bluuebunny/crossref_metadata_2025 huggingface dataset:
How suitable is freshwater sponge Ephydatia fluviatilis (Linnaeus, 1759) for time-integrated biomonitoring of microbial water quality?
Authors: Cartwright Allison , Dooley James S.G. , McGonigle Chris D. , Arnscheidt Joerg
Published: March 2024

Faecal pollution of water by bacteria has a negative effect on water quality and can pose a potential health hazard. Conventional surveillance of microbial water quality relies on the analysis of low frequency spot samples and is thus likely to miss episodic or periodic pollution. This study aimed to investigate the potential of filter feeding sponges for time-integrated biomonitoring of microbial water quality. Laboratory trials tested the effects of different ratios of bacterial abundance and the sequence of exposure on bacterial retention by the freshwater sponge Ephydatia fluviatilis (Linnaeus, 1759) to establish its potential to indicate bacterial exposure.
Gemmule grown sponges were simultaneously exposed to Escherichia coli and Enterococcus faecalis but at different ratios (Trial 1) or individually exposed to each bacterial species but in different sequential order (Trial 2). The E. coli and E. faecalis retained in each sponge was quantified by culture on selective agars. Data analysis was conducted using the Kruskal- Wallis test and/ or the Mann Whitney U test to compare between the numbers of bacteria retained in each treatment. Additionally, the Wilcoxon Matched-Paired Signed-Rank test was used for comparison of the different bacterial abundances retained within each individual sponge.
Sponges from all trials retained E. coli and E. faecalis in small numbers relative to the exposure (<0.05% Trial 1 and <0.07% Trial 2) but exhibited higher retention of E. coli. Higher abundance of either bacterial species resulted in significantly lower (p<0.005) retention of the same species within sponges (Trial 1). An initial exposure to E. coli resulted in significantly higher (p=0.040) retention of both bacterial species than when sponges were exposed to E. faecalis first (Trial 2).
 
Bacterial retention by sponges was neither quantitatively representative of bacterial abundance in the ambient water nor the sequence of exposure. This implies either selective filtration or an attempt by sponges to prevent infection. However, freshwater sponges may still be useful in biomonitoring as qualitative time-integrated samplers of faecal indicator bacteria as they detect different bacteria present in the water even if their quantities cannot be estimated.
Strain background of Candida albicans interacts with SIR2 to alter phenotypic switching
Authors: Woodruff Andrew L. , Berman Judith , Anderson Matthew
Published: March 2024

The genetic background between strains of a single species and within a single strain lineage can significantly impact the expression of biological traits. This genetic variation may also reshape epigenetic mechanisms of cell identity and environmental responses that are controlled by interconnected transcriptional networks and chromatin-modifying enzymes. Histone deacetylases, including sirtuins, are critical regulators of chromatin state and have been directly implicated in governing the phenotypic transition between the ‘sterile’ white state and the mating-competent opaque state in Candida albicans, a common fungal commensal and pathogen of humans. Here, we found that a previously ambiguous role for the sirtuin SIR2 in C. albicans phenotypic switching is likely linked to the genetic background of mutant strains produced in the RM lineage of SC5314. SIR2 mutants in a specific lineage of BWP17 displayed increased frequencies of switching to the opaque state compared to the wild-type. Loss of SIR2 in other SC5314-derived backgrounds, including newly constructed BWP17 sir2Δ/Δ mutants, failed to recapitulate the increased white–opaque switching frequencies observed in the original BWP17 sir2Δ/Δ mutant background. Whole-genome sequencing revealed the presence of multiple imbalanced chromosomes and large loss of heterozygosity tracts that likely interact with SIR2 to increase phenotypic switching in this BWP17 sir2Δ/Δ mutant lineage. These genomic changes are not found in other SC5314-derived sir2Δ/Δ mutants that do not display increased opaque cell formation. Thus, complex karyotypes can emerge during strain construction that modify mutant phenotypes and highlight the importance of validating strain background when interpreting phenotypes.
Misspellings or “miscellings”-non-verifiable cell lines in cancer research publications
Authors: Oste Danielle J. , Pathmendra Pranujan , Richardson Reese A. K. , Johnson Gracen , Ao Yida , Arya Maya D. , Enochs Naomi R. , Hussein Muhammed , Kang Jinghan , Lee Aaron , Danon Jonathan J. , Cabanac Guillaume , Labbé Cyril , Davis Amanda Capes , Stoeger Thomas , Byrne Jennifer A.
Published: March 2024

Reproducible laboratory research relies on correctly identified reagents. We have previously described human gene research papers with wrongly identified nucleotide sequence reagent(s), including papers studyingmiR-145. Manually verifying reagent identities in more recentmiR-145papers found 20/36 (56%) and 6/36 (17%)miR-145papers with misidentified nucleotide sequence reagent(s) and human cell line(s), respectively. We also found 5 cell line identifiers in twomiR-145papers with wrongly identified nucleotide sequences and cell lines, and 18 identifiers published elsewhere that did not correspond to indexed cell lines. These cell line identifiers were described as non-verifiable, as their identities appeared uncertain. Studying 420 papers that mentioned 8 different non-verifiable cell line identifier(s) found 235 papers (56%) that appeared to refer to BGC-803, BSG-803, BSG-823, GSE-1, HGC-7901, HGC-803 and/or MGC-823 as independent cell lines. We could not find publications describing how these cell lines were established, and they were not indexed in claimed externally accessible cell line repositories. While some papers stated that STR profiles had been generated for BGC-803, GSE-1 and/or MGC-823 cells, no STR profiles were identified. In summary, non-verifiable human cell lines represent new challenges to research reproducibility and require further investigation to clarify their identities.

Novelty and Impact Statement

Through verifying reagent identities in research publications, our team found 23 non-verifiable human cell line identifiers, most of which could represent misspellings of contaminated cancer cell lines. Of 8 identifiers studied in detail, 7 non-verifiable identifiers were unexpectedly referred to as independent cell lines across 235 publications. We therefore describe a process “miscelling”, where published cell lines lack descriptions of how they were established, cannot be found in claimed external repositories and lack STR profiles.
HER2 Prognostic Significance and Therapeutic Implications in Gastric Cardia Adenocarcinoma: Insights from Multi-Omics Profiling
Authors: Wang Li-Dong , Xing Pengwei , Zhao Xue-Ke , Song Xin , Wei Meng-Xia , Lei Ling-Ling , Xu Rui-Hua , Wang Ran , Ma Lei , You Duo , Chen Pei-Nan , Xie Minglu , Zhao Miao , Zhang He , Lv Hui-Fang , Li Ai-Li , Wang Xian-Zeng , Zhou Fu-You , Gao She-Gan , Chen Xingqi
Published: March 2024

Therapeutic targets for Gastric Cardia Adenocarcinoma (GCA), particularly for HER2-negative patients, are lacking. Here, we conducted multi-omics profiling on 128 GCA patients using mass spectrometry, whole-exome sequencing, RNA-Seq, and metabolomics. We found HER2 to be a favorable prognostic marker for GCA. Employing molecular counting, we categorized patients into HER2-high, -low, and -negative groups. We uncovered an enrichment of DNA repair features in the HER2-high group, while HER2-low and -negative groups exhibited strong inflammation. We found that tumor mutation burden may not be the distinguishing factor among these three groups. We revealed that the HER2-negative and -low groups have a tumor-suppressive immune microenvironment, and HER2 expression is associated with fatty acid metabolic profiles and inflammation in the blood of patients. Our study revealed anti-inflammatory and immune checkpoint inhibition, targeting PD-L2 and the CD47/SIRPA pair, as therapeutic strategies for HER2-negative GCA patients. These findings highlight promising avenues for personalized treatment for GCA.
Meta-analysis of livestock effects on tree regeneration in oak agroforestry systems
Authors: Wadud Abdullah Ibne , Bugalho Miguel N. , Vaz Pedro Gonçalves
Published: March 2024

Livestock grazing occupies over a quarter of terrestrial land and is prevalent to agroforestry ecosystems, potentially affecting the survival, growth, and density of trees’ early developmental stages, such as seeds, seedlings, and saplings. To address the effects of livestock on tree recruitment in the face of ongoing debates about their impacts, we conducted a 33-year meta-analysis inQuercus-dominated agroforestry systems. Our analysis revealed a consistently negative effect of livestock on oak acorns, seedlings, and saplings. Significantly, livestock body size influenced oak regeneration, with small-sized livestock, notably sheep and goats, having a more pronounced negative impact compared to mixed-size systems, mainly involving cattle and sheep. The effects of small-sized livestock were markedly detrimental on acorn survival and seedling/sapling density, although no studies eligible for meta-analysis examined large livestock impacts on acorns. Overall, mixed-size livestock systems, often involving cattle and sheep, lessen the negative effects. Our findings indicate that the body size and foraging behaviors of livestock should be considered for the ecological sustainability of the tree component in agroforestry systems. While protective measures have long been integral to well-managed agroforestry systems, our results underscore the importance of integrating diverse livestock sizes and applying specific protective strategies, particularly for acorns and saplings, to further refine these practices. Future research should expand to underrepresented regions and livestock types to refine global agroforestry management practices.

Highlights

Livestock reduces oak tree regeneration at acorn, seedling, and sapling stages.

Small livestock effect more negative, especially acorn survival and young oak density.

Mixed-size livestock agroforestry systems reduce harm more than small single-size ones.

We challenge perceptions that replacing cattle with sheep is necessarily less harmful.

We advocate for diverse livestock sizes inQuercus-dominated agroforestry systems.
Haplotype-resolved reconstruction and functional interrogation of cancer karyotypes
Authors: Brunette Gregory J. , Tourdot Richard W. , Wangsa Darawalee , Pellman David , Zhang Cheng-Zhong
Published: March 2024

Genomic characterization has revealed widespread structural complexity in cancer karyotypes, however shotgun sequencing cannot resolve genomic rearrangements with chromosome-length continuity. Here, we describe a two-tiered approach to determine the segmental composition of rearranged chromosomes with haplotype resolution. First, we presentrefLinker, a new method for robust determination of chromosomal haplotypes using cancer Hi-C data. Second, we use haplotype-specific Hi-C contacts to determine the segmental structure of rearranged chromosomes. By contrast with existing methods for diploid haplotype inference, our approach is robust to the confounding effects of large-scale DNA deletions, duplications, and high-level amplification in cancer sequencing. Using this approach, we examine haplotype-specific expression changes on rearranged homologs and provide direct evidence for long-range transcriptional activation and repression associated with rearrangements of the inactive X chromosome (Xi). Together, these results reveal the significant transcriptional consequences of somatic Xi rearrangements, highlightingrefLinker’s broad utility for studying the functional consequences of chromosomal rearrangements.
Tofacitinib uptake by patient-derived intestinal organoids predicts individual clinical responsiveness
Authors: Jang Kyung Ku , Ercelen Defne , Cen Feng Jing Yu Carolina , Gurunathan Sakteesh , Zhou Chaoting , Korman Aryeh , Newell Luke , Hudesman David , Jones Drew R. , Loke P’ng , Axelrad Jordan E. , Cadwell Ken
Published: March 2024

Background & Aims

Despite increasing therapeutic options in the treatment of ulcerative colitis (UC), achieving disease remission remains a major clinical challenge. Nonresponse to therapy is common and clinicians have little guidance in selecting the optimal therapy for an individual patient. This study examined whether patient-derived materials could predict individual clinical responsiveness to the Janus kinase (JAK) inhibitor, tofacitinib, prior to treatment initiation.

Method

In 48 patients with UC initiating tofacitinib, we longitudinally collected clinical covariates, stool, and colonic biopsies to analyze the microbiota, transcriptome, and exome variations associated with clinical responsiveness at week 24. We established patient-derived organoids (n = 23) to determine how their viability upon stimulation with proinflammatory cytokines in the presence of tofacitinib related to drug responsiveness in patients. We performed additional biochemical analyses of organoids and primary tissues to identify the mechanism underlying differential tofacitinib sensitivity.

Results

The composition of the gut microbiota, rectal transcriptome, inflammatory biomarkers, and exome variations were indistinguishable among UC patients prior to tofacitinib treatment. However, a subset of patient-derived organoids displayed reduced sensitivity to tofacitinib as determined by the ability of the drug to inhibit STAT1 phosphorylation and loss of viability upon cytokine stimulation. Remarkably, sensitivity of organoids to tofacitinib predicted individual clinical patient responsiveness. Reduced responsiveness to tofacitinib was associated with decreased levels of the cationic transporter MATE1, which mediates tofacitinib uptake.

Conclusions

Patient-derived intestinal organoids predict and identify mechanisms of individual tofacitinib responsiveness in UC. Specifically, MATE1 expression predicted clinical response to tofacitinib.
Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+T cells to suppress anti-tumor immunity
Authors: Tejero Joanne D. , Hesterberg Rebecca S. , Drapela Stanislav , Ilter Didem , Raizada Devesh , Lazure Felicia , Kashfi Hossein , Liu Min , Fernández-García Juan , Asara John M. , Fendt Sarah-Maria , Cleveland John L. , Gomes Ana P.
Published: March 2024

Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the tumorigenic role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8+T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA leads to suppression of CD8+T cell immunity. Treatment of primary CD8+T cells with MMA induced a dysfunctional phenotype characterized by a robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8+T cells and decreased their effector functions, which drove the suppression of anti-tumor immunityin vitroandin vivo. Mechanistically, MMA-induced CD8+T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.
PCSK9 deficiency promotes the development of peripheral neuropathy
Authors: Jaafar Ali K. , Paulo-Ramos Aurélie , Rastoldo Guillaume , Veeren Bryan , Planesse Cynthia , Bringart Matthieu , Rondeau Philippe , Meilhac Olivier , Lambert Gilles , Bourane Steeve
Published: March 2024

PCSK9 best-known and studied function is to induce the hepatic degradation of the low-density lipoprotein receptor (LDLR), thereby increasing the concentration of LDL-cholesterol (LDL-C) in the blood. Beyond its effects on LDL, recent studies have reported pleiotropic effects of PCSK9 notably in septic shock, vascular inflammation, viral infection, and cancer. While the functional and structural integrity of peripheral nerves are critically influenced by circulating lipids, the impact of PCSK9 in the peripheral nervous system is unknown. In this study, we investigated the consequences of PCSK9 deficiency on peripheral nerves. We found that PCSK9 deletion in mice leads to peripheral neuropathy characterized by a reduction of thermal and mechanical pain sensations. PCSK9 deficient mice also presented skin structural changes with a reduction of number of terminal nociceptive Schwann cells, Remak fiber axonal swelling, as well as hypomyelination of small nerve fibers. Interestingly, peripheral nerves of PCSK9 deficient mice presented an upregulation of the fatty acid transporter CD36 expression which correlated with an increase in nerve lipid contents and structural mitochondrial abnormalities. Our findings demonstrate that PCSK9 plays a critical role in the peripheral nerves by regulating lipid homeostasis, and its deficiency could lead to the development of symptoms related to peripheral neuropathy.

Graphical abstract

PCSK9 modulates nerve energy metabolism and health. Created with BioRender.com.
The immune map of human body
Authors: Gan Rui , Jin Xiangxing , Ren Xianwen
Published: March 2024

The immune system serves as a vital defense mechanism against diseases and infections for human bodies, comprised of a complex network of diverse cells, organs, and tissues. Here, we conduct single-cell deconvolution of 17382 RNA-seq samples from 30 tissues and construct a comprehensive map of the distributions of >1000 different cell states across all the major immune cell types throughout human bodies. This high-resolution immune map covers both sexes and a wide range of ages, enabling interrogation of the immune responses to sex differences and age-related changes. Similarity analysis among the different tissue types depicts the tissue-specific immunity of testis, liver, lung, brain, and kidney besides blood and spleen, and the high immune similarity between breast and adipose tissues for example. This comprehensive immune map may deepen our understanding of human immune system from a holistic perspective.
PFKP regulates AXL-MET oncogenic and metabolic pathways in lung cancer
Authors: Sun Yuze , Zhao Huijie , Feng Huijing , Liu Yue , Li Yu , Chen Sijie , Zhou Zhiqing , Du Yuhui , Zeng Xiaofei , Ren Huan , Su Wenmei , Mei Qi , Chen Guoan
Published: March 2024

Objective: PFKP (Phosphofructokinase, Platelet Type isoform), as an essential metabolic enzyme, contributes to the high glycolysis rates seen in cancers, while its role in oncogenic pathways, especially from a non-metabolic aspect, is not fully understood. Methods: Here we performed a comprehensive analysis of published RNA-seq, microarray data, and immunohistochemistry of tissue microarray to evaluate the significance of PFKP expression in non-small cell lung cancer (NSCLC). Functionally, we tested the cell proliferation, colony formation, invasion, and migration upon PFKP knockdown in lung cancer cells. Mechanistically, we performed RNA-seq, DIA- mass spectrum, western blot, and qPCR to probe the change of cell signaling pathways upon PFKP silencing. Co-immunoprecipitation and mass spectrum were used to uncover potential PFKP interacting proteins. Results: We found that PFKP was highly expressed in NSCLC and was related to poor patient survival. Knockdown of PFKP significantly inhibited cell proliferation, colony formation, invasion, and migration of NSCLC cells. Mechanistically, we found that PFKP can directly bind with AXL and promote its phosphorylation at Y779, thus activating the AXL signaling pathway and promoting MET phosphorylation. In addition, several glycolysis, glutaminolysis, and TCA cycle proteins were downregulated following PFKP silencing. Conclusions: These data demonstrate that PFKP, beyond its known role in glycolysis, also has a distinct non-metabolic function in affecting lung cancer progression by directly interacting with the AXL-MET axis, thus indicating a potential therapeutic target for lung cancer.
Generation of guideline-based clinical decision trees in oncology using large language models
Authors: Miao Brenda Y , Rodriguez Almaraz Eduardo , Ashraf Ganjouei Amir , Suresh Arvind , Zack Travis , Bravo Maxim , Raghavendran Srinidhi , Oskotsky Boris , Alaa Ahmed , Butte Atul J
Published: March 2024

Background: Molecular biomarkers play a pivotal role in the diagnosis and treatment of oncologic diseases but staying updated with the latest guidelines and research can be challenging for healthcare professionals and patients. Large Language Models (LLMs), such as MedPalm-2 and GPT-4, have emerged as potential tools to streamline biomedical information extraction, but their ability to summarize molecular biomarkers for oncologic disease subtyping remains unclear. Auto-generation of clinical nomograms from text guidelines could illustrate a new type of utility for LLMs. Methods: In this cross-sectional study, two LLMs, GPT-4 and Claude-2, were assessed for their ability to generate decision trees for molecular subtyping of oncologic diseases with and without expert-curated guidelines. Clinical evaluators assessed the accuracy of biomarker and cancer subtype generation, as well as validity of molecular subtyping decision trees across five cancer types: colorectal cancer, invasive ductal carcinoma, acute myeloid leukemia, diffuse large B-cell lymphoma, and diffuse glioma. Results: Both GPT-4 and Claude-2 "off the shelf" successfully produced clinical decision trees that contained valid instances of biomarkers and disease subtypes. Overall, GPT-4 and Claude-2 showed limited improvement in the accuracy of decision tree generation when guideline text was added. A Streamlit dashboard was developed for interactive exploration of subtyping trees generated for other oncologic diseases. Conclusion: This study demonstrates the potential of LLMs like GPT-4 and Claude-2 in aiding the summarization of molecular diagnostic guidelines in oncology. While effective in certain aspects, their performance highlights the need for careful interpretation, especially in zero-shot settings. Future research should focus on enhancing these models for more nuanced and probabilistic interpretations in clinical decision-making. The developed tools and methodologies present a promising avenue for expanding LLM applications in various medical specialties.
Assessing Patient Satisfaction in Ibadan South-west Region of Oyo State, Nigeria
Authors: Chukwuemeka Abel Nnandi , Akinsolu Folahanmi Tomiwa , Adekola Marylyn Bukola , Olagunju Mobolaji Timothy , Abodunrin Olunike Rebecca , Adewole Ifeoluwa Eunice , Ola Oluwabukola Mary , Ezechi Oliver Chukwujekwu
Published: March 2024

Introduction

Patient satisfaction plays a critical role in healthcare service delivery. Despite growing studies, patient satisfaction levels are still widely under-reported in Nigeria. This study assessed patient satisfaction among patients in primary and secondary healthcare facilities in Ibadan Southwest local government area of Oyo State, Nigeria.

Method and Materials

In this cross-sectional study, investigators collected data using the Short-form Patient Satisfaction Questionnaire (PSQ-18). The data was analyzed using the Statistical Package for the Social Sciences (SPSS) software with descriptive statistics and One-way analysis of variance (ANOVA).

Results

A total of 387 patients participated in the study, and results showed that overall satisfaction among patients was 67.9%, where Communication (84.5%) and Financial Aspect (54.9%) recorded the highest and lowest percentage of positive responses respectively.

Conclusion

Patient satisfaction is a growing subject in Nigeria. It has a significant influence on healthcare service delivery. Stakeholders, policymakers, and managers should employ policies, strategies, and programs to improve the quality of healthcare service delivery across Nigeria.
Microbe tree metabolite interactions in the soil - phyllosphere continuum of poplar tree: when microbes rewire poplar root exudate and metabolome
Authors: Fracchia F. , Guinet F. , Engle N.L. , Tschaplinski T.J. , Veneault-Fourrey C. , Deveau A.
Published: March 2024

Trees are associated with a broad range of microorganisms colonising the diverse tissues of their host. However, the early dynamics of the assembly of the microbiota from the root to shoot axis and how it is linked to root exudates and metabolite contents of tissues remain unclear.

Here, we characterized how fungal and bacterial communities are altering root exudates as well as root and shoot metabolomes in parallel with their establishment in poplar cuttings (Populus tremula x tremuloidesclone T89) over 30 days of growth. Sterile poplar cuttings were planted in natural or gamma-irradiated soils. Bulk and rhizospheric soils, root and shoot tissues were collected from day 1 to day 30 to track the dynamic changes of fungal and bacterial communities in the different habitats by DNA metabarcoding. Root exudates and root and shoot metabolites were analysed in parallel by gas chromatography-mass spectrometry.

Our study reveals that microbial colonization triggered rapid and substantial alterations in both the composition and quantity of root exudates, with over 70 metabolites exclusively identified in remarkably high abundances in the absence of microorganisms. Noteworthy among these were lipid-related metabolites and defence compounds. The microbial colonization of both roots and shoots exhibited a similar dynamic response, initially involving saprophytic microorganisms and later transitioning to endophytes and symbionts. Key constituents of the shoot microbiota were also discernible at earlier time points in the rhizosphere and roots, indicating that the soil constituted a primary source for shoot microbiota.

Furthermore, the microbial colonization of belowground and aerial compartments induced a reconfiguration of plant metabolism. Specifically, microbial colonization predominantly instigated alterations in primary metabolism in roots, while in shoots, it primarily influenced defence metabolism. This highlighted the profound impact of microbial interactions on metabolic pathways of plants, shedding light on the intricate interplay between plants and their associated microbial communities.
Cell-state dependent regulation of PPARγsignaling by ZBTB9 in adipocytes
Authors: Xu Xuan , Charrier Alyssa , Congrove Sunny , Buchner David A.
Published: March 2024

Adipocytes play a critical role in metabolic homeostasis. Peroxisome proliferator-activated receptor-γ(PPARγ) is a nuclear hormone receptor that is a master regulator of adipocyte differentiation and function. ZBTB9 was predicted to interact with PPARγbased on large-scale protein interaction experiments. In addition, GWAS studies in the type 2 diabetes (T2D) Knowledge Portal revealed associations between Zbtb9and both BMI and T2D risk. Here we show that ZBTB9 positively regulates PPARγactivity in mature adipocytes. Surprisingly Zbtb9knockdown (KD) also increased adipogenesis in 3T3-L1 cells and human preadipocytes.E2Factivity was increased and E2F downstream target genes were upregulated inZbtb9-KD preadipocytes. Accordingly, RB phosphorylation, which regulates E2F activity, was enhanced inZbtb9-KD preadipocytes. Critically, an E2F1 inhibitor blocked the effects ofZbtb9deficiency on adipogenic gene expression and lipid accumulation. Collectively, these results demonstrate thatZbtb9inhibits adipogenesis as a negative regulator ofPpargexpression via altered RB-E2F1 signaling. Our findings reveal complex cell-state dependent roles of ZBTB9 in adipocytes, identifying a new molecule that regulates adipogenesis and adipocyte biology as both a positive and negative regulator of PPARγsignaling depending on the cellular context, and thus may be important in the pathogenesis and treatment of obesity and T2D.
Balancing donor health and plasma collection: a systematic review of the impact of plasmapheresis frequency
Authors: D’aes Tine , van den Hurk Katja , Schroyens Natalie , Mikkelsen Susan , Severijns Pieter , De Buck Emmy , O’Leary Peter , Tiberghien Pierre , Compernolle Veerle , Erikstrup Christian , Van Remoortel Hans
Published: March 2024

Most plasma used for manufacturing plasma-derived medicinal products (PDMPs) such as albumin, immunoglobulin (Ig), and clotting factors is obtained from source plasma collected via plasmapheresis, the majority of which is contributed by the United States (US). While the demand for PDMPs continues to rise, it remains unclear whether high-frequency plasmapheresis, such as the twice-weekly plasma donation allowed in the US, may have any (long-term) adverse health effects on the donor.

To investigate the frequency at which plasma can be donated without harm to the donor, the current systematic review explores the impact of plasma donation frequency on cardiovascular health, protein depletion, and adverse events in healthy plasma donors. We asked the following research question: What is the impact of plasmapheresis frequency (Intervention) on the safety or health (Outcome) of healthy donors (Population)?

Six databases (PubMed, Embase, Web of Science, CINAHL, the Cochrane Library, and Transfusion Evidence Library), two clinical trial registries (ICTRP andclinicaltrials.gov), and the PROSPERO database were searched. Four observational and two experimental studies were included, and one ongoing randomized controlled trial was identified. The results showed that very high-frequency donation (twice per week) may result in a clinically relevant decrease in ferritin and bring IgG levels below the EDQM-defined lower threshold of 6 g/l. However, the evidence is of low to very low certainty, and solid conclusions are hindered by thehealthy donor effectand methodological limitations of the included studies. In order to determine a safe threshold donation frequency that minimizes any possible harmful effect on the donor, more high-quality prospective cohort studies and experimental studies are thus needed. In the meantime, we argue for a precautionary approach and suggest that a sustainable and stable plasma supply may better rely on a large number of voluntary donors donating at a lower frequency (up to two donations per month), rather than on a small number of donors donating at a high frequency.
The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup
Authors: Huang Yu-Jyun , Kurniansyah Nuzulul , Goodman Matthew O , Spitzer Brian W , Wang Jiongming , Stilp Adrienne , Laurie Cecelia , de Vries Paul S , Chen Han , Min Yuan-I , Sims Mario , Peloso Gina M , Guo Xiuqing , Bis Joshua C , Brody Jennifer A , Raffield Laura M , Smith Jennifer A , Zhao Wei , Rotter Jerome I , Rich Stephen S , Redline Susan , Fornage Myriam , Kaplan Robert , Franceschini Nora , Levy Daniel , Morrison Alanna C , Boerwinkle Eric , Smith Nicholas L , Kooperberg Charles , Psaty Bruce M , Zöllner Sebastian ,   the Trans-Omics in Precision Medicine Consortium, Sofer Tamar
Published: March 2024

Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called “expected PRS” (ePRS), the expected value of a PRS based on one’s global or local admixture patterns. We further define the “residual PRS” (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. Similarly, we applied the ePRS framework to six cardiovascular-related traits in the All of Us dataset, and the results are consistent with those from the TOPMed analysis. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.
Voxel-wise hemispheric Amyloid Asymmetry and its association with cerebral metabolism and grey matter density in cognitively normal older adults
Authors: Jayaprakash Hunsica J. , Mizuno Akiko , Snitz Beth E. , Cohen Ann D. , Klunk Willian E. , Aizenstein Howard J. , Karim Helmet T.
Published: March 2024

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by changes in beta amyloid (Aß) and tau as well as changes in cerebral glucose metabolism and gray matter volume. This has been categorized as three distinct stages of amyloid, tau, and neurodegeneration. Past studies have shown asymmetric Aβ accumulation and its association with asymmetric cerebral metabolism in preclinical AD. We analyzed data to replicate these findings and extend them to associations with gray matter volume and cognitive function.

Methods

We recruited 93 (mean age = 76.4±6.1 years) cognitively normal adults who underwent magnetic resonance imaging (MRI) and positron emission tomography (PET) with Pittsburgh compound B (PiB) and Fluorodeoxyglucose (FDG) tracers (to estimate Aβ and glucose metabolism, respectively). We conducted voxel-wise paired t-test on PiB (left vs. right hemispheres) to identify regions that differ in Aβ between the left and right cortex. We identified whether these regions showed asymmetry in FDG and gray matter volume using paired t-tests on each region. We then conducted correlations between asymmetry indices for each region that had significant asymmetry in PiB, FDG, and gray matter volume. We ran a group regression analysis on cognitive functions.

Results

We found 26 regions that had significant rightward asymmetry in PiB including prefrontal cortex, temporal cortex, insula, parahippocampus, caudate, and putamen. All these regions showed significant gray matter rightward asymmetry, and most of these regions showed significant FDG asymmetry except the caudate, orbital cortex, medial frontal gyrus, and superior temporal gyrus. Only in the superior frontal gyrus, we found that greater rightward asymmetry in PiB was associated with greater rightward asymmetry in FDG,r(82) =0.38,p<0.005 (FDR corrected) – no other regions showed significant Aß asymmetry correlation with either FDG or gray matter volume asymmetry. We found that greater rightward FDG asymmetry in the superior frontal gyrus was associated with greater visuospatial processing scores in our cognitive domain group regression analysis.

Discussion

AD has previously been modeled in three-stages: however, our results indicate that cerebral glucose metabolism may be dynamic throughout the disease progression and may serve as a compensatory pathway for maintaining cognitive functioning.
Opto-controlled C9orf72 poly-PR forms anisotropic condensates causative of TDP-43 pathology in the nucleus
Authors: Hodgson Rachel E , Rayment Jessica , Huang Wan-Ping , Avila Anna Sanchez , Shelkovnikova Tatyana A
Published: March 2024

Proteinaceous inclusions formed byC9orf72derived dipeptide-repeat (DPR) proteins are a histopathological hallmark in ~50% of familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) cases. However DPR aggregation/inclusion formation could not be efficiently recapitulated in cell models for four out of five DPRs. In this study, using optogenetics, we achieved chemical-free poly-PR condensation/aggregation in cultured cells, with spatial and temporal control. Strikingly, nuclear poly-PR condensates had anisotropic, hollow-centre appearance, resembling anisosomes formed by aberrant TDP-43 species, and their growth was limited by RNA. These condensates induced abnormal TDP-43 granulation in the nucleus without the activation of stress response. Cytoplasmic poly-PR aggregates that formed under prolonged light stimulation were more persistent than its nuclear condensates, selectively sequestered TDP-43 in a demixed state and surrounded spontaneous stress granules. Our data suggest that poly-PR anisotropic condensation in the nucleus, causative of nuclear TDP-43 dysfunction, may constitute an early pathological event in C9-ALS/FTD. Anisosome-type condensates may represent a more common cellular pathology in neurodegeneration than previously thought.

Highlights

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Optogenetics can be used to modelC9orf72DPR condensation in cultured cells.

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Opto-PR forms hollow nuclear condensates, and RNA limits their growth by fusion.

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Opto-PR condensation leads to stress-independent TDP-43 pathology in the nucleus.

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Cytoplasmic poly-PR assemblies are persistent and selectively sequester TDP-43.

Graphical abstract
Hairpin-locker mediated CRISPR/Cas tandem system for ultrasensitive detection of DNA without pre-amplification
Authors: Deng Fei , Sang Rui , Li Yi , Yang Biyao , Zhai Xiwen , Xue Ruier , Zhang Chengchen , Deng Wei , Goldys Ewa M.
Published: March 2024

Achieving ultra-sensitive detection of DNA is of paramount importance in the field of molecular analytics. Conventional amplification technologies such as polymerase chain reaction (PCR) currently play a leading role in ultrasensitive DNA detection. However, amplicon contamination common in these techniques may lead to false positives. To date, CRISPR-associated nucleases (type V & VI) with their programmable cleavage have been utilised for sensitive detection of unamplified nucleic acids in complex real samples. Nevertheless, without additional amplification strategies, the pM range sensitivity of such CRISPR/Cas sensors is not sufficient for clinical applications. Here, we established a hairpin-locker (H-locker) mediated Cas12-Cas13 tandem biosensing system (Cas12-13 tandem-sensor) for ultrasensitive detection of DNA targets. Without the need for any additional amplification reaction or device, this system is capable of detecting DNA at a notable 1 aM level (<1 copy/uL) sensitivity. In addition, the system was able to distinguish cancer mutations in colorectal cancer (CRC) mice. This is a significant advance for CRISPR/Cas biosensing technology offering simple, highly sensitive, and user-friendly diagnostics for next-generation nucleic acid detection.
Modulating Cas13atrans-cleavage by double strand RNA: Application to the development of an autocatalytic sensor
Authors: Deng Fei , Gulati Sneha , Sang Rui , Li Yi , Goldys Ewa M.
Published: March 2024

Cas13a-based diagnostic systems have been widely utilized for the detection of RNA targets. However, without preamplification such systems have sensitivity in the picomolar range only. Here, we found that double strand RNA (dsRNA) over 20nt is able to effectively activate thetrans-cleavage activity of Cas13a RNP, while the cleavage rates of dsRNA by activated Cas13a RNP are very low. In addition, specially designed small circular RNA constructs (Cir-mediators comprising a 20nt dsRNA trigger with a 5nt ssRNA linker) have limited ability to activate Cas13a RNP, but this activation is restored once the circular structures are cleaved and become linear. Based on this new method to controltrans-cleavage activity of Cas13 RNP, we developed a Cas13a autocatalytic biosensing system assisted by Cir-mediators, which allows one target RNA to activate numerous Cas13a RNPs. With this approach we show ultrasensitive detection of 1aM of synthetic RNA targets without preamplification within 15min. The sensor was successfully applied to monitor miRNA-21 concentration in clinical plasma samples in colorectal cancer. This investigation yields novel insights into the properties of Cas13a RNPs, and the Cir-mediator-based autosensor introduces a novel method for detecting RNA targets with exceptional sensitivity.

Highlights

dsRNA is able to trigger activation of Cas13a RNP.

Activated Cas13a RNP do not cleave dsRNA.

Cir-mediator induces low levels of Cas13a RNP activation.

Cir-mediator based Cas13a auto-catalysis biosensor can detect 1aM RNA targets.
Prophages block cell surface receptors to ensure survival of their viral progeny
Authors: Taylor Véronique L. , Shah Megha , Patel Pramalkumar H. , Yusuf Ahmed , Burk Cayla M. , Gitai Zemer , Davidson Alan R. , Koch Matthias D. , Maxwell Karen L.
Published: March 2024

In microbial communities, viruses compete for host cells to infect, and thus evolved diverse ways to inhibit their competitors. One mechanism is Superinfection exclusion (Sie), whereby a virus that has established an infection prevents a secondary infection. We identified aPseudomonasprophage Sie protein that alters pilus dynamics through the pilus assembly chaperone, PilZ. This protein, known as Zip for PilZ interactingprotein, does not abrogate pilus activity, but fine tunes it, providing strong phage resistance without a fitness cost. This tuning is modulated through quorum sensing, which coordinates Zip production in concert with bacterial cell density to ensure maximal protection when bacterial populations are at the highest risk of phage infection. Most notably, Zip activity prevents internalization and destruction of phage progeny. We refer to this as the “anti-Kronos effect” after the Greek god who devoured his own children and show that it is a conserved feature of diverse prophage-encoded Sie systems.
Modeling and Predicting Second-Harmonic Generation from Protein Molecular Structure
Authors: Asadipour Bahar , Beaurepaire Emmanuel , Zhang Xingjian , Chessel Anatole , Mahou Pierre , Supatto Willy , Schanne-Klein Marie-Claire , Stringari Chiara
Published: March 2024

Polarization resolved second-harmonic generation (pSHG) microscopy is increasingly used for mapping organized arrays of noncentrosymmetric proteins such as collagen, myosin, and tubulin, and holds potential for probing their molecular structure and supramolecular organization in intact tissues. However, the contrast mechanism of pSHG is complex and the development of applications in the life sciences is hampered by the lack of models accurately relating the observed pSHG signals to the underlying molecular and macromolecular organization. In this work, we establish a general multiscale numerical framework relating the micrometer-scale SHG measurements to the atomic-scale and molecular structure of the proteins under study and their supramolecular arrangement. We first develop a new method to automatically analyze pSHG signals independently of the protein type and fiber orientation. We then characterize experimentally pSHG signals in live zebrafish larvae and show that they can be used to distinguish collagen, myosin, and tubulin structures in intact tissues. We then introduce a numerical model that considers the peptide bond (PB) as the elementary SHG source in proteins and takes into account the three-dimensional (3D) distribution of PBs to predict the second-order hyperpolarizability tensor β of proteins, as well as the SHG efficiency and pSHG response of an arbitrary macromolecular assembly. We show that this model accurately reproduces pSHG measurements obtained from collagen, myosin, microtubule, and actin structures, revealing the precise dependence of SHG signals on the 3D distribution of PBs within protein assemblies. We then use our model to analyze pSHG from a 3D distribution of microtubule assemblies as a function of out-of-plane angles, angular disorder, and polarity. Finally, we demonstrate that our model predicts SHG from different molecular conformations of tubulin that are highly relevant from a biomedical point of view as associated with microtubules (de)polymerization. By bridging scales from the molecular bonds to the optical wavelength, our model provides an accurate interpretation of SHG signals in terms of protein structure and supramolecular organization.

Published by the American Physical Society
2024
Measuring the patronage intentions among football fans: the role of corporate social responsibility, brand credibility and brand equity
Authors: Mansouri Hossein , Rasaee Rad Abdullah , Tsiotsou Rodoula H. , Md Husin Maizaitulaidawati
Published: March 2024

Purpose

The study aims to identify critical factors that influence football fans’ support of their favorite team by examining the impact of social responsibility, brand credibility and team brand equity on patronage intentions of professional football teams.

Design/methodology/approach

An online survey collected data from 331 football fans of the Persian Gulf Premier League (PGPL) in Iran. The data were analyzed using partial least squares structural equation modeling (PLS-SEM).

Findings

The findings revealed that corporate social responsibility (CSR) is able to influence brand equity, brand credibility and patronage intentions. Also, brand equity and brand credibility were found to be positively related to patronage intentions. In addition to that, the findings show that brand equity and team credibility partially mediate the relationship between CSR and patronage intentions.

Practical implications

The findings provide valuable insights to sports teams/club managers aiming to attract new fans and retain current ones by investing in CSR and enhancing brand credibility and equity. Strategies to integrate CSR into relationship marketing and brand management are outlined.

Originality/value

This study empirically highlights the critical role of adhering to CSR and the effects of brand credibility and equity in enhancing patronage intentions among football team fans.
The role of mindfulness skill and inclusive leadership in job performance among secondary teachers in Hong Kong
Authors: Hong Liang , Zainal Siti Rohaida Mohamed
Published: March 2024

Purpose

Researcher agreed that job performance has a positive effect on productivity as well as an organisation’s efficiency. Thus, this study aims to investigate the impact of mindfulness skill, inclusive leadership (IL), employee work engagement and self-compassion on the overall job performance of secondary school teachers in Hong Kong. It then evaluates the mediating effect of employee work engagement between the relationships of mindfulness skill, IL and job performance, as well as the moderate effect of self-compassion between the relationships of mindfulness skill, IL and employee work engagement.

Design/methodology/approach

The sample comprised 263 teachers working from three secondary schools in Sha Tin, Hong Kong. The data was then analysed using Smart PLS version 4.0.9.

Findings

The results showed significant positive relationships between mindfulness skill and IL towards employee work engagement and between employee work engagement and job performance; meanwhile, there emerged a significant effect on the relationship between mindfulness skill and IL towards job performance. Furthermore, this research has confirmed that self-compassion did not moderate the relationship between mindfulness skill, IL and employee work engagement, but employee work engagement plays a mediating effect on the relationship between mindfulness skill, IL and job performance.

Originality/value

This research has helped to fill the literature gap by examining the mediating roles of employee work engagement and mediator role of self-compassion in the integrated relationship of multi-factor and job performance. Examining the mediating role of employee work engagement has helped to enhance the understanding of the underlying principle of the indirect influence of mindfulness skill, IL and job performance. The result of this research shows that self-compassion plays a vital role in influencing the employees’ work engagement. Hence, it is important that companies design human resource management policy that enables self-compassion to be used as a consideration psychological-related strategy when structing organisation or teams. It is also crucial for top management and policymakers to define and communicate the organisation’s operating principle, value and goals.