2.42% in 2008, and 2.56% in 2021. Persistent significant associations with neonatal death were observed for low birth weight, lack of breastfeeding, medium-sized households, large households, and high birth weight. A loss of statistical significance of the association with neonatal death over time was observed for a birth interval of 2 to 3 years and 4 years and more, mother’s age 40-49 years, and use of mosquito net by the mother. In 2021, new significant associations with neonatal mortality were identified in the province of Toliara, absence of difficulty in accessing health centers, 4 to 7 ANC visits, and supervised delivery.

The factors associated with neonatal mortality, which have worsened over time in Madagascar, include birth weight abnormalities, delivery in the presence of qualified personnel, and evaluation of neonatal health before discharge from the facility. This deterioration underscores the urgency of improving the quality of perinatal care in healthcare facilities, beyond mere geographical accessibility.
Barriers and facilitators to successful transition to civilian life for ex-servicewomen: the perspective of service providers and policymakers
Authors: Croak Bethany , Rafferty Laura , Sharp Marie-Louise , Smith Alexandria , Khan Rafiyah , Langston Victoria , Greenberg Neil , Fear Nicola T , Stevelink Sharon A.M
Published: August 2024

The role of women in the UK Armed Forces has changed considerably in the last decade. With drives to increase the number of women serving in the military, research must consider the impact of both service and transition into civilian life on the health and wellbeing of service and ex-servicewomen (female veterans). This paper adds to the field by providing the perspective of service providers supporting ex-service personnel with their mental health, employment, housing and other needs in addition to those working in policy affecting ex-servicewomen. This study aimed to explore their understanding of what constitutes a successful transition into civilian life, the barriers and facilitators to achieving this and how transition might be impacted by the gender of the individual transitioning. Interviews and roundtable discussions were held with stakeholders (n=28) and analysed using framework analysis. Four overarching themes were identified: ’Successful transition is individual and all-encompassing’, ‘The conflicting identities of servicewomen’, ’Sexism: women don’t belong in service’ and ’The needs of servicewomen’. The first theme describes how the process and result of successful transition is individual to each ex-servicewoman, whilst the remaining themes outline common challenges faced by ex-servicewomen on this journey. There was no singular definition of ’successful transition’, but stakeholders described barriers to a successful transition. They identified prominent gender-specific barriers rooted in misogyny and inequality during military service that permeated into civilian life and impacted support use and workplace experiences. Ex- servicewomen were often required to juggle multiple responsibilities, mother and partner, and identities, women and warrior, simultaneously. Policies should look to address elements of military culture that may reinforce gender inequality and ensure veteran services are inclusive and welcoming to women and cater for gender-specific needs such as gynaecological health. Whilst in-service and veteran-focused interventions are needed, entrenched sexism in general society should not be ignored.
Pre-trained convolutional neural network with transfer learning by artificial illustrated images classify power Doppler ultrasound images of rheumatoid arthritis joints
Authors: Fukae Jun , Amasaki Yoshiharu , Fujieda Yuichiro , Sone Yuki , Katagishi Ken , Horie Tatsunori , Kamishima Tamotsu , Atsumi Tatsuya
Published: August 2024

Objectives

To study the classification performance of a pre-trained convolutional neural network (CNN) with transfer learning by artificial images of the joint ultrasonography in rheumatoid arthritis (RA).

Methods

We focused on abnormal synovial vascularity and created 870 artificial ultrasound joint images based on the European League Against Rheumatism/Outcome Measure in Rheumatology scoring system. One CNN, the Visual Geometry Group (VGG)-16 was trained with transfer learning using the 870 artificial images for initial training and the original plus five additional images for second training. Actual joint ultrasound images obtained from patients with RA were used for testing our models.

Results

We obtained 156 actual ultrasound joint images from 74 patients with RA. Our initial model showed moderate classification performance, but grade 1 was especially low (area under curve (AUC) 0.59). In our second model, grade 1 showed improvement (AUC 0.73).

Conclusions

We concluded that artificial images were useful for training VGG-16. Our novel approach of using artificial images as an alternative to actual images for training CNN has the potential to be applied in medical imaging fields that face difficulties in collecting real clinical images.

Registration of clinical trials

This study was registered in UMIN Clinical Trials Registry (UMIN000054321).
Understanding the clinical characteristics and timeliness of diagnosis for patients diagnosed with Long COVID: A retrospective observational cohort study from North West London
Authors: Prociuk Denys , Clarke Jonathan , Smith Nikki , Milne Ruairidh , Lee Cassie , de Lusignan Simon , Mir Ghazala , Kock Johannes De , Mayer Erik , Delaney Brendan C ,   LOCOMOTION Consortium
Published: August 2024

Background

Long COVID is a multisystem condition first identified in the COVID-19 pandemic characterised by a wide range of symptoms including fatigue, breathlessness and cognitive impairment. Considerable disagreement exists in who is most at risk of developing Long COVID, driven in part by incomplete coding of a Long COVID diagnosis in medical records.

Methods

This was a retrospective observational cohort study using an integrated primary and secondary care dataset from North West London, covering over 2.7 million patients. Patients with Long COVID were identified through clinical terms in their primary care record. Multivariate logistic regression was used to identify factors associated with having Long COVID diagnosis, while multivariate quantile regression was used to identify factors predicting the time a Long COVID diagnosis was recorded.

Findings

A total of 6078 patients were identified with a Long COVID clinical term in their primary care record, 0.33% of the total registered adult population. Women, those aged 41 to 70 years or of Asian ethnicity were more likely to have a recorded Long COVID diagnosis, alongside those with pre-existing anxiety, asthma, depressive disorder or eczema and those living outside of the most socioeconomically deprived areas. Men, those aged 41 to 70 years, or of black ethnicity were diagnosed earlier in the pandemic, while those with depressive disorder were diagnosed later.

Interpretation

Long COVID is poorly coded in primary care records, and significant differences exist between patient groups in the likelihood of receiving a Long COVID diagnosis. Long COVID is more likely in those with pre-existing long-term conditions and is also associated with the frequent incidence of new long-term conditions. The experience of patients with Long COVID provides a crucial insight into inequities in access to timely care for complex multisystem conditions, and the importance of effective health informatics practices to provide robust, timely analytical support for front-line clinical services.

Funding

National Institute for Health and Care Research (NIHR) Ref: COV-LT2-0016
Spatial and Temporal Hotspot Analysis of COVID-19 in Toronto
Authors: Amoako Afia , Carabali Mabel , Ge Erjia , Tuite Ashleigh R , Fisman David N
Published: August 2024

The COVID-19 pandemic in Toronto, Canada was unequal for its 2.7 million residents. As a dynamic pandemic, COVID-19 trends might have also varied over space and time. We conducted a spatiotemporal hotspot analysis of COVID-19 over the first four major waves of COVID-19 using three different applications of Moran’s I to highlight the variable experience of COVID-19 infections in Toronto, while describing the potential impact of socioeconomic and sociodemographic factors on increased risk of COVID-19 exposure and infection. Results highlight potential clustering of COVID-19 case rate hot spots in areas with higher concentrations of immigrant and low-income residents and cold spots in areas with more affluent and non-immigrant residents during the first three waves. By the fourth wave, case rate clustering patterns were more dynamic. In all, a better understanding of the unequal COVID-19 pandemic experience in Toronto needs to also consider the dynamic nature of the pandemic.

HIGHLIGHTS

- The COVID-19 pandemic was spatially and temporarily dynamic in the City of Toronto.

- At first, hotspots were concentrated in areas with more marginalized residents.

- Later, COVID-19 spatial trends diverged from initially identified patterns.

- East Asian enclaves in the city disproportionally had lower COVID-19 case counts.

- COVID-19 studies need to consider the dynamic nature of the pandemic.
Recent and forecasted increases in coccidioidomycosis incidence in California linked to hydroclimatic swings
Authors: Camponuri Simon K. , Heaney Alexandra K. , Cooksey Gail Sondermeyer , Vugia Duc J. , Jain Seema , Swain Daniel L. , Balmes John , Remais Justin V. , Head Jennifer R
Published: August 2024

Coccidioidomycosis, or Valley fever, is an infectious disease caused by inhalation ofCoccidioidesspp., fungi found primarily in soils of the southwestern United States. Prior work showed that coccidioidomycosis cases in California sharply increase by nearly 2-fold following wet winters that occur one- and two-years following drought. Statewide drought between 2020-2022 followed by heavy precipitation during the 2022-2023 winter raised concerns over potential increases in coccidioidomycosis cases in the fall of 2023, prompting California Department of Public Health (CDPH) to issue public health alerts. As anticipated, California saw a near record number of cases in 2023, with 9,054 provisional cases reported. During the 2023-2024 California wet season, precipitation was 115% the long-term average, furthering concerns about continued high coccidioidomycosis risk. We developed an ensemble model to forecast coccidioidomycosis cases in California in 2024-2025. Using this model, we predicted a total of 11,846 cases (90% PI: 10,056–14,094) in California between April 1, 2023, and March 31, 2024, encompassing the preliminary state report of 10,593. Our model forecasted 12,244 cases statewide between April 1, 2024, and March 31, 2025 — a 62% increase over the cases reported during the same period two years prior, and on par with the high incidence seen in 2023. The Southern San Joaquin Valley (5,398 cases, 90% PI: 4,556–6,442), Southern Coast (3,322, 90% PI: 2,694–3,961), and Central Coast (1,207 cases, 90% PI: 867–1,585) regions are expected to see the largest number of infections. Our model forecasts that disease incidence will exhibit pronounced seasonality, particularly in endemic regions, with cases rising in June and peaking in November at 1,411 (90% PI: 815–2,172) cases statewide – 98% higher than the peak two years prior (714) and nearly as high as the peak in 2023 (1,462). Near-term forecasts have the potential to inform public health messaging to enhance provider and patient awareness, encourage risk reduction practices, and improve recognition and management of coccidioidomycosis.
A wheat tandem kinase and NLR pair confers resistance to multiple fungal pathogens
Authors: Lu Ping , Zhang Gaohua , Li Jing , Gong Zhen , Wang Gaojie , Dong Lingli , Zhang Huaizhi , Guo Guanghao , Su Min , Wang Yueming , Zhu Keyu , Wu Qiuhong , Chen Yongxing , Li Miaomiao , Huang Baoge , Li Beibei , Li Wenling , Dong Lei , Hou Yikun , Cui Xuejia , Fu Hongkui , Qiu Dan , Yuan Chengguo , Li Hongjie , Zhou Jianmin , Han Guan-Zhu , Chen Yuhang , Liu Zhiyong
Published: August 2024

Recently discovered tandem kinase proteins (TKPs) are pivotal to the innate immune systems of cereal plants, yet how they initiate plant immune responses remains unclear. This report identifies the wheat protein WTN1, a non-canonical NLR receptor featuring tandem NB-ARC domains, as crucial forWTK3-mediated disease resistance. Both WTK3 and its allelic variant Rwt4, known for conferring resistance to wheat powdery mildew and blast respectively, are capable of recognizing the blast effector PWT4, and activate WTN1 to form calcium-permeable channels, akin to ZAR1 and Sr35. This study unveils a unique plant defense mechanism wherein TKPs and associated NLRs operate as “sensor-executor” pairs against fungal pathogens. Additionally, evolutionary analyses reveal a co-evolutionary trajectory of the TKP-NLR module, highlighting their synergistic role in triggering plant immunity.

One Sentence Summary

An ancient synergistic TKP-NLR pair triggers innate immunity for multiple disease resistance in wheat.
Areas of high risk for mammalian biodiversity and Nature’s Contributions to People under global warming
Authors: Cimatti Marta , Sacchi Andrea , Di Marco Moreno
Published: August 2024

Climate change has reached unprecedented levels, causing frequent extreme events like droughts and fires. Combined with land-use change, this crisis has impacted biodiversity, increasing species extinction rates, and Nature’s Contributions to People (NCP), degrading ecosystem functions. We developed a comparative extinction risk model for mammals sensitive to fire, drought, and extreme temperatures, utilizing a Random Forest algorithm to predict future extinction probabilities under different climatic scenarios. We then identified high-risk areas for both mammals and NCP under global warming, aiming to find synergies between biodiversity conservation and NCP preservation. Our results show that 288 out of 454 species (63%) face an increased extinction risk (mean increase 0.28), while 166 species (37%) show a predicted decrease (mean decrease 0.20) under the extreme "Fossil-fueled development" scenario. The highest risk increase was observed in Malaysia, Western Indonesia, Madagascar, Eastern Australia, and South Africa, under both pessimistic and optimistic ("Sustainability") scenarios. These regions also represent high-risk areas for several NCP: freshwater regulation, air quality, mitigation of extreme events. Preserving these high-risk regions is crucial for reducing habitat loss and human-induced extinctions. Safeguarding these ecosystems, which provide vital contributions like carbon storage, clean water, and extreme fire mitigation, should be a high priority. These regions warrant targeted policy and management interventions, including sustainable land-use practices and climate adaptation actions, to benefit both biodiversity and human well-being.
Creating anatomically-derived, standardized, customizable, and three-dimensional printable head caps for functional neuroimaging
Authors: McCann Ashlyn , Xu Edward , Yen Fan-Yu , Joseph Noah , Fang Qianqian
Published: August 2024

Abstract

Significance

Consistent and accurate probe placement is a crucial step towards enhancing the reproducibility of longitudinal and group-based functional neuroimaging studies. While the selection of headgear is central to these efforts, there does not currently exist a standardized design that can accommodate diverse probe configurations and experimental procedures.

Aim

We aim to provide the community with an open-source software pipeline for conveniently creating low-cost, 3-D printable neuroimaging head caps with anatomically significant landmarks integrated into the structure of the cap.

Approach

We utilize our advanced 3-D head mesh generation toolbox and 10-20 head landmark calculations to quickly convert a subject’s anatomical scan or an atlas into a 3-D printable head cap model. The 3-D modeling environment of the open-source Blender platform permits advanced mesh processing features to customize the cap. The design process is streamlined into a Blender add-on named “NeuroCaptain”.

Results

Using the intuitive user interface, we create various head cap models using brain atlases, and share those with the community. The resulting mesh-based head cap designs are readily 3-D printable using off-the-shelf printers and filaments while accurately preserving the head topology and landmarks.

Conclusions

The methods developed in this work result in a widely accessible tool for community members to design, customize and fabricate caps that incorporate anatomically derived landmarks. This not only permits person-alized head cap designs to achieve improved accuracy, but also offers an open platform for the community to propose standardizable head caps to facilitate multi-centered data collection and sharing.
Vagal Heart Rate Variability During Rapid Eye Movement Sleep Reduces Negative Memory Bias
Authors: Morehouse Allison B. , Simon Katharine C. , Chen Pin-Chun , Mednick Sara C.
Published: August 2024

Emotional memories change over time, but the mechanisms supporting this change are not well understood. Sleep has been identified as one mechanism that supports memory consolidation, with sleep selectively benefitting negative emotional consolidation at the expense of neutral memories, with specific oscillatory events linked to this process. In contrast, the consolidation of neutral and positive memories, compared to negative memories, has been associated with increased vagally-mediated vagal heart rate variability (HRV) during wakefulness. However, how HRV during sleep contributes to emotional memory consolidation remains unexplored. We investigated how sleep oscillations and vagal contributions during sleep contribute to the consolidation of neutral and negative memories. Using a double-blind, placebo-controlled, within-subject, cross-over design, we examined the impact of pharmacological vagal suppression using zolpidem on overnight emotional memory consolidation. Thirty-two participants encoded neutral and negative pictures in the morning, followed by picture recognition tests before and after a night of sleep. Zolpidem or placebo was administered in the evening before overnight sleep, and participants were monitored with electroencephalography and electrocardiography. In the placebo condition, greater overnight improvement for neutral pictures was associated with higher vagal HRV in both Non-Rapid Eye Movement Slow Wave Sleep (NREM SWS) and REM. Additionally, the emotional memory tradeoff (i.e., difference between consolidation of neutral versus negative memories) was associated with higher vagal HRV during REM, but in this case, neutral memories were remembered better than negative memories, indicating a potential role for REM vagal HRV in promoting a positive memory bias overnight. Zolpidem, on the other hand, reduced vagal HRV during SWS, increased NREM sigma power, and eliminated the positive memory bias. Lastly, we used a stepwise linear mixed effects regression to determine how NREM sigma power and vagal HRV during REM independently explained the variance in the emotional memory tradeoff effect. We found that the addition of vagal HRV in combination with sleep significantly improved the model’s fit. Overall, our results suggest that sleep brain oscillations and vagal signals synergistically interact in the overnight consolidation of emotional memories, with REM vagal HRV critically contributing to the positive memory bias.
Self-Assembled Generation of Multi-zonal Liver Organoids from Human Pluripotent Stem Cells
Authors: Al Reza Hasan , Santangelo Connie , Al Reza Abid , Iwasawa Kentaro , Sachiko Sachiko , Glaser Kathryn , Bondoc Alexander , Merola Jonathan , Takebe Takanori
Published: August 2024

Distinct hepatocyte subpopulations are spatially segregated along the portal-central axis and critical to understanding metabolic homeostasis and liver injury. While several bioactive molecules have been described to play a role in directing zonal fates, including ascorbate and bilirubin,in vitroreplication of zonal liver architecture has not been achieved to date. In order to evaluate hepatic zonal polarity, we developed a self-assembling zone-specific liver organoid culture by co-culturing ascorbate and bilirubin enriched hepatic progenitors derived from human induced pluripotent stem cells. We found that preconditioned hepatocyte-like cells exhibited zone-specific functions associated with urea cycle, glutathione synthesis and glutamate synthesis. Single nucleus RNA sequencing analysis of these zonally patterned organoids identifies hepatoblast differentiation trajectory that mimics periportal-, interzonal-, and pericentral human hepatocytes. Epigenetic and transcriptomic analysis showed that zonal identity is orchestrated by ascorbate or bilirubin dependent binding of histone acetyltransferase p300 (EP300) to methylcytosine dioxygenase TET1 or hypoxia-inducible factor 1-alpha (HIF1α). Transplantation of the self-assembled zonally patterned human organoids improved survival of immunodeficient rats who underwent bile duct ligation by ameliorating the hyperammonemia and hyperbilirubinemia. Overall, this multi-zonal organoid system serves as anin vitrohuman model to better recapitulate hepatic architecture relevant to liver development and disease.
LAPTM4B Alleviates Pulmonary Fibrosis by Enhancing NEDD4L-Mediated TGF-β Signaling Suppression
Authors: Xu Kai , Pan Xiaoyue , Lian Hui , Wang Yaxuan , Wan Ruyan , Li Zhongzheng , Pan Xin , Li Yajun , Yang Juntang , Rosas Ivan , Wang Lan , Yu Guoying
Published: August 2024

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with fatal outcome and a poorly understood pathogenesis. The lysosomal protein transmembrane 4 beta (LAPTM4B), a multi-transmembrane endo-lysosomal membrane protein, has been implicated in the pathogenesis of several diseases. However, its involvement in IPF remains unexplored. This study aimed to investigate the role of LAPTM4B in lung fibrosis and elucidate its underlying mechanisms. The results showed that LAPTM4B was significantly reduced in IPF and mouse fibrotic lungs. In vivo studies showed that the deficiency of LAPTM4B exacerbated bleomycin-induced lung fibrosis, while the restoration of LAPTM4B alleviated fibrosis. Mechanistically, LAPTM4B recruits the NEDD4 like E3 ubiquitin protein ligase (NEDD4L) to endosomes, leading to increased ubiquitin-mediated proteasomal degradation of TGFRB2 and active SMAD2/3, thereby blocking the TGF-β/SMAD signaling pathway. Overall, our data provided a novel insight for a deeper understanding of the pathogenesis of IPF, supporting the therapeutic potential of restoration of LAPTM4B as a promising therapeutic approach for the treatment of pulmonary fibrosis.

Abstract Figure
Sympathetic Stimulation Can Compensate for Hypocalcaemia-Induced Bradycardia in Human and Rabbit Sinoatrial Node Cells
Authors: Linder Moritz , Stary Tomas , Bitay Gergő , Nagy Norbert , Loewe Axel
Published: August 2024

Regular activation of the heart originates from cyclic spontaneous depolarisations of sinoatrial node cells (SANC). Variations in electrolyte levels, commonly observed in haemodialysis (HD) patients, and the autonomic nervous system (ANS) profoundly affect the SANC function. Thus, we investigated the effects of hypocalcaemia and sympathetic stimulation on SANC beating rate (BR).

The β-adrenergic (β-AR) signalling cascade, as described by Behar et al., was incorporated into the SANC models of Severi et al. (rabbit) and Fabbri et al. (human). Simulations were conducted across various extracellular calcium ([Ca2+]o) (0.6 to 1.8 mM) and isoprenaline concentrations [ISO] (0 to 1000 nM) for a sufficient time to allow transient oscillations to equilibrate and reach a limit cycle. The β-AR cell response of the extended models was validated against new Langendorff-perfused rabbit heart experiments and literature data.

The extended models revealed that decreased [Ca2+]onecessitated an exponential-like increase in [ISO] to restore the basal BR. Specifically, at 1.2 mM [Ca2+]o, the Severi and Fabbri model required 15.5 and 7.3 nM [ISO], respectively, to restore the initial BR. Further reduction of [Ca2+]oto 0.6 mM required 60.0 and 41.7 nM [ISO] to compensate for hypocalcaemia. A sudden loss of sympathetic tone at low [Ca2+]oresulted in extreme bradycardia or even loss of automaticity within seconds.

These findings suggest that hypocalcaemic bradycardia can be compensated for by an elevated sympathetic tone. The integration of the β-AR pathways led to a logarithmic BR increase and offers insights into potential pathomechanisms underlying sudden cardiac death (SCD) in HD patients.

Key Points

- We extended the sinoatrial node cell (SANC) models of Severi et al. (rabbit) and Fabbri et al. (human) with the β-adrenergic (β-AR) signalling cascade Behar et al. described.

- Simulations were conducted across various extracellular calcium ([Ca2+]o) (0.6 to 1.8 mM) and isoprenaline concentrations [ISO] (0 to 1000 nM) to mimic conditions in haemodialysis patients.

- An exponential-like increase in [ISO] compensated for hypocalcaemia-induced bradycardia in both models, while inter-species differences lead to more sensitivity of the extended Fabbri model towards hypocalcaemia and increased sympathetic tone.

- The extended models may help to further understand the pathomechanisms of several cardiovascular diseases affecting pacemaking, such as the high occurrence of sudden cardiac death (SCD) in chronic kidney disease (CKD) patients.
How do self-fertilising and facultative sexual populations differ in mutation accumulation?
Authors: Kopčak Dominik , Hartfield Matthew
Published: August 2024

Self-fertilisation and asexual reproduction are both hypothesised to lead to long-term extinction due to inefficient selection acting against deleterious mutations. Self-fertilisation can counter these effects through creating homozygous genotypes and purging deleterious mutations. Although complete asexuality lacks meiotic gene exchange, mitotic gene conversion is a mechanism for creating homozygous regions that could limit deleterious mutation accumulation in a similar manner to self-fertilisation. Here, we compare mutation accumulation in self-fertilising and facultative sexual populations subject to mitotic gene conversion, to determine if the latter can purge deleterious mutations in an analogous manner to self-fertilisation. We first show analytically that this purging is most effective with high levels of asexuality and gene conversion, and when deleterious mutations are recessive. We further show using simulations that, when mitotic gene conversion becomes sufficiently high in obligate asexuals, there is a sudden reduction in the mutation count and a jump in homozygosity, reflecting mutation purging. However, this mechanism is not necessarily as efficient at purging compared to high levels of self-fertilisation, and elevated rates of mitotic gene conversion seem to be needed compared to empirical estimates. Hence, while mitotic gene conversion can remove recessive deleterious mutations, self-fertilisation seems to be a more effective mechanism for doing so.

Teaser Text

Asexuality has been argued to be an evolutionary ‘dead end’, due to a lack of gene exchange causing inefficient selection acting against deleterious mutations. It has been proposed that asexuals can counter these negative effects through mitotic gene conversion, which exposes mutations to selection within individual lineages. Here, we theoretically investigate how effective this mechanism is. We compare results to those obtained when individuals reproduce by self-fertilisation, which has similar effects on exposing deleterious variants. While mitotic gene conversion can be effective in removing recessive deleterious mutations, high rates are required and it is not always as effective as selfing.
Two-Photon NAD(P)H-FLIM reveals unperturbed energy metabolism ofAscaris suumlarvae, in contrast to host macrophages upon artemisinin derivatives exposure
Authors: Musimbi Zaneta D. , Kundik Arkadi , Krücken Jürgen , Hauser Anja E. , Rausch Sebastian , Seeberger Peter H. , Niesner Raluca , Leben Ruth , Hartmann Susanne
Published: August 2024

Soil-transmitted helminths (STH) are widespread, withAscaris lumbricoidesinfecting millions globally. Malaria and STH co-infections are common in co-endemic regions. Artemisinin derivatives (ARTs)—artesunate, artemether, and dihydroartemisinin—are standard malaria treatments and are also known to influence the energy metabolism of parasites, tumors, and immune cells. Herein, we explore the potential of ARTs to influence ascariasis either by directly affecting larvae or indirectly by modifying macrophage responses.Ascaris suumthird-stage larvae and porcine IL-4 polarised (M2-like) macrophages were exposed to ARTsin vitro, and their metabolism was evaluated using two-photon NAD(P)H-FLIM. Both larvae and M2-like macrophages exhibited a steady-state bioenergetic profile of high oxidative phosphorylation and low anaerobic glycolysis. InA. suumlarvae, two metabolically distinct regions were identified, with particularly high DUOX activity in the pharynx compared to the midgut. The metabolic profile of both larval regions were, however, unperturbed by ARTs exposure. In contrast, exposure of M2-like macrophages to ARTs induced a metabolic shift towards high anaerobic glycolysis and reduced metabolic activity, suggesting a possible indirect effect of ARTs on the helminth infection. Overall, two-photon NAD(P)H-FLIM proved to be a powerful tool for studying specific metabolic pathways inAscarislarvae and host macrophages, offering valuable insights into the metabolic mechanisms of drug action on both parasite and host.
Simulation study of factors affecting the accuracy of transcriptome models under complex environments
Authors: Eiju Dan , Hashida Yoichi , Maeda Taro , Nagano Atsushi J.
Published: August 2024

Characterization of molecular responses in real and complex field environments is essential for understanding the environmental response of plants. Field transcriptomics, i.e. modelling large amounts of transcriptomic and meteorological data, is the most comprehensive method of studying gene expression dynamics in complex environments. However, it is not clear what factors influence the accuracy of field transcriptome models. In this study, a novel simulation system was developed. Using the system, we performed a large-scale simulation to reveal the factors affecting the accuracy of the models. We found that the factors that had the greatest impact on the accuracy are, in order of importance, the expression pattern of the gene, the number of samples in the training data, the diurnal coverage of the training data, and the temperature coverage of the training data. Validation using actually measured transcriptome data showed similar results to the simulations. Our simulation system and the analysis results will be helpful for developing efficient sampling strategies for training data and for generating simulated data for benchmarking new modelling methods. It will also be valuable to dissect the relative importance of various factors behind transcriptome dynamics in the real environment.

Key message

Novel simulation system revealed how prediction accuracy of field transcriptome was affected by number and diversity of training data