bluuebunny/crossref_metadata_2025 huggingface dataset:
Very-Low-Level Viremia, Inflammatory Biomarkers, and Associated Baseline Variables: Three-Year Results of the Randomized TANGO Study
Authors: Wang Ruolan , Underwood Mark , Llibre Josep M , Bernal Morell Enrique , Brinson Cynthia , Sanz Moreno José , Scholten Stefan , Moore Richard , Saggu Parminder , Oyee James , Moodley Riya , Wynne Brian , Kisare Michelle , Jones Bryn , Ait-Khaled Mounir
Published: December 2023

Background

We compared proportions of participants with target detected, target not detected (TND), and elevated viral load (VL) and assessed baseline variables associated with week 144 inflammatory biomarker levels between dolutegravir-lamivudine (DTG/3TC) and tenofovir alafenamide–based regimens (TBRs) in the TANGO study (post hoc).

Methods

TANGO is an open-label, multicenter, phase 3 study that randomized adults with VL <50 copies/mL to switch to once-daily fixed-dose DTG/3TC or continue TBR. At baseline and each study visit, the VL was measured. Elevated VL event frequencies were assessed, including “blips.” Interleukin 6, D-dimer, high-sensitivity C-reactive protein, soluble CD14, and soluble CD163 were measured at baseline and at week 144. Loge-transformed week 144 biomarker levels were compared between treatment groups using an analysis of covariance model adjusting for baseline variables.

Results

High, comparable proportions of participants had VL <40 copies/mL and TND at week 144 (DTG/3TC, 279 of 369 [76%]; TBR, 267 of 372 [72%], intention-to-treat exposed Snapshot analysis; adjusted difference, 3.9% [95% confidence interval, −2.5% to 10.2%]), with similar TND proportions at all postbaseline visits (123 of 369 [33%] vs 101 of 372 [27%], respectively). Similar proportions of DTG/3TC participants had ≥1 postbaseline VL ≥50 copies/mL (28 of 369 [8%] vs 42 of 372 [11%] for TBR), primarily blips (18 of 369 [5%] and 26 of 372 [7%], respectively). Week 144 inflammatory biomarker levels were low and comparable between groups and associated with multiple demographic and baseline characteristics, including baseline biomarker levels, indicating a multifactorial inflammatory response.

Conclusions

Week 144 biomarker levels were low and generally comparable between treatment groups, reflecting similar, robust, and durable viral suppression observed using the stringent TND end point.

Trial registration: ClinicalTrials.gov, NCT03446573.
The significance of long non-coding RNAs in the pathogenesis, diagnosis and treatment of inflammatory bowel disease
Authors: Jiang Fei , Wu Min , Li Rongpeng
Published: December 2023

Inflammatory bowel diseases (IBD) are a group of chronic relapsing gastrointestinal inflammatory diseases with significant global incidence. Although the pathomechanism of IBD has been extensively investigated, several aspects of its pathogenesis remain unclear. Long non-coding RNAs (lncRNAs) are transcripts with more than 200 nucleotides in length that have potential protein-coding functions. LncRNAs play important roles in biological processes such as epigenetic modification, transcriptional regulation and post-transcriptional regulation. In this review, we summarize recent advances in research on IBD-related lncRNAs from the perspective of the overall intestinal microenvironment, as well as their potential roles as immune regulators, diagnostic biomarkers and therapeutic targets or agents for IBD.
Understanding Pandemic Solidarity: Mutual Support During the First COVID-19 Lockdown in the United Kingdom
Authors: Johnson Stephanie , Roberts Stephen , Hayes Sarah , Fiske Amelia , Lucivero Federica , McLennan Stuart , Phillips Amicia , Samuel Gabrielle , Prainsack Barbara
Published: December 2023

Throughout the COVID-19 pandemic, the concept of solidarity has been invoked frequently. Much interest has centred around how citizens and communities support one another during times of uncertainty. Yet, empirical research which accounts and understands citizen’s views on pandemic solidarity, or their actual practices has remained limited. Drawing upon the analysis of data from 35 qualitative interviews, this article investigates how residents in England and Scotland enacted, understood, or criticised (the lack of) solidarity during the first national lockdown in the United Kingdom in April 2020—at a time when media celebrated solidarity as being at an all-time high. It finds that although solidarity was practiced by some people, the perceived lack of solidarity was just as pronounced. We conclude that despite frequent mobilisations of solidarity by policy makers and other public actors, actual practices of solidarity are poorly understood—despite the importance of solidarity for public health and policy.
Isolation and characterization of bacteria from the gut of a mesopelagic copepod Cephalophanes reflugens (Copepoda: Calanoida)
Authors: Hirano Katsushi , Nakai Toshihiro , Nagai Takahiro , Takada Kentaro , Fujii Sotaro , Sambongi Yoshihiro , Kondo Yusuke , Komeda Sota , Nakaguchi Kazumitsu , Yamaguchi Shuhei , Maekawa Youichi , Nakamura Toru , Oba Yuichi , Ohtsuka Susumu
Published: December 2023

The mesopelagic calanoid copepod Cephalophanes reflugens is characterized by its large eyes with semi-parabolic reflectors. It is hypothesized that the eyes aid in finding crustacean carcasses as food in poor deep-sea light and oligotrophic conditions. Here, the crustacean carcasses-associated luminous, chitin-degrading bacteria may play a vital role in detecting and digesting foods by the copepod. In this study, we collected adult female C. reflugens (n = 9) from the mesopelagic layers off southwestern Japan in the Pacific Ocean and obtained a total of 47 bacterial isolates from the gut contents. None of the isolates were luminescent, but almost half of the isolates were chitinolytic. Based on the 16S rRNA gene sequences, these chitinolytic bacteria were identified as members of the genus Vibrio, Photobacterium and Pseudoalteromonas. In culture experiments at 15°C, most of the chitinolytic isolates efficiently utilized colloidal chitin as the sole carbon source and degraded the carapace strip of shrimp (Litopenaeus vannamei). Some isolates showed these chitinoclastic activities even at low temperatures (<5°C), equivalent to that of the deep-sea waters. The present results imply that chitin-degrading bacteria significantly contribute to chitin digestion in the gut of C. reflugens, whereas the involvement of luminous bacteria in the feeding mechanism remains unidentified.
Climate Change and Adaptation in Global Supply-Chain Networks
Authors: Pankratz Nora M C , Schiller Christoph M
Published: December 2023

This paper examines how physical climate exposure affects firm performance and global supply chains. We document that heat at supplier locations reduces the operating income of suppliers and their customers. Further, customers respond to perceived changes in suppliers’ exposure: when suppliers’ realized exposure exceeds ex ante expectations, customers are 7% more likely to terminate supplier relationships. Consistent with experience-based learning, this effect increases with signal strength and repetition and decreases with country-level climate adaptation. Subsequent replacement suppliers show a lower expected and realized but similar projected heat exposure. We find similar results for suppliers’ exposure to floods.
Refugee Labour Mobility to the EU: A Tool Contributing to Fairer Sharing of Responsibilities in the Context of Forced Displacement?
Authors: Vankova Zvezda
Published: December 2023

The idea of facilitating labour mobility for refugees as a pathway for admission is back on the policy agenda. Such complementary pathways are promoted in the Global Compact for Refugees as means to facilitate access to protection and solutions in addition to resettlement, and praised by United Nations High Commissioner for Refugees as directly contributing to easing pressure on host countries by promoting a fairer sharing of responsibilities. Yet, a significant shortcoming of work-based pathways is that in most cases they do not lead directly to a durable solution but rather offer “a journey to a durable solution” on the basis of temporary residence permits. This begs the question, to what extent can we rely on such pathways to support responsibility sharing and what happens in cases where beneficiaries of such complementary pathways lose residence rights? By comparing the different approaches applied to Ukrainian and Syrian refugees in the European Union, this article concludes that refugee labour mobility in its current state has the potential to contribute to fairer responsibility sharing only cumulatively with other durable solutions and complementary pathways, and when it provides admission facilitation coupled with a fast and clear path to permanent residence or legal mechanisms, ensuring possibilities for extension of residence rights and legality of stay.
Self-Disorder in Schizophrenia: A Revised View (1. Comprehensive Review–Dualities of Self- and World-Experience)
Authors: Feyaerts Jasper , Sass Louis
Published: December 2023

A growing body of research supports the role of self-disorders as core phenotypic features of schizophrenia-spectrum disorders. Self-disorders comprise various alterations of conscious experience whose theoretical understanding continues to present a challenge. The following 2 articles aim to provide further clarification of the nature of self-disorders in schizophrenia by offering a comprehensive review (article 1) and theoretical revision (article 2) of the currently most influential model of altered selfhood in schizophrenia: the basic-self-disturbance or ipseity-disorder model (IDM). This article presents a state-of-the-art overview of the current self-disturbance model and critically assesses its descriptive adequacy with respect to the clinical variability and heterogeneity of the alterations in self- and world-awareness characteristic of schizophrenia. Special attention is paid to experiences of exaggerated basic self, increased “grip” or “hold” on the world, and paradoxical combinations. The next article proposes a theoretical revision of the self-disturbance model by considering how hyperreflexivity might form the crucial common thread or generating factor that unifies the phenomenologically heterogeneous, and sometimes even contradictory features of schizophrenic self-disorders. We outline the implications of our revised model for explanatory research, therapeutic practice, and our general understanding of the abnormalities in question.
Long-term effects of vaginal surgery and endogenous ovarian hormones on the vagina and bladder
Authors: Ho Tam , Zhang Jerry , Wen Yan , Guo Song , Dobberfuhl Amy Diane , Chen Bertha
Published: December 2023

Background

Surgery is a common treatment for pelvic organ prolapse (POP); however, risk of recurrence and reoperation is high, resulting in a negative impact on quality of life and sexual function.

Aim

To examine the long-term effects of POP surgery and endogenous circulating ovarian hormones on the vagina and bladder.

Methods

Our animal model simulated surgical injury of the vagina and bladder during POP surgery. Female Rowett nude rats were divided into 4 groups: intact control (IC), vaginal surgery only (V), ovariectomy only (O), and ovariectomy + vaginal surgery (OV). Rats were euthanized 10 weeks postsurgery. Proximal vagina and bladder dome/trigone underwent (1) organ bath myography to assess smooth muscle contractility; (2) real-time quantitative polymerase chain reaction to quantify mRNA expression of elastin, collagen I and III, and PGP9.5 (protein gene product 9.5); (3) enzyme-linked immunosorbent assay for protein quantification of elastin and collagen I and III; and (4) hematoxylin-eosin/immunohistochemistry staining.

Outcomes

The primary outcome was tissue contractility as measured by organ bath myography. Secondary outcomes included gene and protein expression of collagen I and III and elastin.

Results

O and OV showed reduced vaginal wall contractility vs IC and V (P < .002). Bladder dome and trigone displayed different contractile patterns, with significant differences between O and OV (P < .05), suggesting a negative effect from surgery rather than ovariectomy. OV demonstrated consistent reductions in contractility and elastin/collagen protein expression for the vagina and bladder vs IC. V had similar contractility and increased collagen I expression vs IC, suggesting a protective effect of ovarian hormones. Vaginal epithelium thinning was confirmed in the ovariectomized groups (P = .001), although there was no statistical significance in muscularis thinning with surgery or ovariectomy. O, V, and OV showed significant downregulation of PGP9.5 mRNA expression vs IC.

Clinical Translation

These data allow researchers to gain insights into the long-term effects of surgery and deprivation of ovarian hormones. Future studies can use this animal model to investigate other mechanisms that may affect long-term tissue changes due to surgical intervention.

Strengths and Limitations

Major strengths are long-term data on the effects of POP surgery and development of an animal model for future studies. However, the animal model limits our ability to extrapolate to humans, where tissue healing is modulated by many factors.

Conclusion

Our animal model provides evidence that ovarian hormone deprivation and POP surgery result in negative long-term effects on tissue function and extracellular matrix.
How Will the Retained EU Law (Revocation and Reform) Act 2023 Affect the Principle of EU-Law Conforming Construction in UK Law?
Authors: Barth Fabian
Published: December 2023

Following prolonged political controversy, the provisions from the initial Retained EU Law (Revocation and Reform) Bill which abolish general principles of EU law, as well as its supremacy, have been enacted. This article investigates whether this is likely to affect the principle of EU-law conforming construction, and contemplates three scenarios how EU-derived UK law might be interpreted in the future.
Division-Independent Differentiation of Muscle Stem Cells During a Growth Stimulus
Authors: Ismaeel Ahmed , Goh Jensen , Mobley C Brooks , Murach Kevin A , Brett Jamie O , de Morrée Antoine , Rando Thomas A , Peterson Charlotte A , Wen Yuan , McCarthy John J
Published: December 2023

Adult muscle stem cells (MuSCs) are known to replicate upon activation before differentiating and fusing to regenerate myofibers. It is unclear whether MuSC differentiation is intrinsically linked to cell division, which has implications for stem cell population maintenance. We use single-cell RNA-sequencing to identify transcriptionally diverse subpopulations of MuSCs after 5 days of a growth stimulus in adult muscle. Trajectory inference in combination with a novel mouse model for tracking MuSC-derived myonuclei and in vivo labeling of DNA replication revealed an MuSC population that exhibited division-independent differentiation and fusion. These findings demonstrate that in response to a growth stimulus in the presence of intact myofibers, MuSC division is not obligatory.
Does transport stress have any effect on carcass quality of Nellore cattle (Bos taurus indicus) in Brazil? — A case study
Authors: da Silva Rodrigues Mendes Nathalia , Rodrigues Silva Renato , Ferreira de Oliveira Tatianne , Ellies-Oury Marie-Pierre , Hocquette Jean-François , Chriki Sghaier
Published: December 2023

With the increasing concomitant demands for Brazilian beef and in particular high-quality beef, there is a need for observational studies of the effects of pre- and post-slaughter practices on beef carcass traits. We hypothesized in our case study that pre-slaughter transport of bovines over significant distances would induce stress in animals, and that this would reduce carcass quality because of higher pH resulting from long-distance transportation. To test this hypothesis, 30,230 Nellore carcasses from a private slaughterhouse were evaluated 24 h postmortem. Analysis showed correlations between animal maturity, ultimate pH, distance, and carcass weight. More precisely, there was a slight positive correlation between ultimate pH and weight (but not with transportation distance) and a slight positive correlation between maturity and weight. A linear regression model (R2 = 0.016) failed to show distance having a significant effect on ultimate pH (P = 0.63), while carcass weight significantly affected ultimate pH (P < 0.001) with a low coefficient of 0.0003. Maturity negatively affected ultimate pH also (P < 0.001) but with also a small effect (−0.0008). Results (from 95% confidence intervals of variance of the random effects and of the random errors) showed that the variability within farms was higher than between farms. The linear mixed model showed that maturity had a significant effect on carcass weight value (P < 0.001) with a large coefficient of 2.90. The R2 of the linear mixed model was 46.03%. In conclusion, while weight and maturity both affect ultimate pH, long distances did not significantly impact ultimate pH and therefore the beef quality from Nellore cattle. This could be because of low stress during transport, as well as the physical characteristics of the Nellore breed that favor greater resistance to tropical climatic conditions.
Flying singers: spatio-temporal distribution and acoustic dynamics of two species of Carinetini (Hemiptera: Cicadidae) cicadas in sympatry
Authors: Acosta Riuler C , Ruschel Tatiana P , Kaminski Lucas A
Published: December 2023

The natural history of Neotropical cicadas is poorly understood. Here, we describe comparatively the spatio-temporal distribution and acoustic dynamics of two Carinetini cicadas in sympatry: colourful-cicada, Carineta diardi, and eryngo-cicada, Guaranisaria llanoi. Males of both species emit conspicuous acoustic signals during flight, a rare behaviour in cicadas. Although sympatric and synchronic, these species are not syntopic, occurring in different habitats: colourful-cicada occurs in Atlantic Forest and eryngo-cicada in native Pampean grasslands. Vertical stratification also occurs: colourful-cicada flies, sings, and copulates along the forest edge and canopy (above 2 m), while eryngo-cicada flies, sings, and copulates only in open areas (below 1 m), performing directional flights between the ‘Gravatá’ eryngo patches—a keystone plant species used as shelter, and calling and reproduction site. Acoustic repertoires vary between species: colourful-cicada presents two types of signals (flying and calling songs) and eryngo-cicada has four types (flying, calling, courtship, and wing-flicks emitted by the females). Furthermore, acoustic differences between species were found in the flying songs, but no specific differences were found in the peak frequency of their calling songs. These results show that spatial use of ‘flying singer’ cicadas can vary in habitat, providing coexistence in sympatry.
The cadmium-hypertolerant fern,Athyrium yokoscense, exhibits two cadmium stress mitigation strategies in the roots and the aerial parts
Authors: Ukai Yuko , Taoka Hiroki , Kamada Manaka , Wakui Yuko , Goto Fumiyuki , Kitazaki Kazuyoshi , Abe Tomoko , Hokura Akiko , Yoshihara Toshihiro , Shimada Hiroaki
Published: December 2023

Athyrium yokoscenseis hypertolerant to cadmium (Cd) and can grow normally under a high Cd concentration despite Cd being a highly toxic heavy metal. To mitigate Cd stress in general plant species, Cd is promptly chelated with a thiol compound and is isolated into vacuoles. Generated active oxygen species (ROS) in the cytoplasm are removed by reduced glutathione. However, we found many differences in the countermeasures inA. yokoscense. Thiol compounds accumulated in the stele of the roots, although a long-term Cd exposure induced Cd accumulation in the aerial parts. Synchrotron radiation-based X-ray fluorescence (SR-XRF) analysis indicated that a large amount of Cd was localized in the cell walls of the roots. Overexpression ofAyNramp5a, encoding a representative Fe and Mn transporter ofA. yokoscense, increased both Cd uptake and iron and manganese uptake in rice calli under the Cd exposure conditions. Organic acids were abundantly detected inA. yokoscenseroots. Investigating the chemical forms of the Cd molecules by X-ray absorption fine structure (XAFS) analysis detected many compounds with Cd-oxygen (Cd-O) binding inA. yokoscenseroots, whereas in the aerial parts, the ratio of the compounds with Cd-sulfur (Cd-S) binding was increased. Together, our results imply that the strong Cd tolerance ofA. yokoscenseis an attribute of the following two mechanisms: Cd-O compound formation in the cell wall is a barrier to reduce Cd uptake into aerial parts. Thiol compounds in the region of root stele are involved in detoxication of Cd by formation of Cd-S compounds.

Statements and Declarations

No potential conflict of interest was reported by the authors.
Spatial and temporal detection of root exudates with a paper-based microfluidic device
Authors: Patko Daniel , Gunatilake Udara Bimendra , Dupuy Lionel X. , Basabe-Desmonts Lourdes , Benito-Lopez Fernando
Published: December 2023

Root exudates control critical processes in the rhizosphere, retaining water, selecting for beneficial microorganisms or solubilising nutrients prior to uptake by the plant. Analysing root exudation patterns however is challenging because existing methods are often destructive and unable to resolve spatial and temporal variations in the production of root exudates. Here, we present a paper-based microfluidic device with integrated colorimetric sensors for the continuous extraction of root exudates along plant roots. The microfluidic device used standard filter paper wax printer to create channels for water to carry the exudates towards the sensors. TiO2nanotubes/alginate hydrogel-based sensors were used to analyse the glucose content of the root exudates of living plants. The study shows that the paper microfluidic substrate successfully extracts the released glucose from the root, and transfers it to the hydrogel-based sensor to be calorimetrically detected from independent sections of the root at different times, up to 7 days. The method was tested on two different wheat varietiesTriticum aestivum(rgt Tocayo and Filon varieties), where significant differences in exudation patterns were recorded. The researchdemonstrates the feasibility of low cost technological solution for high precision screening and diagnostic of the biochemical composition of root exudates.
scELMo: Embeddings from Language Models are Good Learners for Single-cell Data Analysis
Authors: Liu Tianyu , Chen Tianqi , Zheng Wangjie , Luo Xiao , Zhao Hongyu
Published: December 2023

Various Foundation Models (FMs) have been built based on the pre-training and fine-tuning framework to analyze single-cell data with different degrees of success. In this manuscript, we propose a method named scELMo (Single-cell Embedding from Language Models), to analyze single-cell data that utilizes Large Language Models (LLMs) as a generator for both the description of metadata information and the embeddings for such descriptions. We combine the embeddings from LLMs with the raw data under the zero-shot learning framework to further extend its function by using the fine-tuning framework to handle different tasks. We demonstrate that scELMo is capable of cell clustering, batch effect correction, and cell-type annotation without training a new model. Moreover, the fine-tuning framework of scELMo can help with more challenging tasks including in-silico treatment analysis or modeling perturbation. scELMo has a lighter structure and lower requirements for resources. Our method also outperforms recent large-scale FMs (such as scGPT [1], Geneformer [2]) and other LLM-based single-cell data analysis pipelines (such as GenePT [3] and GPTCelltype [4]) based on our evaluations, suggesting a promising path for developing domain-specific FMs.
Rapid integration of face detection and task set in visually guided reaching
Authors: Mekhaiel David Y. , Goodale Melvyn A. , Corneil Brian D.
Published: December 2023

The superior colliculus (SC) has been increasingly implicated in the rapid processing of evolutionarily relevant visual stimuli like faces, but the behavioural relevance of such processing is not clear. The SC has also been implicated in the generation of upper-limb Express Visuomotor Responses (EVRs) on upper limb muscles, which are very short-latency (within ∼80 ms) bursts of muscle activity time-locked to visual target presentation. This reasoning led us to investigate the influence of faces on EVRs.

We recorded upper limb muscle activity from young healthy participants as they reached toward left or right targets in the presence of a distractor stimulus presented on the opposite side. Across blocks of trials, we varied the instruction as to which stimulus served as the target or distractor. Doing so allowed us to assess the impact of instruction on muscle recruitment by examining trials when the exact same stimuli required a reach to either the left or right. We found that EVRs were uniquely modulated in tasks involving face selection, promoting reaches toward or away from faces depending on instruction. Follow-up experiments confirmed that this phenomenon required highly salient repeated faces, and was not observed to non-facial salient stimuli nor to faces expressing different affect. We conclude that our results attest to an integration of top-down task set and bottom-up feature detection to promote rapid motor responses to faces at latencies that match or precede the arrival of face information in human cortex.

STATEMENT OF SIGNIFICANCE

The tecto-reticulo-spinal pathway is hypothesized to mediate the express visuomotor response (EVR). This study extends this hypothesis by demonstrating that face detection in the subcortex impacts low-latency movement via the EVR at latencies preceding cortical activity for face perception. To date, this constitutes the most direct evidence for direct behavioural relevance of rapid face detection in the brainstem. Further, we find that this response can be modulated by task context, allowing for different instruction-based responses given the exact same visual stimulus and implicating top-down cortical control of the EVR.
The gut microbiome-linked long chain fatty acid stearate suppresses colorectal cancer
Authors: Tsenkova Mina , Brauer Madita , Pozdeev Vitaly , Kasakin Marat , Busi Susheel Bhanu , Schmoetten Maryse , Cheung Dean , Meyers Marianne , Rodriguez Fabien , Gaigneaux Anthoula , Koncina Eric , Gilson Cedric , Schlicker Lisa , Herebian Diran , Schmitz Martine , Nies Laura de , Mayatepek Ertan , Haan Serge , Beaufort Carine de , Cramer Thorsten , Meiser Johannes , Linster Carole L. , Wilmes Paul , Letellier Elisabeth
Published: December 2023

Colorectal cancer (CRC) patients have been shown to possess an altered gut microbiome. Diet is a well-established modulator of the microbiome, and thus, dietary interventions might have a beneficial effect on CRC. An attenuating effect of the ketogenic diet (KD) on CRC cell growth has been previously observed, however the role of the gut microbiome in driving this effect remains unknown. Here, we describe a reduced colonic tumor burden upon KD consumption in a CRC mouse model with a humanized microbiome. Importantly, we demonstrate a causal relationship through microbiome transplantation into germ-free mice, whereby alterations in the gut microbiota were maintained in the absence of continued selective pressure from the KD. Specifically, we identify a shift toward bacterial species that produce stearic acid in ketogenic conditions, whereas consumers were depleted, resulting in elevated levels of free stearate in the gut lumen. This microbial product demonstrated tumor-suppressing properties by inducing apoptosis in cancer cells and decreasing colonic Th17 immune cell populations. Taken together, the beneficial effects of the KD are mediated through alterations in the gut microbiome, including, among others, increased stearic acid production, which in turn significantly reduces intestinal tumor growth.
Newly obtained genome of fungi-related amoeba is enriched with genes shared with animals-related protists
Authors: Pozdnyakov Igor R. , Potapenko Evgeny V. , Kalashnikova Vera A. , Barzasekova Christina O. , Zlatogursky Vasily V. , Selyuk Alexey O. , Sukhanova Ksenia M. , Babenko Vladislav V. , Boldyreva Daria I.
Published: December 2023

Nuclearariids are a group of Opisthokonta, forming the deepest branch in Holomycota - one of the two major Opisthokonta clades, containing Fungi as a crawn group. They are the only members of Holomycota retaining the filose amoeboid state ancestral for Opisthokonta. The newly assembled genome ofNuclearia thermophila(Holomycota, Rotosphaerida) had a total length of 49 Mb, 15 321 protein-coding genes and a GC percentage of 44%. This is the first sequenced genome for this genus and the the third for Rotosphaerida as a whole. It was shown that N. thermophila shares more protein domains with Holozoa, than with the rest of Holomycota. Protein domains that were presumably acquired or lost by the common ancestors of the Holomycota and Holozoa groups were identified. The Holomycota ancestor had probably more gains and losses of protein domains compared to the Holozoa ancestor, which is particularly true for metabolism-related domains. However, this trend should be confirmed by studying the genomes of free-living organisms of the Teretosporea group.
INHBA/Activin A promotes tumor growth and induces resistance to anti-PD-L1 therapy by suppressing IFN-γ signaling
Authors: Li Fanglin , Gu Longhua , Tong Yongliang , Yu Xiaolu , Chen Runqiu , Liu Nan , Chen Shiyi , Lu Jiangling , Si Yuan , Sun Jianhua , Chen Jing , Long Yiru , Gong Likun
Published: December 2023

Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, respectively, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. As evidenced by our RNA-Seq and in vitro results, the interferon-γ (IFN-γ) signaling pathway was significantly down-regulated by tumor intrinsic activin A. Tumor INHBA deficiency led to lower expression of PD-L1 induced by IFN-γ, resulting in poor responsiveness to anti-PD-L1 therapy. On the other hand, decreased secretion of IFN-γ-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment. Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy. Our findings reveal that INHBA/activin A is involved in anti-tumor immunity by inhibiting the IFN-γ signaling pathway and considered to be a potential target to overcome anti-PD-L1 resistance in clinical cancer treatment.
Solution to what? Global assessment of nature-based solutions, urban challenges, and outcomes
Authors: Li Meng , Remme Roy P. , Van Bodegom Peter M. , Van Oudenhoven Alexander P.E.
Published: December 2023

In response to multiple societal challenges faced in cities, nature-based solutions (NbS) are gaining prominence as means to support sustainable and resilient urban planning. However, NbS are being implemented in cities around the globe without comprehensive evidence on their effectiveness in addressing urban challenges. Based on a systematic mapping methodology, we synthesized 547 empirical cases of NbS in 197 cities globally, yielding 799 outcomes encompassing biodiversity, health well-being, and regulating ecosystem services. To structure this evidence we developed an urban NbS classification and categories of urban challenges and outcomes. Effectiveness of NbS was assessed through synthesizing which urban challenges are addressed by NbS, which outcomes are generated, and how these outcomes perform compared to alternative solutions. Our analysis suggests that specific urban challenges were mostly linked to closely related outcomes, but rarely to multiple outcomes. Specifically, forests & trees and general parks were commonly used to enhance health and well-being, while grassland and gardens were applied to mitigate biodiversity loss. Furthermore, urban NbS generally yielded positive effects compared to non-NbS, particularly in relation to microclimate mitigation and mental health outcomes. However, we note a scarcity of evidence on multifunctional NbS, especially on studies that report multiple outcomes related to biodiversity and well-being simultaneously. Our study provides a foundation for further understanding NbS effectiveness and can inform urban planners and policymakers with measurable evidenced-based targets for the application of NbS.
Cryptic endogenous retrovirus subfamilies in the primate lineage
Authors: Chen Xun , Zhang Zicong , Yan Yizhi , Goubert Clement , Bourque Guillaume , Inoue Fumitaka
Published: December 2023

Many endogenous retroviruses (ERVs) in the human genome are primate-specific and have contributed novel cis-regulatory elements and transcripts. However, current approaches for classifying and annotating ERVs and their long terminal repeats (LTRs) have limited resolution and are inaccurate. Here, we developed a new annotation based on phylogenetic analysis and cross-species conservation. Focusing on the evolutionary young MER11A/B/C subfamilies, we revealed the presence of 4 ‘new subfamilies’, that better explained the epigenetic heterogeneity observed within the MER11 instances, suggesting a new annotation for 412 (19.8%) of these repeat elements. Furthermore, we functionally validated the regulatory potential of these four new subfamilies using a massively parallel reporter assay (MPRA), which also identified motifs associated with their differential activities. Combining MPRA with new annotations across primates revealed an apes-specific gain of SOX related motifs through a single-nucleotide deletion. Lastly, by applying our approach across 53 simian-enriched LTR subfamilies, we defined a total of 75 new subfamilies and found that 3,807 (30.0%) instances from 26 LTR subfamilies could be categorized into a novel annotation, many of which with a distinct epigenetic profile. Thus, with our refined annotation of simian-enriched LTRs, it will be possible to better understand the evolution in primate genomes and potentially identify new roles for ERVs and their LTRs in the hosts.
Machine Learning Elucidates Design Features of Plasmid DNA Lipid Nanoparticles for Cell Type-Preferential Transfection
Authors: Cheng Leonardo , Zhu Yining , Ma Jingyao , Aggarwal Ataes , Toh Wu Han , Shin Charles , Sangpachatanaruk Will , Weng Gene , Kumar Ramya , Mao Hai-Quan
Published: December 2023

For cell and gene therapies to become more broadly accessible, it is critical to develop and optimize non-viral cell type-preferential gene carriers such as lipid nanoparticles (LNPs).

Despite the effectiveness of high throughput screening (HTS) approaches in expediting LNP discovery, they are often costly, labor-intensive, and often do not provide actionable LNP design rules that focus screening efforts on the most relevant chemical and formulation parameters. Here we employed a machine learning (ML) workflow using well-curated plasmid DNA LNP transfection datasets across six cell types to maximize chemical insights from HTS studies and has achieved predictions with 5–9% error on average depending on cell type. By applying Shapley additive explanations to our ML models, we unveiled composition-function relationships dictating cell type-preferential LNP transfection efficiency. Notably, we identified consistent LNP composition parameters that enhancein vitrotransfection efficiency across diverse cell types, such as ionizable to helper lipid ratios near 1:1 or 10:1 and the incorporation of cationic/zwitterionic helper lipids. In addition, several parameters were found to modulate cell type-preferentiality, including the ionizable and helper lipid total molar percentage, N/P ratio, cholesterol to PEGylated lipid ratio, and the chemical identity of the helper lipid. This study leverages HTS of compositionally diverse LNP libraries and ML analysis to understand the interactions between lipid components in LNP formulations; and offers fundamental insights that contribute to the establishment of unique sets of LNP compositions tailored for cell type-preferential transfection.
Systematic benchmarking of imaging spatial transcriptomics platforms in FFPE tissues
Authors: Wang Huan , Huang Ruixu , Nelson Jack , Gao Ce , Tran Miles , Yeaton Anna , Felt Kristen , Pfaff Kathleen L. , Bowman Teri , Rodig Scott J. , Wei Kevin , Goods Brittany A. , Farhi Samouil L.
Published: December 2023

Emerging imaging spatial transcriptomics (iST) platforms and coupled analytical methods can recover cell-to-cell interactions, groups of spatially covarying genes, and gene signatures associated with pathological features, and are thus particularly well-suited for applications in formalin fixed paraffin embedded (FFPE) tissues. Here, we benchmarked the performance of three commercial iST platforms on serial sections from tissue microarrays (TMAs) containing 23 tumor and normal tissue types for both relative technical and biological performance. On matched genes, we found that 10x Xenium shows higher transcript counts per gene without sacrificing specificity, but that all three platforms concord to orthogonal RNA-seq datasets and can perform spatially resolved cell typing, albeit with different false discovery rates, cell segmentation error frequencies, and with varying degrees of sub-clustering for downstream biological analyses. Taken together, our analyses provide a comprehensive benchmark to guide the choice of iST method as researchers design studies with precious samples in this rapidly evolving field.
Movement-related increases in subthalamic activity optimize locomotion
Authors: Callahan Joshua W. , Morales Juan Carlos , Atherton Jeremy F. , Wang Dorothy , Kostic Selena , Bevan Mark D.
Published: December 2023

The subthalamic nucleus (STN) is traditionally thought to restrict movement. Lesion or prolonged STN inhibition increases movement vigor and propensity, while optogenetic excitation typically has opposing effects. Subthalamic and motor activity are also inversely correlated in movement disorders. However, most STN neurons exhibit movement-related increases in firing. To address this paradox, STN activity was recorded and manipulated in head-fixed mice at rest and during self-initiated and -paced treadmill locomotion. The majority of STN neurons (type 1) exhibited locomotion-dependent increases in activity, with half encoding the locomotor cycle. A minority of neurons exhibited dips in activity or were uncorrelated with movement. Brief optogenetic inhibition of the dorsolateral STN (where type 1 neurons are concentrated) slowed and prematurely terminated locomotion. In Q175 Huntington’s disease mice abnormally brief, low-velocity locomotion was specifically associated with type 1 hypoactivity. Together these data argue that movement-related increases in STN activity contribute to optimal locomotor performance.
Atlas of nascent RNA transcripts reveals enhancer to gene linkages
Authors: Sigauke Rutendo F. , Sanford Lynn , Maas Zachary L. , Jones Taylor , Stanley Jacob T. , Townsend Hope A. , Allen Mary A. , Dowell Robin D.
Published: December 2023

Gene transcription is controlled and modulated by regulatory regions, including enhancers and promoters. These regions are abundant in unstable, non-coding bidirectional transcription. Using nascent RNA transcription data across hundreds of human samples, we identified over 800,000 regions containing bidirectional transcription. We then identify highly correlated transcription between bidirectional and gene regions. The identified correlated pairs, a bidirectional region and a gene, are enriched for disease associated SNPs and often supported by independent 3D data. We present these resources as an SQL database which serves as a resource for future studies into gene regulation, enhancer associated RNAs, and transcription factors.
Direct stimulation of anterior insula and ventromedial prefrontal cortex disrupts economic choices
Authors: Cecchi Romane , Collomb-Clerc Antoine , Rachidi Inès , Minotti Lorella , Kahane Philippe , Pessiglione Mathias , Bastin Julien
Published: December 2023

Neural activities within the ventromedial prefrontal cortex and anterior insula are associated with economic choices. However, whether these brain regions are causally related to these processes remains unclear. To address this issue, we leveraged rare intracerebral electrical stimulation (iES) data in epileptic patients. We show that opposite effects of iES on choice depend on the location of stimulation on a dorso-ventral axis within each area, thus demonstrating dissociable neural circuits causally involved in accepting versus avoiding challenges.
Adaptive Regularized Tri-Factor Non-Negative Matrix Factorization for Cell Type Deconvolution
Authors: Liu Tianyi , Liu Chuwen , Li Quefeng , Zheng Xiaojing , Zou Fei
Published: December 2023

Accurate deconvolution of cell types from bulk gene expression is crucial for understanding cellular compositions and uncovering cell-type specific differential expression and physiological states of diseased tissues. Existing deconvolution methods have limitations, such as requiring complete cellular gene expression signatures or neglecting partial biological information. Moreover, these methods often overlook varying cell-type mRNA amounts, leading to biased proportion estimates. Additionally, they do not effectively utilize valuable reference information from external studies, such as means and ranges of population cell-type proportions. To address these challenges, we introduce an Adaptive Regularized Tri-factor non-negative matrix factorization approach for deconvolution (ARTdeConv). We rigorously establish the numerical convergence of our algorithm. Through benchmark simulations, we demonstrate the superior performance of ARTdeConv compared to state-of-the-art semi-reference-based and reference-free methods. In a real-world application, our method accurately estimates cell proportions, as evidenced by the nearly perfect Pearson’s correlation between ARTdeConv estimates and flow cytometry measurements in a dataset from a trivalent influenza vaccine study. Moreover, our analysis of ARTdeConv estimates in COVID-19 patients reveals patterns consistent with important immunological phenomena observed in other studies. The proposed method, ARTdeConv, is implemented as an R package and can be accessed on GitHub for researchers and practitioners.
Variations in cellular unfolded protein response, respiratory capacity, and stress tolerance in skin and lung fibroblasts of deer mice (Peromyscus maniculatus)
Authors: Yap Kang Nian , Yamada KayLene , Zikeli Shelby L , Zhang Yufeng , Zhang Youwen , Naderi Asieh , Soltanmohammadi Elham , Kavazis Andreas N , Roberts Michael D , Kiaris Hippokratis , Hood Wendy R
Published: December 2023

Evolutionary physiologists have long been interested in physiological mechanisms underpinning variation in life-history performance. Recent efforts to elucidate these mechanisms focused on bioenergetics and oxidative stress. One underappreciated area that could play a role in mediating variation in performance is the unfolded protein response (UPR), a cellular stress response that reduces secretory protein load, enhances endoplasmic reticulum (ER) protein folding and clearance capacity during stress and during its adaptive phase. Given that the ER and mitochondria interact to regulate cellular homeostasis, it seems intuitive that UPR phenotype would correlate strongly with mitochondrial physiology, which in turn would contribute to variations in whole-organism metabolism. One way researchers have been studying cellular controls of life-history traits is by assessing stress resistance and bioenergetic properties of primary dermal fibroblasts. However, it is unclear if findings from dermal fibroblasts can be generalized to other cell and tissue types, and if fibroblasts’ phenotypes are repeatable across different life-history stages. This study aimed to explore the relationships between UPR profile, cellular respiration, and stress resistance using primary dermal fibroblasts isolated at puberty and primary lung fibroblasts isolated at adulthood. Specifically, we tested if 1) UPR profile of dermal fibroblasts isolated at puberty corresponds to UPR profile of lung fibroblasts isolated at adulthood, 2) UPR profile of dermal fibroblasts isolated at puberty and lung fibroblasts isolated at adulthood correspond to cellular bioenergetics of lung fibroblasts isolated at adulthood, and 3) UPR profile of dermal fibroblasts isolated at puberty corresponds to multiplex stress resistance (ER stress, oxidative stress, DNA damage) of lung fibroblasts isolated at adulthood. We found that only tunicamycin induced BiP expression was repeatable in skin and lung fibroblasts. Tunicamycin induced expressions of BiP, GRP94, and CNX in skin fibroblasts predicted resistance of lung fibroblasts to tunicamycin, (but not thapsigargin and other inducers of lethal stress), which is indicative for the pro-survival role of UPR during stress. Tunicamycin induced BiP expression in skin and lung fibroblasts also predicted multiple cellular bioenergetics parameters in lung fibroblasts.

Statements and Declarations

No competing interests declared. This work was supported by National Science Foundation grants IOS1453784 and OIA1736150 to W.R.H., IOS1755670 to the PGSC, and a National Science Foundation EPSCoR pilot grant to K.N.Y. The funders did not have any input into the content of the manuscript nor require approval prior to submission.
CRISPR Spacers Acquired from Plasmids Primarily Target Backbone Genes, Making Them Valuable for Predicting Potential Hosts and Host Range
Authors: Androsiuk Lucy , Maane Sivan , Tal Shay
Published: December 2023

In recent years, there has been a surge in metagenomic studies focused on identifying plasmids in environmental samples. While these studies have unearthed numerous novel plasmids, enriching our understanding of their environmental roles, a significant gap remains: the scarcity of information regarding the bacterial hosts of these newly discovered plasmids. Furthermore, even when plasmids are identified within bacterial isolates, the reported host is typically limited to the original isolate, with no insight into alternative hosts or the plasmid’s potential host range. Given that plasmids depend on hosts for their existence, investigating plasmids without knowledge of potential hosts offers only a partial perspective.

This study introduces a method for identifying potential hosts and host ranges for plasmids through alignment with CRISPR spacers. To validate the method, we compared the PLSDB plasmids database with the CRISPR spacers database, yielding host predictions for 46% of the plasmids. When compared to reported hosts, our predictions achieved an 84% concordance at the family level and 99% concordance at the phylum level. Moreover, the method frequently identified multiple potential hosts for a plasmid, thereby enabling predictions of alternative hosts and the host range.

Notably, we found that CRISPR spacers predominantly target plasmid backbone genes while sparing functional genes, such as those linked to antibiotic resistance, aligning with our hypothesis that CRISPR spacers are acquired from plasmid-specific regions rather than insertion elements from diverse sources. Lastly, we illustrate the network of connections among different bacterial taxa through plasmids, revealing potential pathways for horizontal gene transfer.

IMPORTANCE

Plasmids are notorious for their role in distributing antibiotic resistance genes, but they may also carry and distribute other environmentally important genes. Since plasmids are not free-living entities and rely on host bacteria for survival and propagation, predicting their hosts is essential. This study presents a method for predicting potential hosts for plasmids and offers insights into the potential paths for spreading functional genes between different bacteria. Understanding plasmid-host relationships is crucial for comprehending the ecological and clinical impact of plasmids and implications for various biological processes.