bluuebunny/crossref_metadata_2025 huggingface dataset:
Biosynthesis of gibberellin-related compounds modulates far-red light responses in the liverwort Marchantia polymorpha
Authors: Sun Rui , Okabe Maiko , Miyazaki Sho , Ishida Toshiaki , Mashiguchi Kiyoshi , Inoue Keisuke , Yoshitake Yoshihiro , Yamaoka Shohei , Nishihama Ryuichi , Kawaide Hiroshi , Nakajima Masatoshi , Yamaguchi Shinjiro , Kohchi Takayuki
Published: August 2023

Gibberellins (GAs) are key phytohormones that regulate growth, development, and environmental responses in angiosperms. From an evolutionary perspective, all major steps of GA biosynthesis are conserved among vascular plants, while GA biosynthesis intermediates such as ent-kaurenoic acid (KA) are also produced by bryophytes. Here, we show that in the liverwort Marchantia polymorpha, KA and GA12 are synthesized by evolutionarily conserved enzymes, which are required for developmental responses to far-red light (FR). Under FR-enriched conditions, mutants of various biosynthesis enzymes consistently exhibited altered thallus growth allometry, delayed initiation of gametogenesis, and abnormal morphology of gamete-bearing structures (gametangiophores). By chemical treatments and liquid chromatography–tandem mass spectrometry (LC-MS/MS) analyses, we confirmed that these phenotypes were caused by the deficiency of some GA-related compounds derived from KA, but not bioactive GAs from vascular plants. Transcriptome analysis showed that FR enrichment induced the up-regulation of genes related to stress responses and secondary metabolism in M. polymorpha, which was largely dependent on the biosynthesis of GA-related compounds. Due to the lack of canonical GA receptors in bryophytes, we hypothesize that GA-related compounds are commonly synthesized in land plants but were co-opted independently to regulate responses to light quality change in different plant lineages during the past 450 million years of evolution.
What makes police officers resist research and evidence-based policing? Examining the role of organizational and environmental factors
Authors: Kuen Kiseong , Lum Cynthia , Kim Seung Hyun
Published: August 2023

Despite a growing body of research on police officers’ receptivity or resistance to evidence-based policing (EBP) and research, the mechanisms behind officers’ resistance have received limited attention. To address this gap, we investigate the impact of organizational factors (i.e. organizational justice, supervisor support, cynicism towards organizational change) and environmental factors (i.e. disrespected experience by citizens, citizen animus, crime trends) on shaping officer resistance to EBP and research using survey data from 457 front-line officers from seven police departments in Seoul, South Korea. Our findings reveal that cynicism towards organizational change significantly impacts officer resistance to EBP and research, more so than the impact of officers’ dispositional resistance to change. Furthermore, we find that organizational justice and supervisor support have significant indirect effects on officer resistance to EBP and research through cynicism towards organizational change. These results underscore the importance of improving organizational climates to reduce officer resistance to EBP and research.
Have increased deaths at home during the pandemic returned to pre-pandemic levels? An analysis of publicly available Scottish death registrations
Authors: Savinc J , Atherton I M
Published: August 2023

Background

Deaths at home increased in Scotland at the start of the Coronavirus disease 2019 (COVID-19) pandemic by ~35%. The majority did not involve COVID-19. This has implications for resource allocation and care at the end of life.

Methods

Publicly available weekly death registrations by National Records Scotland (NRS) between 2015 and week 25 of 2023 were summarized by place of death. Linear and logistic regressions of the number and proportion of deaths at home, respectively, between 2015 and 2019, were used to estimate the expected number and proportion of deaths in the period 2020–2023 had the pandemic not happened.

Results and conclusion

The number of deaths at home continues in 2023 at rates similar to the pandemic period and has not reverted to pre-pandemic levels. Had the pre-pandemic trend of growth in deaths at home continued, the number of deaths observed in 2020 would not be observed until 2025–2032. Deaths at home increased across Local Authorities but the scale of the increase varied. The impact of the increased number of deaths at home on quality of care and quality of death is not known and requires further study.
Serious Mental Illness, Glycemic Control, and Neighborhood Factors within an Urban Diabetes Cohort
Authors: Iturralde Esti , Rubinsky Anna D , Nguyen Kim H , Anderson Chelsie , Lyles Courtney R , Mangurian Christina
Published: August 2023

Background and Hypothesis

Serious mental illness (SMI) may compromise diabetes self-management. This study assessed the association between SMI and glycemic control, and explored sociodemographic predictors and geographic clustering of this outcome among patients with and without SMI.

Study Design

We used electronic health record data for adult primary care patients with diabetes from 2 San Francisco health care delivery systems. The primary outcome was poor glycemic control (hemoglobin A1c >9.0%), which was modeled on SMI diagnosis status and sociodemographics. Geospatial analyses examined hotspots of poor glycemic control and neighborhood characteristics.

Study Results

The study included 11 694 participants with diabetes, 21% with comorbid SMI, of whom 22% had a schizophrenia spectrum or bipolar disorder. Median age was 62 years; 52% were female and 79% were Asian, Black, or Hispanic. In adjusted models, having schizophrenia spectrum disorder or bipolar disorder was associated with greater risk for poor glycemic control (vs participants without SMI, adjusted relative risk [aRR] = 1.24; 95% confidence interval, 1.02, 1.49), but having broadly defined SMI was not. People with and without SMI had similar sociodemographic correlates of poor glycemic control including younger versus older age, Hispanic versus non-Hispanic White race/ethnicity, and English versus Chinese language preference. Hotspots for poor glycemic control were found in neighborhoods with more lower-income, Hispanic, and Black residents.

Conclusions

Poor diabetes control was significantly related to having a schizophrenia spectrum or bipolar disorder, and to sociodemographic factors and neighborhood. Community-based mental health clinics in hotspots could be targets for implementation of diabetes management services.
Anti-inflammatory and antioxidative effects of elderberry diet in the rat model of seizure: a behavioral and histological investigation on the hippocampus
Authors: Bayat Amir-Hossein , Eskandari Neda , Sani Mojtaba , Fotouhi Farid , Shenasandeh Zahra , Saeidikhoo Sara , Rohani Razieh , Sabbagh Alvani Mohammadamin , Mafi Balani Mohammadreza , Eskandarian Boroujeni Mahdi , Abdollahifar Mohammad-Amin , Tajari Faezeh , Aliaghaei Abbas , Hassani Moghaddam Meysam
Published: August 2023

The present study was designed to evaluate whether elderberry (EB) effectively reduces inflammation and oxidative stress in hippocampal cells to modify seizure damage. Seizure was induced in rats by the injection of pentylenetetrazol (PTZ). In the Seizure + EB group, EB powder was added to the rats’ routine diet for eight consecutive weeks. The study included several behavioral tests, immunohistopathology, Voronoi tessellation (to estimate the spatial distribution of cells in the hippocampus), and Sholl analysis. The results in the Seizure + EB group showed an improvement in the behavioral aspects of the study, a reduction in astrogliosis, astrocyte process length, number of branches, and intersections distal to the soma in the hippocampus of rats compared to controls. Further analysis showed that EB diet increased nuclear factor-like 2 expression and decreased caspase-3 expression in the hippocampus in the Seizure + EB group. In addition, EB protected hippocampal pyramidal neurons from PTZ toxicity and improved the spatial distribution of hippocampal neurons in the pyramidal layer and dentate gyrus. The results of the present study suggest that EB can be considered a potent modifier of astrocyte reactivation and inflammatory responses.
The putative protein kinase Stk36 is essential for ciliogenesis and CSF flow by associating with Ulk4
Authors: Zhang Hongye , Yang Meimei , Zhang Jianhua , Li Li , Guan Tianyuan , Liu Jiaxin , Gong Xuanwei , Yang Fan , Shen Sanbing , Liu Min , Han Yongfeng
Published: August 2023

Motile cilia lining on the ependymal cells are crucial for cerebrospinal fluid (CSF) flow and its dysfunction is often associated with hydrocephalus. Unc51‐like‐kinase 4 (Ulk4) was previously linked to CSF flow and motile ciliogenesis in mice, as the hypomorph mutant of Ulk4 (Ulk4tm1a/tm1a) developed hydrocephalic phenotype resulted from defective ciliogenesis and disturbed ciliary motility, while the underling mechanism is largely obscure. Here, we report that serine/threonine kinase 36 (STK36), a paralog of ULK4, directly interacts with ULK4 and this was demonstrated by yeast two‐hybrid (Y2H) in yeast and coimmunoprecipitation (co‐IP) assays in HEK293T cells, respectively. The interaction region was confined to their respective N‐terminal kinase domain. The hypomorph mutant of Stk36 (Stk36tmE4−/−) also developed progressive hydrocephalus postnatally and dysfunctional CSF flow, with multiple defects of motile cilia, including reduced ciliary number, disorganized ciliary orientation, defected axonemal structure and inconsistent base body (BB) orientation. Stk36tmE4−/− also disturbed the expression of Foxj1 transcription factor and a range of other ciliogenesis‐related genes. All these morphological changes, motile cilia defects and transcriptional dysregulation in the Stk36tmE4−/− are practically copied from that in Ulk4tm1a/tm1a mice. Taken together, we conclude that both Stk36 and Ulk4 are crucial for CSF flow, they cooperate by direct binding with their kinase domain to regulate the Foxj1 transcription factor pathways for ciliogenesis and cilia function, not limited to CSF flow. The underlying molecular mechanism probably conserved in evolution and could be extended to other metazoans.
Cholesterol metabolism in T‐cell aging: Accomplices or victims
Authors: Hu Cexun , Wu Hongliang , Zhu Qun , Cao Na , Wang Hui
Published: August 2023

Aging has a significant impact on the function and metabolism of T cells. Cholesterol, the most important sterol in mammals, is known as the “gold of the body” because it maintains membrane fluidity, rigidity, and signal transduction while also serving as a precursor of oxysterols, bile acids, and steroid hormones. Cholesterol homeostasis is primarily controlled by uptake, biosynthesis, efflux, and regulatory mechanisms. Previous studies have suggested that there are reciprocal interactions between cholesterol metabolism and T lymphocytes. Here, we will summarize the most recent advances in the effects of cholesterol and its derivatives on T‐cell aging. We will furthermore discuss interventions that might be used to help older individuals with immune deficiencies or diminishing immune competence.
The Warburg effect drives cachectic states in patients with pancreatobiliary adenocarcinoma
Authors: Li Qiuju , Zhang Dapeng , Sui Xiaojun , Song Tao , Hu Lijuan , Xu Xiaoqing , Wang Ximo , Wang Feng
Published: August 2023

We have studied whether the Warburg effect (uncontrolled glycolysis) in pancreatobiliary adenocarcinoma triggers cachexia in the patient. After 74 pancreatobiliary adenocarcinomas were removed by surgery, their glucose transporter‐1 and four glycolytic enzymes were quantified using Western blotting. Based on the resulting data, the adenocarcinomas were equally divided into a group of low glycolysis (LG) and a group of high glycolysis (HG). Energy homeostasis was assessed in these cancer patients and in 74 non‐cancer controls, using serum albumin and C‐reactive protein and morphometrical analysis of abdominal skeletal muscle and fat on computed tomography scans. Some removed adenocarcinomas were transplanted in nude mice to see their impacts on host energy homeostasis. Separately, nude mice carrying tumor grafts of MiaPaCa‐2 pancreatic adenocarcinoma cells were treated with the glycolytic inhibitor 3‐bromopyruvate and with emodin that inhibited glycolysis by decreasing hypoxia‐inducible factor‐1α. Adenocarcinomas in both group LG and group HG impaired energy homeostasis in the cancer patients, compared to the non‐cancer reference. The impaired energy homeostasis induced by the adenocarcinomas in group HG was more pronounced than that by the adenocarcinomas in group LG. When original adenocarcinomas were grown in nude mice, their glycolytic abilities determined the levels of hepatic gluconeogenesis, skeletal muscle proteolysis, adipose‐tissue lipolysis, and weight loss in the mice. When MiaPaCa‐2 cells were grown as tumors in nude mice, 3‐bromopyruvate and emodin decreased tumor‐induced glycolysis and cachexia, with the best effects being seen when the drugs were administered in combination. In conclusion, the Warburg effect in pancreatobiliary adenocarcinoma triggers cancer cachexia.
Cuproptosis enhances docetaxel chemosensitivity by inhibiting autophagy via the DLAT/mTOR pathway in prostate cancer
Authors: Wen Hongzhuang , Qu Changbao , Wang Zhu , Gao Haitao , Liu Wuyao , Wang Hu , Sun Hao , Gu Junfei , Yang Zhan , Wang Xiaolu
Published: August 2023

Cuproptosis, a newly discovered programmed cell death induced by copper ions, is associated with the progression and drug resistance of various tumors. Docetaxel plays a vital role as a first‐line chemotherapeutic agent for advanced prostate cancer; however, most patients end up with prostate cancer progression because of inherent or acquired resistance. Herein, we examined the role of cuproptosis in the chemotherapeutic resistance of prostate cancer to docetaxel. We treated prostate cancer cell lines with elesclomol–CuCl2, as well as with docetaxel. We performed analyses of CCK8, colony formation tests, cell cycle flow assay, transmission electron microscopy, and mTOR signaling in treated cells, and treated a xenograft prostate cancer model with elesclomol–CuCl2 and docetaxel in vivo, and performed immunohistochemistry and Western blotting analysis in treated tumors. We found that elesclomol–CuCl2 could promote cell death and enhance chemosensitivity to docetaxel. Elesclomol–CuCl2 induced cell death and inhibited the growth of prostate cancer cells relying on copper ions‐induced cuproptosis, not elesclomol. In addition, dihydrolipoamide S‐acetyltransferase (DLAT) was involved in cuproptosis‐enhanced drug sensitivity to docetaxel. Mechanistically, upregulated DLAT by cuproptosis inhibited autophagy, promoted G2/M phase retention of cells, and enhanced the sensitivity to docetaxel chemotherapy in vitro and in vivo via the mTOR signaling pathway. Our findings demonstrated that the cuproptosis‐regulated DLAT/mTOR pathway inhibited autophagy and promoted cells in G2/M phase retention, thus enhancing the chemosensitivity to docetaxel. This discovery may provide an effective therapeutic option for treating advanced prostate cancer by inhibiting the chemotherapeutic resistance to docetaxel.
Improving Operating Room Efficiency Through Reducing First Start Delays in an Academic Center
Authors: Singh Dylan , Cai Lawrence , Watt Dominique , Scoggins Elise , Wald Samuel , Nazerali Rahim
Published: August 2023

Background:

Delays in operating room (OR) first-case start times can cause additional costs for hospitals, healthcare team frustration and delay in patient care. Here, a novel process improvement strategy to improving first-case start times is presented.

Methods:

First case in room start times were recorded for ORs at an academic medical center. Three interventions—automatic preoperative orders, dot phrases to permit re-creation of unavailable consent forms, and improved H&P linking to the surgical encounter—were implemented to target documentation-related delays. Monthly percentages of first-case on-time starts (FCOTS) and time saved were compared with the “preintervention” time period, and total cost savings were estimated.

Results:

During the first 3-months after implementation of the interventions, the percentage of FCOTS improved from an average of 36.7%–52.7%. Total time savings across all ORs over the same time period was found to be 55.63 hours, which is estimated to have saved a total of $121,834.52 over the 3-month interventional period.

Conclusions:

By implementing multiple quality improvement interventions, delays to first start in room OR cases can be meaningfully reduced. Quality improvement protocols targeted toward root causes of OR delays can be a significant driver to reduce healthcare costs.
All-night spectral and microstate EEG analysis in patients with Recurrent Isolated Sleep Paralysis (RISP)
Authors: Černý Filip , Piorecká Václava , Kliková Monika , Kopřivová Jana , Bušková Jitka , Piorecký Marek
Published: August 2023

The pathophysiology of recurrent isolated sleep paralysis (RISP) has yet to be fully clarified. Very little research has been performed on electroencephalographic (EEG) signatures outside RISP episodes. This study aimed to investigate whether sleep is disturbed even without the occurrence of a RISP episode and in a stage different than conventional REM sleep. 17 RISP patients and 17 control subjects underwent two consecutive full-night video-polysomnography recordings. Spectral analysis was performed on all sleep stages in the delta, theta, and alpha band. EEG microstate (MS) analysis was performed on the NREM 3 phase due to the overall high correlation of subject template maps with canonical templates. Spectral analysis showed a significantly higher power of theta band activity in REM and NREM 2 sleep stages in RISP patients. The observed rise was also apparent in other sleep stages. Conversely, alpha power showed a downward trend in RISP patients’ deep sleep. MS maps similar to canonical topographies were obtained indicating the preservation of prototypical EEG generators in RISP patients. RISP patients showed significant differences in the temporal dynamics of MS, expressed by different transitions between MS C and D and between MS A and B. Both spectral analysis and MS characteristics showed abnormalities in the sleep of non-episodic RISP subjects. Our findings suggest that in order to understand the neurobiological background of RISP, there is a need to extend the analyses beyond REM-related processes and highlight the value of EEG microstate dynamics as promising functional biomarkers of RISP.

Significance Statement

We focused on tracking electrophysiological traces of RISP (a REM parasomnia) beyond REM sleep of subjects clinically diagnosed with RISP outside of RISP episodes. We observed a rise of theta band activity in NREM 2 sleep of RISP patients. This may point to a larger dysregulation of sleep mechanism making the person more prone to sudden awakenings in the upcoming REM sleep. Theta band differences were further observed in REM sleep. We additionally utilized the EEG MS methodology on deep sleep to investigate differences in dominant brain topographies. Though dominant brain topographies are consistent with canonical MS, RISP patients show significantly different transitioning between sleep-related topographies suggesting a difference in their sleep regulation mechanisms.
Multi-omics map revealed PPARαactivation protecting against myocardial ischemia-reperfusion injury by maintaining cardiac metabolic homeostasis
Authors: Gao Yun , Huang Fei , Ruan Fanwei , Lai Dongwu , Zhang Zhe , Zhang Yuan , Zhu Jun , Lu Yuwen , Shen Liyin , He Jin , Liu Yan , Fu Guosheng , Zhu Yang , Shen Li , Zhuang Lenan
Published: August 2023

Timely percutaneous coronary intervention is the most effective initial therapy for the acute myocardial infarction (MI). However, the mechanism in energy metabolism underlying time-dependent coronary reperfusion remains largely unknown. Here, we generated an integrative map of cardiac cells using bulk and single-nucleus RNA-seq combined with metabolomics profiling of hearts with reperfusion at distinct time points post MI in rat. We found early time reperfusion (ETR), but not late time reperfusion (LTR) reduced myocardial injury by maintaining cardiac energy homeostasis. PPARα was identified as a key regulator for maintaining fatty acid metabolism after MI/R injury. Importantly, pretreatment with FDA-approved PPARα agonist, fenofibrate, improved the transcriptional signatures, and ameliorated the function of the MI/R injured hearts, particularly in the ETR. Together, our data not only deciphered the protective effect of ETR by maintaining cardiac energy homeostasis, but also provided insights into the translational potential of PPARα activation in alleviating MI/R injury.
CryptoCEN: A Co-Expression Network forCryptococcus neoformansreveals novel proteins involved in DNA damage repair
Authors: O’Meara Matthew J. , Rapala Jackson R. , Nichols Connie B. , Alexandre Christina , Billmyre R. Blake , Steenwyk Jacob L , Alspaugh J. Andrew , O’Meara Teresa R.
Published: August 2023

Elucidating gene function is a major goal in biology, especially among non-model organisms. However, doing so is complicated by the fact that molecular conservation does not always mirror functional conservation, and that complex relationships among genes are responsible for encoding pathways and higher-order biological processes. Co-expression, a promising approach for predicting gene function, relies on the general principal that genes with similar expression patterns across multiple conditions will likely be involved in the same biological process. ForCryptococcus neoformans,a prevalent human fungal pathogen greatly diverged from model yeasts, approximately 60% of the predicted genes in the genome lack functional annotations. Here, we leveraged a large amount of publicly available transcriptomic data to generate aC. neoformansCo-Expression Network (CryptoCEN), successfully recapitulating known protein networks, predicting gene function, and enabling insights into the principles influencing co-expression. With 100% predictive accuracy, we used CryptoCEN to identify 13 new DNA damage response genes, underscoring the utility of guilt-by-association for determining gene function. Overall, co-expression is a powerful tool for uncovering gene function, and decreases the experimental tests needed to identify functions for currently under-annotated genes.
Replicating RNA as a component of scrapie fibrils
Authors: Bridges Leslie R.
Published: August 2023

Recently, electron cryo-microscopy (cryo-EM) maps of fibrils from the brains of mice and hamsters with five infectious scrapie strains have been published1–5and deposited in the electron microscopy data bank (EMDB)6. This represents long-awaited near-atomic level structural evidence, widely expected to confirm the protein-only prion hypothesis7,8. Instead, the maps reveal a second component, other than protein. The aim of the present study was to identify the nature of this second component, in the published maps1–5, using anin silicoapproach. Extra densities (EDs) containing this component were continuous, straight, axial, at right angles to protein rungs and within hydrogen-bonding distance of protein, consistent with a role as guide and support in fibril construction. EDs co-located with strips of basic residues, notably lysines, and formed a conspicuous cladding over parts of the N-terminal lobe of the protein. In one ED, there was evidence of a Y-shaped polymer forming two antiparallel chains, consistent with replicating RNA. Although the protein-only prion hypothesis7is still popular, convincing counter-evidence for an essential role of RNA as a cofactor has amassed in the last 20 years8. The present findings go beyond this in providing evidence for RNA as the genetic element of scrapie. To reflect the monotonous nature of the protein interface, it is suggested that the RNA may be a tandem repeat. This is against the protein-only prion hypothesis and in favour of a more orthodox agent, more akin to a virus. Fibrils from brains of patients with Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and other neurodegenerations also contain EDs9and may be of a similar aetiology.
Temperate gut phages are prevalent, diverse, and predominantly inactive
Authors: Dahlman Sofia , Avellaneda-Franco Laura , Kett Ciaran , Subedi Dinesh , Young Remy B. , Gould Jodee A. , Rutten Emily L. , Gulliver Emily L. , Turkington Christopher J.R. , Nezam-Abadi Neda , Grasis Juris A. , Lyras Dena , Edwards Robert A. , Forster Samuel C. , Barr Jeremy J.
Published: August 2023

Large-scale metagenomic and data mining efforts have uncovered an expansive diversity of bacteriophages (phages) within the human gut1–3. These insights include broader phage populational dynamics such as temporal stability4, interindividual uniqueness5,6and potential associations to specific disease states7,8. However, the functional understanding of phage-host interactions and their impacts within this complex ecosystem have been limited due to a lack of cultured isolates for experimental validation. Here we characterise 125 active prophages originating from 252 diverse human gut bacterial isolates using seven different induction conditions to substantially expand the experimentally validated temperate phage-host pairs originating from the human gut. Importantly, only 17% of computationally predicted prophages were induced with common induction agents and these exhibited distinct gene patterns compared to non-induced predictions. Active Bacteroidota prophages were among the most prevalent members of the gut virome, with extensive use of diversity generating retroelements and exhibiting broad host ranges. Moreover, active polylysogeny was present in 52% of studied gut lysogens and led to coordinated prophage induction across diverse conditions. This study represents a substantial expansion of experimentally validated gut prophages, providing key insights into their diversity and genetics, including a genetic pathway for prophage domestication and demonstration that differential induction was complex and influenced by divergent prophage integration sites. More broadly, it highlights the importance of experimental validation alongside genomic based computational prediction to enable further functional understanding of these commensal viruses within the human gut.
Metabolism of glucose and trehalose by cyclic pentose phosphate pathway is essential for effective immune response inDrosophila
Authors: Kazek Michalina , Chodáková Lenka , Lehr Katharina , Strych Lukáš , Nedbalová Pavla , McMullen Ellen , Bajgar Adam , Šimek Petr , Moos Martin , Doležal Tomáš
Published: August 2023

Activation of immune cells requires the remodeling of cell metabolism in order to support immune function. We study these metabolic changes through the infection ofDrosophilalarvae by parasitoid wasp. Neutralization of the parasitoid egg involves the differentiation of lamellocytes, which encapsulate the egg. A melanization cascade is initiated, producing toxic molecules to destroy the egg; meanwhile the capsule created also protects the host from the toxic reaction. We combine transcriptomics and metabolomics, including 13C-labeled glucose and trehalose tracing, as well as genetic manipulation of sugar metabolism to study changes in metabolism, specifically inDrosophilahemocytes. We found that hemocytes increase the expression of several carbohydrate transporters, and accordingly uptake of sugar during infection. These carbohydrates are metabolized by increased glycolysis, associated with lactate production, and cyclic pentose phosphate pathway (PPP), in which glucose-6-phosphate is re-oxidized to maximize NADPH production. Oxidative PPP is required for lamellocyte differentiation and resistance, as is systemic trehalose metabolism. In addition, fully differentiated lamellocytes use a cytoplasmic form of trehalase to cleave trehalose to glucose, within the cell, to fuel cyclic PPP. Intracellular trehalose metabolism is not required for resistance, but may be associated with host protection from its own toxic response. Thus, our results suggest that sugar metabolism within immune cells, and specifically in cyclic PPP, may be important for not only fighting infection, but also for protecting the host from its own immune response and ensuring sufficient fitness of the survivor.
Biocompatible hydrogel electrodeposition enables the simultaneous preparation of multi-microinterfaces for ligand bioconjugation and multiplexed electrochemical detection
Authors: Juska Vuslat B. , Moukri Nadia , Estrela Pedro , Maxwell Graeme D. , Hendriks Stacey , Santillan-Urquiza Esmeralda , O’Brien Bernadette , Patella Bernardo , Inguanta Rosalinda , O’Riordan Alan
Published: August 2023

Affinity based electrochemical biosensing systems with integrated miniaturised interfaces has enabled key advancement toward rapid, sensitive, precise and deployable detection platforms. Manufacturing silicon micro/nano devices for biology interface has been a highly promising platform to design and develop electrochemical sensors for the detection of very low concentrations of the target molecules. However, the biofouling challenge of the biosensors when the surface is exposed to a complex matrix such as blood, serum, milk, has been a road blocker. Here we introduce a simple, rapid formation of an anti-biofouling coating onto several electroactive surface areas present on a single chip simultaneously. Using such a multiplexed surface, we were able to investigate the optimum working conditions on-chip. Concentrating on two individual bioassay platforms for stress biomarkers, haptoglobin and cortisol, we demonstrate the broad applicability of the developed universal platform with excellent performance in bovine serum and correlation with conventional ELISA using milk samples.
Calcium regulation of theArabidopsisNa+/K+transporter HKT1;1 improves seed germination under salt stress
Authors: Chandran Ancy E.J. , Finkler Aliza , Hait Tom Aharon , Kiere Yvonne , David Sivan , Pasmanik-Chor Metsada , Shkolnik Doron
Published: August 2023

Calcium is known to improve seed-germination rates under salt stress. We investigated the involvement of calcium ions (Ca2+) in regulatingHIGH-AFFINITY K+TRANSPORTER 1(HKT1;1), which encodes a Na+/K+transporter, and its post-translational regulatorTYPE 2C PROTEIN PHOSPHATASE 49(PP2C49), in germinatingArabidopsis thalianaseedlings. Germination rates ofhkt1mutant seeds under salt stress remained unchanged by CaCl2treatment in wild-typeArabidopsis, whereaspp2c49mutant seeds displayed improved salt-stress tolerance in the absence of CaCl2supplementation. Analysis ofHKT1;1andPP2C49promoter activity revealed that CaCl2treatment results in radicle-focused expression ofHKT1;1and reduction of the native radicle-exclusive expression ofPP2C49. Ion-content analysis indicated that CaCl2treatment improves K+retention in germinating wild-type seedlings under salt stress, but not inhkt1seedlings. Transgenic seedlings designed to exclusively expressHKT1;1in the radicle during germination displayed higher germination rates under salt stress than the wild type in the absence of CaCl2treatment. Transcriptome analysis of germinating seedlings treated with CaCl2, NaCl, or both revealed 118 upregulated and 94 downregulated genes as responsive to the combined treatment. Bioinformatics analysis of the upstream sequences of CaCl2–NaCl-treatment-responsive upregulated genes revealed the abscisic acid response element CACGTGTC, a potential CaM-binding transcription activator-binding motif, as most prominent. Our findings suggest a key role for Ca2+in mediating salt-stress responses during germination by regulating genes that function to maintain Na+and K+homeostasis, which is vital for seed germination under salt stress.
A model of sediment retention by vegetation for Great Britain: new methodologies & validation
Authors: Hooftman Danny A.P. , Bullock James M. , Evans Paul M. , Redhead John W. , Ridding Lucy E. , Varma Varun , Pywell Richard F.
Published: August 2023

Soil erosion is an substantial environmental concern worldwide. It has been historically and is of increasingly concern currently. Next to natural processes, over 2 million hectares of soil are at risk of erosion through intensifying agriculture in the Great Britain (England, Wales, Scotland and their territorial islands). Predictive soil erosion models, in the form of Ecosystem Service tools, aid in helping to identify areas that are vulnerable to soil erosion. Yet, no predictions for erosion or sediment retention by vegetation based on local data have been developed for Great Britain or the United Kingdom as a whole.

Here we develop an erosion retention model using the InVEST platform, which is based on the RUSLE mathematical framework. We parameterise the model, as far as feasible, with GB specific input data. The developed model estimations are validated against suspended solids concentrations (sediments) in throughout England and Wales.

Next to presenting the first GB wide estimate of erosion and erosion retention using the InVEST SDR module, we test three approaches here that differ from more widely applicable RUSLE model inputs, such as created for Europe as a whole. Here, we incorporate (1) periodicity to allow erosion to potentially fluctuate within years; (2) GB-specific cover periodic management factors estimates, including a range of crop types, based on observed satellite NDVI values (3) soil erosivity under heavy rainfall following GB estimates for 2000-2019.

We conclude that both the GB created erosivity layer as the added periodicity do not seem to be provide substantial improvement over non-periodic estimated created with more widely available data, when validated against this set of suspended solids in rivers. In contrast, the observed cover management factors calculated from NDVI are a good improvement affecting the ranking order among catchments. Therefore, the generating of cover management factors using NDVI data could be promoted as method for InVEST SDR model development and in more general for developing RUSLE-based erosion estimates worldwide.
Reward contingency modulates olfactory bulb output via pathway-dependent peri-somatic inhibition
Authors: Lindeman Sander , Fu Xiaochen , Reinert Janine K , Fukunaga Izumi
Published: August 2023

Associating values to environmental cues is a critical aspect of learning from experiences, allowing animals to predict and maximise future rewards. Value-related signals in the brain were once considered a property of higher sensory regions, but its wide distribution across many brain regions is increasingly recognised. Here, we investigate how reward-related signals begin to be incorporated, mechanistically, at the earliest stage of olfactory processing, namely, in the olfactory bulb. In head-fixed mice performing Go/No-Go discrimination of closely related olfactory mixtures, rewarded odours evoke widespread inhibition in one class of output neurons, that is, in mitral cells but not tufted cells. The temporal characteristics of this reward-related inhibition suggest it is odour-driven, but it is also context-dependent since it is absent during pseudo-conditioning and pharmacological silencing of the piriform cortex. Further, the reward-related modulation is present in the somata but not in the apical dendritic tuft of mitral cells, suggesting an involvement of circuit component located deep in the olfactory bulb. Depth-resolved imaging from granule cell dendritic gemmules suggests that granule cells that target mitral cells receive a reward-related extrinsic drive. Our results support the notion that value-related modulation appears at the early stages of sensory processing and provide constraints on long-range and local circuit mechanisms.
Loss of Carnitine Palmitoyltransferase 1a Reduces Docosahexaenoic Acid-Containing Phospholipids and Drives Sexually Dimorphic Liver Disease in Mice
Authors: Zelows Mikala M. , Cady Corissa , Dharanipragada Nikitha , Mead Anna E. , Kipp Zachary A. , Bates Evelyn A. , Varadharajan Venkateshwari , Banerjee Rakhee , Park Se-Hyung , Shelman Nathan R. , Clarke Harrison A. , Hawkinson Tara R. , Medina Terrymar , Sun Ramon C. , Lydic Todd A. , Hinds Terry D. , Brown J. Mark , Softic Samir , Graf Gregory A. , Helsley Robert N.
Published: August 2023

Background and Aims

Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the impact by which liver-specific CPT1a deletion impacts hepatic lipid metabolism.

Approach and Results

Six-to-eight-week old male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (HFD; 60% kcal fat) for 15 weeks. Mice were necropsied after a 16 hour fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase (ALT) levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in both whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2,Cidec,G0S2) and in polyunsaturated fatty acid (PUFA) metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A (PKA) activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice.

Conclusions

Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury.

Graphical Summary
Spider mites collectively avoid plants with cadmium irrespective of their frequency or the presence of competitors
Authors: Godinho Diogo Prino , Fragata Inês , de la Masselière Maud Charlery , Magalhães Sara
Published: August 2023

Accumulation of heavy metals by plants can serve as a defence against herbivory. Herbivores, in turn, may avoid feeding on contaminated tissues. Such avoidance, however, may hinge upon the specific conditions faced by herbivores. Here, we tested whether the spider miteTetranychus urticaeavoids tomato plants contaminated with cadmium in presence of conspecifics or heterospecifics and depending on the frequency of contaminated plants. We show that individual spider mite females do not preferentially move to leaf tissues with or without cadmium, despite clear costs on their performance. However, in a set-up where 200 mites were simultaneously given the choice between four plants with or without cadmium, they collectively avoided plants with cadmium, irrespective of the proportion of plants with cadmium. In addition,T. urticaedid not discriminate between plants infested with its competitorT. evansiand other uncontaminated plants but they preferred plants with competitors when the other plants contained cadmium. Our results show that aggregation may facilitate avoidance of contaminated plants. They also indicate that cadmium accumulation in plants is a stronger selective pressure than interspecific competition withT. evansi.Therefore, collective avoidance of metal-accumulating plants by herbivores is robust to environmental conditions and may have important consequences for species distribution and interactions in metal contaminated sites.
Reinforcement motor learning after cerebellar damage is related to state estimation
Authors: White Christopher M. , Snow Evan C. , Therrien Amanda S.
Published: August 2023

Recent work showed that individuals with cerebellar degeneration could leverage intact reinforcement learning (RL) to alter their movement. However, there was marked inter-individual variability in learning, and the factors underlying it were unclear. Cerebellum-dependent sensory prediction may contribute to RL in motor contexts by enhancing body state estimates, which are necessary to solve the credit-assignment problem. The objective of this study was to test the relationship between the predictive component of state estimation and RL in individuals with cerebellar degeneration. Individuals with cerebellar degeneration and neurotypical control participants completed two tasks: an RL task that required them to alter the angle of reaching movements and a state estimation task that tested the somatosensory perception of active and passive movement. The state estimation task permitted calculation of the active benefit shown by each participant, which is thought to reflect the cerebellum-dependent predictive component of state estimation. We found that the cerebellar and control groups showed similar magnitudes of learning with reinforcement and active benefit on average, but there was substantial variability across individuals. Using multiple regression, we assessed potential predictors of RL. Our analysis included active benefit, somatosensory acuity, clinical ataxia severity, movement variability, movement speed, and age. We found a significant relationship in which greater active benefit predicted better learning with reinforcement in the cerebellar, but not the control group. No other variables showed significant relationships with learning. Overall, our results support the hypothesis that the integrity of sensory prediction is a strong predictor of RL after cerebellar damage.
Soft extracellular matrix drives an endoplasmic reticulum stress-dependent S quiescence underlying molecular traits of pulmonary basal cells
Authors: Laval Pierre-Alexandre , Piecyk Marie , Le Guen Pauli , Ilie Mirela-Diana , Fauvre Joelle , Coste Isabelle , Renno Toufic , Aznar Nicolas , Hadji Celine , Migdal Camille , Duret Cedric , Bertolino Philippe , Ferraro-Peyret Carole , Nicolas Alice , Chaveroux Cedric
Published: August 2023

Cell culture on soft matrix, either in 2D and 3D, preserves the characteristics of progenitors. However, the mechanism by which the mechanical microenvironment determines progenitor phenotype, and its relevance to human biology, remains poorly described. Here we designed multi-well hydrogel plates with a high degree of physico-chemical uniformity to reliably address the molecular mechanism underlying cell state modification driven by physiological stiffness. Cell cycle, differentiation and metabolic activity could be studied in parallel assays, showing that the soft environment promotes an atypical S-phase quiescence and prevents cell drift, while preserving the differentiation capacities of human bronchoepithelial cells. These softness-sensitive responses are driven by defects in proteostasis and enhanced basal endoplasmic reticulum stress. The analysis of available single cell data of the human lung also showed that this non-conventional state coming from the soft extracellular environment is indeed consistent with molecular feature of pulmonary basal cells. Overall, this study demonstrates that mechanical mimicry in 2D culture supports allows to maintain progenitor cells in a state of high physiological relevance for characterizing novel molecular events that govern progenitor biology in human tissues.
SPTF-3/SP1 orchestrates mitochondrial biogenesis upon ribosomal stress and acute starvation
Authors: Hemerling Johannes CW , Pavlenko Victor , Herholz Marija , Baumann Linda , Zečić Aleksandra , Kukat Alexandra , Popovic Milica , Szczepanowska Karolina , Cores Estela Cepeda , Vilchez David , Kurian Leo , Trifunovic Aleksandra
Published: August 2023

When cells have increased energy demand, they respond by elevating the production of new mitochondria through the process of mitochondrial biogenesis. This complex physiological undertaking requires precise coordination of mitochondrial and nuclear gene expression to extend the existing mitochondrial network in the cell. Using C. elegans as a model system we have identified stress-induced transcription factor SPTF-3 as a novel regulator of mitochondrial biogenesis on-demand upon increased heat stress, dietary restriction, and acute starvation. We show that SPTF-3 also regulates ATFS-1, the main transcriptional regulator of UPRmt(mitochondrial unfolded protein response). Thus, by orchestrating two parallel programs – mitochondrial biogenesis and UPRmt, SPTF-3 safeguards mitochondrial wellbeing and function upon stress, thus allowing survival in unfavorable conditions. Mitochondrial biogenesis is induced by disturbances in cytoplasmic ribosomal assembly, which leads to preferential translation of SPTF-3. Importantly, we demonstrated that the role of SPTF-3 in the regulation of mitochondrial biogenesis upon nutrient deprivation is conserved in mammals through its homolog SP1.
CD56-mediated activation of human natural killer cells is triggered byAspergillus fumigatusgalactosaminogalactan
Authors: Heilig Linda , Natasha Fariha , Trinks Nora , Aimanianda Vishukumar , Sze Wah Wong Sarah , Fontaine Thierry , Terpitz Ulrich , Strobel Lea , Le Mauff François , Sheppard Donald C. , Schäuble Sascha , Kurzai Oliver , Hünniger Kerstin , Weiss Esther , Vargas Mario , Howell P. Lynne , Panagiotou Gianni , Wurster Sebastian , Einsele Hermann , Löffler Jürgen
Published: August 2023

Invasive aspergillosis causes significant morbidity and mortality in immunocompromised patients. Natural killer (NK) cells are pivotal for antifungal defense. Thus far, CD56 is the only knownpathogen recognition receptoron NK cells triggering potent antifungal activity againstAspergillus fumigatus. However, the underlying cellular mechanisms and the fungal ligand of CD56 have remained unknown. Using purified cell wall components, biochemical treatments, andA. fumigatusmutants with altered cell wall composition, we herein found that CD56 interacts with theA. fumigatuscell wall carbohydrate galactosaminogalactan (GAG). This interaction induced NK cell activation, degranulation, and secretion of immune-enhancing chemokines and cytotoxic effectors. Supernatants from GAG-stimulated NK cells elicited antifungal activity and enhanced antifungal effector responses of polymorphonuclear cells. In conclusion, we identifiedA. fumigatusGAG as a ligand of CD56 on human primary NK cells, stimulating potent antifungal effector responses and activating other immune cells.
Identification and mapping of human lymph node stromal cell subsets by combining single-cell RNA sequencing with spatial transcriptomics
Authors: Grasso Cristoforo , Roet Janna , Gago de Graça Catarina , Semmelink Johanna F. , Remmerswaal Ester , Jongejan Aldo , Moerland Perry D. , Mebius Reina E. , van Baarsen Lisa G. M.
Published: August 2023

Lymph node stromal cells (LNSCs) have a crucial immunomodulatory function, but their heterogeneity in human is incompletely understood. Here, we report the single cell RNA sequencing (scRNA-seq) of 12’000 LNSCs isolated from a human lymph node (LN). This study comprehensively defines the gene signatures of 10 fibroblast subtypes: CCL21+SC, CCL19+SC, CD34+CXCL14+SC, pericytes, DES+SC, LAMP5+SC, NR4A1+BCAM+SC, HLA-DR+SC, SEPT4+SC and GLDN+SC. To explore the heterogeneous stromal compartment within the complex LN tissue architecture, we integrated the scRNA-seq profiles of the identified LNSC subsets with a publicly available human spatial transcriptomic LN dataset and predicted their location within the complex LN tissue architecture. Each LNSC subtype was spatially restricted to specific LN regions, indicating different LNSC-lymphocyte interactions which was further investigated using NicheNet. The positioning of distinct LNSC subtypes in different LN regions sets the stage for future research on the relationship between LNSC-specific niches and immunomodulatory function during health and disease.