bluuebunny/crossref_metadata_2025 huggingface dataset:
Metaproteomic portrait of the healthy human gut microbiota
Authors: Tanca Alessandro , Palomba Antonio , Fiorito Giovanni , Abbondio Marcello , Pagnozzi Daniela , Uzzau Sergio
Published: June 2024

Gut metaproteomics can provide direct evidence of microbial functions actively expressed in the colonic environments, contributing to clarify the role of the gut microbiota in human physiology. In this study, we re-analyzed 10 fecal metaproteomics datasets of healthy individuals from different continents and countries, with the aim of identifying stable and variable gut microbial functions and defining the contribution of specific bacterial taxa to the main metabolic pathways. The “core” metaproteome included 182 microbial functions and 83 pathways that were identified in all individuals analyzed. Several enzymes involved in glucose and pyruvate metabolism, along with glutamate dehydrogenase, acetate kinase, elongation factors G and Tu and DnaK, were the proteins with the lowest abundance variability in the cohorts under study. On the contrary, proteins involved in chemotaxis, response to stress and cell adhesion were among the most variable functions. Random-effect meta-analysis of correlation trends between taxa, functions and pathways revealed key ecological and molecular associations within the gut microbiota. The contribution of specific bacterial taxa to the main biological processes was also investigated, finding that Faecalibacterium is the most stable genus and the top contributor to anti-inflammatory butyrate production in the healthy gut microbiota. Active production of other mucosal immunomodulators facilitating host tolerance was observed, including Roseburia flagellin and lipopolysaccharide biosynthetic enzymes expressed by members of Bacteroidota. Our study provides a detailed picture of the healthy human gut microbiota, contributing to unveil its functional mechanisms and its relationship with nutrition, immunity, and environmental stressors.
Simple bioelectrical microsensor: oocyte quality prediction via membrane electrophysiological characterization
Authors: Palay Peyman , Fathi Davood , Saffari Hassan , Hassani Fatemeh , Hajiaghalou Samira , Fathi Rouhollah
Published: June 2024

Introducing a novel electrical evaluation approach as an alternative to or an enhancer of the conventional approach for oocyte quality evaluation.
Understanding oxide ion transport in cation-ordered yttria-stabilized zirconia
Authors: Madhual Sudeshna , Padma Kumar P.
Published: June 2024

With maximal dispersion of the dopant, a multi-fold increase in ionic conductivity is predicted.
APTES functionalization in SBA-15: the effect on SO2 capture and detection applications
Authors: Obeso Juan L. , López Cervantes Valeria B. , Flores Catalina V. , García-Carvajal Celene , Garduño-Albino Carlos E. , Peralta Ricardo A. , Trejos Víctor M. , Huerta Arcos L. , Ibarra Ilich A. , Solis-Ibarra Diego , Cordero-Sánchez Salomón , Portillo-Vélez Nora S. , Esparza-Schulz J. Marcos
Published: June 2024

SBA-15 functionalized with APTES enables the selective detection of the SO2 molecule.
Metal ion interference therapy: metal-based nanomaterial-mediated mechanisms and strategies to boost intracellular “ion overload” for cancer treatment
Authors: Li Yutang , Wang Yandong , Zhao Li , Stenzel Martina H. , Jiang Yanyan
Published: June 2024

This comprehensive review systematically summarizes the intrinsic mechanism of different metal ion (such as Fe3+/Fe2+, Cu2+/Cu+, Ca2+, Zn2+, Mn2+, Na+/K+, and Mg2+)-mediated interference therapies and their research progress in cancer treatment.
Enzymatic synthesis of ligand-bearing oligonucleotides for the development of metal-responsive DNA materials
Authors: Takezawa Yusuke , Shionoya Mitsuhiko
Published: June 2024

This review provides an overview of enzymatic synthesis methods for DNA strands with ligand-type artificial nucleotides forming metal-mediated base pairs, which have been applied in developing metal-responsive functional DNA molecules.
Fabrication of high-surface-area mesoporous frameworks of β-Ni(OH)2–CdIn2S4 p–n nano-heterojunctions for improved visible light photocatalytic hydrogen production
Authors: Andreou Evangelos K. , Vamvasakis Ioannis , Armatas Gerasimos S.
Published: June 2024

High-surface-area mesoporous frameworks of Ni-decorated CdIn2S4 nanocrystals offer prominent advantages for light-induced catalysis due to the large surface area and improved charge carrier separation kinetics at the p–n β-Ni(OH)2/CdIn2S4 junctions.
Comparison of Early Fungicidal Activity and Mortality Between Daily Liposomal Amphotericin B and Daily Amphotericin B Deoxycholate for Cryptococcal Meningitis
Authors: Kimuda Sarah , Kwizera Richard , Dai Biyue , Kigozi Enos , Kasozi Derrick , Rutakingirwa Morris K , Tukundane Asmus , Shifah Nabbaale , Luggya Tony , Luswata Andrew , Ndyetukira Jane Frances , Yueh Spencer L , Mulwana Suzan , Wele Abduljewad , Bahr Nathan C , Meya David B , Boulware David R , Skipper Caleb P
Published: June 2024

Background

Limited data exist on the antifungal activity of daily liposomal amphotericin B with flucytosine induction regimens for cryptococcal meningitis, which are recommended in high-income countries. Liposomal amphotericin B monotherapy at 3 mg/kg previously failed to meet noninferiority criteria compared to amphotericin B deoxycholate in its registrational clinical trial. We aimed to compare the quantitative antifungal activity and mortality between daily amphotericin B deoxycholate and daily liposomal amphotericin B among persons with human immunodeficiency virus (HIV)–related cryptococcal meningitis receiving adjunctive flucytosine 100 mg/kg/day.

Methods

We analyzed data from 3 clinical studies involving participants with HIV-associated cryptococcal meningitis receiving either daily liposomal amphotericin B at 3 mg/kg/day with flucytosine (n = 94) or amphotericin B deoxycholate at 0.7–1.0 mg/kg/day with flucytosine (n = 404) as induction therapy. We compared participant baseline characteristics, cerebrospinal fluid (CSF) early fungicidal activity (EFA), and 10-week mortality.

Results

We included 498 participants in this analysis, of whom 201 had available EFA data (n = 46 liposomal amphotericin B; n = 155 amphotericin B deoxycholate). Overall, there is no statistical evidence that the antifungal activity of liposomal amphotericin B (mean EFA, 0.495 [95% confidence interval {CI}, .355–.634] log10 colony-forming units [CFU]/mL/day) differ from amphotericin B deoxycholate (mean EFA, 0.402 [95% CI, .360–.445] log10 CFU/mL) (P = .13). Mortality at 10 weeks trended lower for liposomal amphotericin B (28.2%) versus amphotericin B deoxycholate (34.6%) but was not statistically different when adjusting for baseline characteristics (adjusted hazard ratio, 0.74 [95% CI, .44–1.25]; P = .26).

Conclusions

Daily liposomal amphotericin B induction demonstrated a similar rate of CSF fungal clearance and 10-week mortality as amphotericin B deoxycholate when combined with flucytosine for the treatment of HIV-associated cryptococcal meningitis.
Associations of neighborhood social cohesion and changes in BMI—The Maastricht Study
Authors: Chan Jeffrey A , Koster Annemarie , Lakerveld Jeroen , Schram Miranda T , van Greevenbroek Marleen , Bosma Hans
Published: June 2024

The role of the social environment can facilitate positive health outcomes through active community engagement, normalization of healthy behaviors, and stress buffering. We aim to examine the associations of neighborhood social cohesion with changes in BMI over time. A total of 7641 participants from The Maastricht Study between the ages of 40 and 75 years were analyzed. Weight and height were measured at baseline, and weight was self-reported annually up to 10 years of follow-up (median = 4.7 years). Perceived social cohesion was obtained by questionnaire. Home addresses for each participant were linked to geographic information system data from the Geoscience and Health Cohort Consortium to create neighborhood exposure variables including area level social cohesion, neighborhood walkability, and food environment within a 1000 m Euclidian buffer. Linear regression analyses were performed with BMI adjusted for socioeconomic variables. A mixed model analysis was carried out to examine changes in BMI. Living in the highest quartile area of individually perceived social cohesion was associated with lower BMI (Q4 B: −.53; 95% CI = −.79, −.28) compared to the lowest quartile. Similar findings were discovered using the area level measure (Q4 B: −.97; 95% CI = −1.29, −.65). There was no longitudinal association between social cohesion and BMI. Neighborhood social cohesion was associated with lower BMI classifying it as an obesogenic area characteristic that influences weight, independent of conventional built environment features.
Atoning vs. evading when caught transgressing: two multi-theory-based experiments investigating strategies for politicians responding to scandal
Authors: Clementson David E , Zhao Wenqing , Beatty Michael J
Published: June 2024

Politicians tend to try deflecting scandals. Based on an attribution theory-driven perspective on persuasion, however, politicians should proactively confess. In a preregistered, multiple-message design, we conduct controlled, random assignment experiments. A mediation model is tested. Inspired by crisis communication’s change-of-meaning concept, the first variable appraises the extent to which voters perceive that the messaging indicates the politician is engaging in a cover-up. The second linkage is the politician’s credibility. The outcome variable is voters’ behavioral intentions. In Experiment 1 (N = 905 U.S. voters), stealing thunder and apologizing outperform stonewalling, changing the subject, sequentially apologizing plus deflecting, or silence. Experiment 2 (N = 277) finds that, in a sex scandal, stealing thunder and apologizing continue to perform equally well. Our theoretical contribution resides in enhancing the explanatory power of theories designed to explain image repair, as well as empirically testing the independent and combined role of apology and stealing thunder.
Risks, innovation, and adaptability in the UK’s incrementalism versus the European Union’s comprehensive artificial intelligence regulation
Authors: Gikay Asress Adimi
Published: June 2024

The regulation of artificial intelligence (AI) should strike a balance between addressing the risks of the technology and its benefits through enabling useful innovation whilst remaining adaptable to evolving risks. The European Union’s (EU) overarching risk-based regulation subjects AI systems across industries to a set of regulatory standards depending on where they fall in the risk bucket, whilst the UK’s sectoral approach advocates for an incremental regulation. By demonstrating the EU AI Act’s inability to adapt to evolving risks and regulate the technology proportionately, this article argues that the UK should avoid the EU AI Act’s compartmentalized high-risk classification system. The UK should refine its incremental regulation by adopting a generic principle for risk classification that allows for contextual risk assessment whilst adapting to evolving risks. The article contends that if refined appropriately, the UK’s incremental approach that relies on coordinate sectionalism encourages innovation without undermining the UK technology sector’s competitiveness in the global market of compliant AI, while also mitigating the potential risks presented by the technology.
New approaches to the control of chronic inflammatory diseases with a focus on the endolysosomal system of immune cells
Authors: Toyama-Sorimachi Noriko
Published: June 2024

Chronic inflammation is implicated in many types of diseases, including cardiovascular, neurodegenerative, metabolic, and immune disorders. The search for therapeutic targets to control chronic inflammation often involves narrowing down the various molecules associated with pathology that have been discovered by various omics analyses. Herein, a different approach to identify therapeutic targets against chronic inflammation is proposed and one such target is discussed as an example. In chronically inflamed tissues, a large number of cells receive diverse proinflammatory signals, the intracellular signals are intricately integrated, and complicated intercellular interactions are orchestrated. This review focuses on effectively blocking this chaotic inflammatory signaling network via the endolysosomal system, which acts as a cellular signaling hub. In endolysosomes, the inflammatory signals mediated by pathogen sensors, such as Toll-like receptors, and the signals from nutrient and metabolic pathways are integrally regulated. Disruption of endolysosome signaling results in a strong anti-inflammatory effect by disrupting various signaling pathways, including pathogen sensor-mediated signals, in multiple immune cells. The endolysosome-resident amino acid transporter, solute carrier family 15 member 4 (SLC15A4), which plays an important role in the regulation of endolysosome-mediated signals, is a promising therapeutic target for several inflammatory diseases, including autoimmune diseases. The mechanisms by which SLC15A4 regulates inflammatory responses may provide a proof of concept for the efficacy of therapeutic strategies targeting immune cell endolysosomes.
Effectiveness of Autologous Skin Cell Suspension in Large Total Body Surface Area Burns: Analysis of Clinical Outcomes and Patient Charges
Authors: Elkady Djoni , Larson Brandon M , Sharma Steffi , McNinch Neil L , Beaucock Beverly , Richard B Lou , Khandelwal Anjay
Published: June 2024

Autologous skin cell suspension (ASCS) is an adjunct to conventional split-thickness skin grafts (STSG) for acute burns, enhancing healing and reducing donor site requirements. This study validates ASCS’s predictive benefits in hospital stay reduction and cost savings by analyzing outcomes and real-world charges post-ASCS implementation at a single institution. A retrospective study (2018-2022) included burn patients with ≥10% TBSA. The study population comprised 2 groups: burns treated either with a combination of ASCS ± STSG or with STSG alone. Outcomes included LOS, surgeries, infection, complications, days on antibiotics, and adjusted charge per TBSA. The ASCS ± STSG group demonstrated significantly shorter LOS (Mdn: 16.0 days, IQR: 10-26) than the STSG group (Mdn: 20.0 days, IQR: 14-36; P = .017), and fewer surgeries (Mdn: 1.0, IQR: 1-2) versus the STSG group (Mdn: 1.0, IQR: 1-4; P = .020). Postoperative complications were significantly lower in ASCS ± STSG (11% vs. 36%; P < .001). The STSG group had a longer distribution of antibiotic days (IQR: 0-7.0, min–max: 0-76) than the ASCS ± STSG group (IQR: 0-0, min–max: 0-37; P = .014). Wound infection incidence did not differ (P = .843). ASCS ± STSG showed a lower distribution of adjusted charge per TBSA (IQR: $10 788.5-$28 332.6) compared to the STSG group (IQR: $12 336.8-$29 507.3; P = .602) with a lower mean adjusted charge per TBSA ($20 995.0 vs. $24 882.3), although this was not statistically significant. ASCS ± STSG utilization demonstrated significant reductions in LOS, surgeries, postoperative complications, antibiotics, and potential cost savings. These findings underscore the practicality of integrating ASCS in burn management, offering substantial benefits to patients and healthcare institutions.
Biosensors for the detection of chorismate and cis,cis-muconic acid in Corynebacterium glutamicum
Authors: Velasquez-Guzman Jeanette C , Huttanus Herbert M , Morales Demosthenes P , Werner Tara S , Carroll Austin L , Guss Adam M , Yeager Chris M , Dale Taraka , Jha Ramesh K
Published: June 2024

Corynebacterium glutamicum ATCC 13032 is a promising microbial chassis for industrial production of valuable compounds, including aromatic amino acids derived from the shikimate pathway. In this work, we developed two whole-cell, transcription factor based fluorescent biosensors to track cis,cis-muconic acid (ccMA) and chorismate in C. glutamicum. Chorismate is a key intermediate in the shikimate pathway from which value-added chemicals can be produced, and a shunt from the shikimate pathway can divert carbon to ccMA, a high value chemical. We transferred a ccMA-inducible transcription factor, CatM, from Acinetobacter baylyi ADP1 into C. glutamicum and screened a promoter library to isolate variants with high sensitivity and dynamic range to ccMA by providing benzoate, which is converted to ccMA intracellularly. The biosensor also detected exogenously supplied ccMA, suggesting the presence of a putative ccMA transporter in C. glutamicum, though the external ccMA concentration threshold to elicit a response was 100-fold higher than the concentration of benzoate required to do so through intracellular ccMA production. We then developed a chorismate biosensor, in which a chorismate inducible promoter regulated by natively expressed QsuR was optimized to exhibit a dose-dependent response to exogenously supplemented quinate (a chorismate precursor). A chorismate–pyruvate lyase encoding gene, ubiC, was introduced into C. glutamicum to lower the intracellular chorismate pool, which resulted in loss of dose dependence to quinate. Further, a knockout strain that blocked the conversion of quinate to chorismate also resulted in absence of dose dependence to quinate, validating that the chorismate biosensor is specific to intracellular chorismate pool. The ccMA and chorismate biosensors were dually inserted into C. glutamicum to simultaneously detect intracellularly produced chorismate and ccMA. Biosensors, such as those developed in this study, can be applied in C. glutamicum for multiplex sensing to expedite pathway design and optimization through metabolic engineering in this promising chassis organism.

One-Sentence Summary

High-throughput screening of promoter libraries in Corynebacterium glutamicum to establish transcription factor based biosensors for key metabolic intermediates in shikimate and β-ketoadipate pathways.
Association between response to enfortumab vedotin and peripheral neuropathy in urothelial carcinoma patients: a multicenter retrospective study
Authors: Hayakawa Nozomi , Kikuchi Eiji , Kaneko Go , Yamashita Ryo , Ikarashi Daiki , Endo Yuki , Usui Kimitsugu , Obara Wataru , Oyama Masafumi , Kondo Yukihiro
Published: June 2024

Background

Enfortumab vedotin (EV) was approved for patients with metastatic urothelial carcinoma (mUC) who progressed after anticancer therapy on September 2021 in Japan. The association between the occurrence of EV-related side effects and clinical outcome remains to be elucidated.

Methods

We identified 97 mUC patients treated with EV therapy at our five institutions from the date of approval to March 2023. The median follow-up period was 7.0 months. We retrospectively analyzed the efficacy and safety of EV.

Results

The median age of the patients was 71 years old, 39% had PS of 1 or more, and 56.7% had primary tumor in upper urinary tract. Overall response rate (ORR) to EV therapy, median progression-free survival (PFS), and overall survival (OS) were 43.3%, 7.52 months, and 12.78 months, respectively. Any grade of treatment-related skin disorder, dysgeusia, peripheral neuropathy, gastrointestinal disorder, and hyperglycemia occurred in 61 (62.9%), 36 (37.1%), 34 (35.1%), 29 (29.9%), and 18 (18.6%) patients, respectively. The patients with EV-associated peripheral neuropathy had significantly higher ORR (58.8% vs. 34.9%, P = .032) and longer median PFS (8.05 vs. 6.31 months, P = .017) and OS (not reached vs. 11.57 months, P = .008, respectively) than those without. The occurrence of peripheral neuropathy after EV treatment and the presence of peritoneal dissemination were factors independently associated with PFS (hazard ratio = 0.46, P = .008 and hazard raito = 3.83, P = .004, respectively) and OS (hazard ratio = 0.30, P = .005 and hazard raito = 4.53, P = .002, respectively).

Conclusions

The occurrence of EV-related peripheral neuropathy might be associated with the efficacy of EV therapy in mUC patients.
Association of the modified Glasgow prognostic score and prognostic nutritional index with duration of oral anamorelin administration in patients with cancer cachexia: a retrospective cohort study
Authors: Fujita Kazuma , Akamine Yumiko , Igarashi Haruka , Fukushi Yayoi , Sasaki Katsuya , Fukuda Koji , Kikuchi Masafumi , Shibata Hiroyuki
Published: June 2024

Background

The modified Glasgow Prognostic Score (mGPS) and Prognostic Nutritional Index (PNI) are indicators of nutritional status in cancer patients; however, the effects of baseline mGPS and PNI on the duration of administration of the ghrelin receptor agonist anamorelin, which is used to treat cachexia in patients with cancer, are unclear. This study aimed to clarify the association of mGPS and PNI with the duration of oral anamorelin administration for patients who did not have beneficial effects from anamorelin.

Methods

The attending physician determined the duration of oral anamorelin administration based on discontinuation due to cancer progression, poor efficacy, adverse events, or death.

Results

The 12-week continuation rate of oral anamorelin was 30.4%. Univariate analysis revealed that an Eastern Cooperative Oncology Group performance status (ECOG-PS) of ≥2 (P < .001), concurrent chemotherapy (P = .002), albumin level (P = .005), C-reactive protein level (P = .013), and a mGPS of 2 (P = .014) were statistically significant predictors of the 12-week continuation rate of oral anamorelin. In the multivariate analysis, a mGPS of 2 remained a significant risk factor, and the ECOG-PS and concurrent chemotherapy had no effect on the association between the mGPS and 12-week continuation rate of oral anamorelin.

Conclusion

Patients with a mGPS of 2, compared with mGPS of 0 or 1, are less likely to maintain oral anamorelin therapy, regardless of the ECOG-PS or concurrent chemotherapy. Therefore, it is necessary to consider initiating anamorelin administration at mGPS 0 or 1.
Breast cancer with biomarker reversal during the course of treatment: a case report
Authors: Yoshino Ryusei , Nakatsubo Masaki , Ujiie Nanami , Kitada Masahiro
Published: June 2024

During breast cancer recurrence, drug therapy is planned based on the biological characteristics of the primary tumor. However, the mechanisms underlying these changes have not yet been clarified. A 59-year-old woman underwent breast cancer surgery 23 years previously and received postoperative hormone therapy for 2 years. She had abdominal distention and ascites effusion and was diagnosed with carcinomatous peritonitis due to luminal-type breast cancer after ascites puncture. She received up to the fourth line of treatment. Subsequently, pleural effusion was observed and human epidermal growth factor receptor 2 type breast cancer was diagnosed because of pleurodesis. This case suggests that the cell block diagnostic method based on thoracic and ascites fluid cytology is useful not only for confirming the primary tumor but also for diagnosing the biological characteristics of breast cancer. In the treatment of breast cancer recurrence, it is important to plan the treatment, including aggressive re-biopsy of metastases.
Neutron star accretion events in AGN discs: mutimessenger implications
Authors: Zhang Shu-Rui , Yuan Ye-Fei , Wang Jian-Min , Ho Luis C
Published: June 2024

This paper investigates the accretion of neutron stars (NSs) in active galactic nucleus (AGN) accretion discs. We classify potential accretion modes of NSs in AGN discs, proposing a hierarchical model of NS accretion: accretion flow from the Bondi sphere to accretion columns. The accretion of NSs in AGN discs differs from that of BHs, especially within the scale of the NS’s magnetosphere due to its hard surface and magnetic field. As the accretion flow approaches the magnetosphere, the magnetic fields guide the accretion flow to form accretion columns, primarily dominated by neutrinos. While neutrinos generated from single NS accretion may not have observable effects, considering the all-sky background, they contribute to the neutrino background in the sub-MeV energy range comparable to that of supernova explosions. NS accretion may also lead to the generation of mass quadrupole moments, consequently generating gravitational waves (GWs). The GWs, which exhibit characteristic effects like periodic modulations and echoes, could be observed by third-generation GW detectors. The emission of neutrinos and GWs carries away energy and angular momentum brought by accretion, reducing the feedback effect on the AGN disc. This results in an exceptionally high NS accretion rate, leading to a collapse time-scale shorter than the migration-merge time-scale, making it less likely that binary NS mergers originate from AGN discs.
Damping wing-like features in the stacked Ly α forest: Potential neutral hydrogen islands at z < 6
Authors: Zhu Yongda , Becker George D , Bosman Sarah E I , Cain Christopher , Keating Laura C , Nasir Fahad , D’Odorico Valentina , Bañados Eduardo , Bian Fuyan , Bischetti Manuela , Bolton James S , Chen Huanqing , D’Aloisio Anson , Davies Frederick B , Davies Rebecca L , Eilers Anna-Christina , Fan Xiaohui , Gaikwad Prakash , Greig Bradley , Haehnelt Martin G , Kulkarni Girish , Lai Samuel , Puchwein Ewald , Qin Yuxiang , Ryan-Weber Emma V , Satyavolu Sindhu , Spina Benedetta , Walter Fabian , Wang Feige , Wolfson Molly , Yang Jinyi
Published: June 2024

Recent quasar absorption line observations suggest that reionization may end as late as $z \approx 5.3$. As a means to search for large neutral hydrogen islands at $z\ \lt\ 6$, we revisit long dark gaps in the Ly $\beta$ forest in Very Large Telescope/X-Shooter and Keck/Echellette Spectrograph and Imager quasar spectra. We stack the Ly $\alpha$ forest corresponding to both edges of these Ly $\beta$ dark gaps and identify a damping wing-like extended absorption profile. The average redshift of the stacked forest is $z=5.8$. By comparing these observations with reionization simulations, we infer that such a damping wing-like feature can be naturally explained if these gaps are at least partially created by neutral islands. Conversely, simulated dark gaps lacking neutral hydrogen struggle to replicate the observed damping wing features. Furthermore, this damping wing-like profile implies that the volume-averaged neutral hydrogen fraction must be $\langle x_{\rm H\,{\small {I}}} \rangle \ge 6.1 \pm 3.9~{{\ \rm per\ cent}}$ at $z = 5.8$. Our results offer robust evidence that reionization extends below $z=6$.
Assessing the impact of transcriptomics data analysis pipelines on downstream functional enrichment results
Authors: Paton Victor , Ramirez Flores Ricardo Omar , Gabor Attila , Badia-i-Mompel Pau , Tanevski Jovan , Garrido-Rodriguez Martin , Saez-Rodriguez Julio
Published: June 2024

Transcriptomics is widely used to assess the state of biological systems. There are many tools for the different steps, such as normalization, differential expression, and enrichment. While numerous studies have examined the impact of method choices on differential expression results, little attention has been paid to their effects on further downstream functional analysis, which typically provides the basis for interpretation and follow-up experiments. To address this, we introduce FLOP, a comprehensive nextflow-based workflow combining methods to perform end-to-end analyses of transcriptomics data. We illustrate FLOP on datasets ranging from end-stage heart failure patients to cancer cell lines. We discovered effects not noticeable at the gene-level, and observed that not filtering the data had the highest impact on the correlation between pipelines in the gene set space. Moreover, we performed three benchmarks to evaluate the 12 pipelines included in FLOP, and confirmed that filtering is essential in scenarios of expected moderate-to-low biological signal. Overall, our results underscore the impact of carefully evaluating the consequences of the choice of preprocessing methods on downstream enrichment analyses. We envision FLOP as a valuable tool to measure the robustness of functional analyses, ultimately leading to more reliable and conclusive biological findings.
PRPF40A induces inclusion of exons in GC-rich regions important for human myeloid cell differentiation
Authors: Tan Cheryl Weiqi , Sim Donald Yuhui , Zhen Yashu , Tian Haobo , Koh Jace , Roca Xavier
Published: June 2024

We characterized the regulatory mechanisms and role in human myeloid cell survival and differentiation of PRPF40A, a splicing factor lacking a canonical RNA Binding Domain. Upon PRPF40A knockdown, HL-60 cells displayed increased cell death, decreased proliferation and slight differentiation phenotype with upregulation of immune activation genes. Suggestive of both redundant and specific functions, cell death but not proliferation was rescued by overexpression of its paralog PRPF40B. Transcriptomic analysis revealed the predominant role of PRPF40A as an activator of cassette exon inclusion of functionally relevant splicing events. Mechanistically, the exons exclusively upregulated by PRPF40A are flanked by short and GC-rich introns which tend to localize to nuclear speckles in the nucleus center. These PRPF40A regulatory features are shared with other splicing regulators such as SRRM2, SON, PCBP1/2, and to a lesser extent TRA2B and SRSF2, as a part of a functional network that regulates splicing partly via co-localization in the nucleus.
The IDH paradox: Meta-analysis of alkylating chemotherapy in IDH-wild type and -mutant lower grade gliomas
Authors: Kinslow Connor J , Roy Soumyajit , Iwamoto Fabio M , Brown Paul D , DeStephano David M , Canoll Peter D , Qureshi Summer S , Gallito Matthew , Sisti Michael B , Bruce Jeffrey N , Horowitz David P , Kachnic Lisa A , Neugut Alfred I , Yu James B , Mehta Minesh P , Cheng Simon K , Wang Tony J C
Published: June 2024

Background

IDH-wild type (-wt) status is a prerequisite for the diagnosis of glioblastoma (GBM); however, IDH-wt gliomas with low-grade or anaplastic morphology have historically been excluded from GBM trials and may represent a distinct prognostic entity. While alkylating agent chemotherapy improves overall survival (OS) and progression-free survival (PFS) for IDH-wt GBM and also IDH-mutant gliomas, irrespective of grade, the benefit for IDH-wt diffuse histologic lower-grade gliomas is unclear.

Methods

We performed a meta-analysis of randomized clinical trials for World Health Organization (WHO) grades 2–3 gliomas (2009 to present) to determine the effect of alkylating chemotherapy on IDH-wt and -mutant gliomas using a random-effects model with inverse-variance pooling.

Results

We identified 6 trials with 1204 patients (430 IDH-wt, 774 IDH-mutant) that evaluated alkylating chemoradiotherapy versus radiotherapy alone, allowing us to perform an analysis focused on the value of adding alkylating chemotherapy to radiotherapy. For patients with IDH-wt tumors, alkylating chemotherapy added to radiotherapy was associated with improved PFS (HR:0.77 [95% CI: 0.62–0.97], P = .03) but not OS (HR:0.87 [95% CI: 0.64–1.18], P = .17). For patients with IDH-mutant tumors, alkylating chemotherapy added to radiotherapy improved both OS (HR:0.52 [95% CI: 0.42–0.64], P < .001) and PFS (HR = 0.47 [95% CI: 0.39–0.57], P < .001) compared to radiotherapy alone. The magnitude of benefit was similar for IDH-mutant gliomas with or without 1p19q-codeletion.

Conclusions

Alkylating chemotherapy reduces mortality by 48% and progression by 53% for patients with IDH-mutant gliomas. Optimal management of IDH-wt diffuse histologic lower-grade gliomas remains to be determined, as there is little evidence supporting an OS benefit from alkylating chemotherapy.
Revisiting Representations of Quark Mixing Matrix
Authors: Kaur Gurjit , Bagai Aakriti , Ahuja Gulsheen , Gupta Manmohan
Published: June 2024

Using unitarity, unlike the approaches available in the literature, we construct 9 independent representations of the Cabibbo–Kobayashi–Maskawa) CKM matrix starting with each of the 9 elements of the matrix. The relationship of these independently constructed representations with those already available in the literature is compared and discussed. Further, the implications of these representations are explored for some of the CKM parameters such as $\delta$, J and $\epsilon _k$. Interestingly, we find that the PDG representation which is equivalent to our first representation seems to be most appropriate to incorporate the hierarchy of the elements of the CKM matrix as well as to describe the related phenomenology.
Combination of gene/protein and metabolite multiomics to reveal biomarkers of nickel ion cytotoxicity and the underlying mechanism
Authors: Huang Yan , Zhang Fudan , Zhang Yajing , Chen Rong , Lü Xiaoying
Published: June 2024

Biomarkers have been applied for toxicity assessment of biomaterials due to their advantages. However, research on biomarkers for biomaterials is still in its early stages. There is a lack of integrated analysis in biomarker research based on multiomics studies. Herein, we report a new approach for combining of gene/protein and metabolite multiomics to reveal biomarkers of nickel ion (Ni2+) cytotoxicity and the underlying mechanism. Firstly, differentially expressed genes and proteins were compared to screen gene/protein pairs exhibiting consistent differential expression within the same Ni2+-treated groups. Next, metabolic pathway analysis was carried out to reveal pathways in which gene/protein pairs and metabolites showed upstream and downstream relationships. Important networks composed of gene/protein pairs, metabolites and metabolic pathways and candidate biomarkers were subsequently identified. Through expression level and function validation, the gene/protein/metabolite biomarkers were confirmed, and the underlying mechanism was revealed: Ni2+ influenced the expression of the Rrm2 gene biomarker, which subsequently affected the expression of the RRM2 protein biomarker. These changes in turn impacted the levels of uric acid and uridine metabolite biomarkers, ultimately inhibiting DNA synthesis, suppressing cell proliferation, increasing intracellular ROS levels and reducing ATP content.
Tristetraprolin mediates immune evasion of mycobacterial infection in macrophages
Authors: Wei Jiawei , Ning Huan , Ramos‐Espinosa Octavio , Eickhoff Christopher S. , Hou Rong , Wang Qinghong , Fu Mingui , Liu Ethan Y. , Fan Daping , Hoft Daniel F. , Liu Jianguo
Published: June 2024

Immune evasion of Mycobacterium tuberculosis (Mtb) facilitates intracellular bacterial growth. The mechanisms of immune evasion, however, are still not fully understood. In this study, we reveal that tristetraprolin (TTP), one of the best characterized RNA‐binding proteins controlling the stability of targeted mRNAs, mediates innate immune evasion of mycobacteria. We found that TTP knockout mice displayed reduced bacterial burden in the early stage after Mtb aerosol challenge. Macrophages deficient in TTP also showed an inhibition in intracellular mycobacterial growth. Live mycobacteria induced TTP protein expression in macrophages, which was blocked by the mTOR inhibitor rapamycin. Rapamycin and AZD8055 specifically blocked 4EBP1 phosphorylation in infected macrophages and suppressed intracellular BCG growth. Rapamycin promoted TTP protein degradation through the ubiquitination pathway, whereas the proteasome inhibitor MG‐132 blocked rapamycin function and thus stabilized TTP protein. TTP induction suppressed the expression of iNOS/TNF‐α/IL‐12/IL‐23, and weakened protective immune responses in macrophages, whereas rapamycin enhanced the bactericidal effects through TTP inhibition. Moreover, blocking TTP binding increased the expression of TNF‐α and iNOS and suppressed intracellular mycobacterial growth. Overall, our study reveals a novel role for RNA‐binding protein TTP in Mtb immune evasion mechanisms and provides a potential target for host‐directed therapy against tuberculosis (TB).
NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion
Authors: Dahabieh Michael S. , DeCamp Lisa M. , Oswald Brandon M. , Kitchen-Goosen Susan M. , Fu Zhen , Vos Matthew , Compton Shelby E. , Longo Joseph , Williams Kelsey S. , Ellis Abigail E. , Johnson Amy , Sodiya Ibukunoluwa , Vincent Michael , Lee Hyoungjoo , Sheldon Ryan D. , Krawczyk Connie M. , Yao Chen , Wu Tuoqi , Jones Russell G.
Published: June 2024

The progressive decline of CD8 T cell effector function—also known as terminal exhaustion—is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Texterm) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+TIM-3+) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.

One Sentence Summary

The KEAP1-NRF2 pathway is hyperactivated in terminally exhausted CD8 T cells and drives T cell dysfunction via transcriptional regulation of the prostacyclin receptor,Ptgir.
Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors
Authors: Hegde Samarth , Giotti Bruno , Soong Brian Y. , Halasz Laszlo , Berichel Jessica Le , Magen Assaf , Kloeckner Benoit , Mattiuz Raphaël , Park Matthew D. , Marks Adam , Belabed Meriem , Hamon Pauline , Chin Theodore , Troncoso Leanna , Lee Juliana J. , Ahimovic Dughan , Bale Michael , Chung Grace , D’souza Darwin , Angeliadis Krista , Dawson Travis , Kim-Schulze Seunghee , Flores Raja M. , Kaufman Andrew J. , Ginhoux Florent , Josefowicz Steven Z. , Ma Sai , Tsankov Alexander M. , Marron Thomas U. , Brown Brian D. , Merad Miriam
Published: June 2024

ABSTRACT

Monocyte–derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs’ survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.
Repetitive Somatosensory Stimulation Shrinks The Body Image
Authors: Azaroual-Sentucq Malika , Macchione Silvia , Miller Luke E. , Koun Eric , Salemme Romeo , Longo Matthew R. , Muret Dollyane , Farnè Alessandro
Published: June 2024

Current models of mental body representations (MBRs) indicate that tactile inputs feed several of them for different functions, implying that altering tactile inputs may affect MBRs differently. Here we tested this hypothesis by leveraging Repetitive Somatosensory Stimulation (RSS), known to improve tactile perception by modulating primary somatosensory cortex (SI) activity, and measured its effects over thebody image, thebody modeland thesuperficial schemain a randomized sham-controlled, double-blind cross-over study. Results show that RSS affected thebody image, participants perceiving their finger size as being smaller after RSS. While previous work showed increase of finger size perception after tactile anesthesia (Gandevia & Phegan 1999), these findings reveal that tactile inputs can diametrically modulate the body image. In contrast, RSS did not alter thebody modelorsuperficial schema. In addition, we report a novel mislocalization pattern, with a bias towards the middle finger in the distal phalanges that reverses towards the thumb in the proximal phalanx, enriching the known distortions of thesuperficial schema. Overall, these findings provide novel insights into the functional organization of MBRs and their relationships with somatosensory information. Reducing the perceived body size through RSS could be useful in helping treat body image disturbance.
Anti-Toxoplasma gondii screening of eight species and bio-guided identification of metabolites of Elaeis guineensis leaves, a preliminary study
Authors: Ouattara Nangouban , Magid Abdulmagid Alabdul , Escotte-Binet Sandie , Yao-Kouassi Philomène Akoua , Villena Isabelle , Voutquenne-Nazabadioko Laurence
Published: June 2024

The apicomplexan parasite Toxoplasma gondii causes toxoplasmosis, a ubiquitous and cosmopolitan parasitosis, generally asymptomatic and potentially dangerous for the fetus and highly immunocompromised patients. Pyrimethamine and sulfadiazine, supplemented with folic acid, are the drugs of choice to treating the disease, but they produce severe side effects and treatments fail due to drug resistance. New anti-Toxoplasma compounds are needed, and natural compounds can be a good source for obtaining them. The antiparasitic activity of 40 polar and non-polar extracts of eight antiparasitic medicinal plants used in Côte d'Ivoire, and selected based on ethnopharmacological survey, were evaluated in vitro against T. gondii. Among them, the hydromethanolic extract of the Elaeis guineensis leaves exhibited the best parasite growth inhibition (94% ± 0.07) at 25 μg/mL without being cytotoxic at the same dose. The fractionation of this extract did not allow the recovery of antitoxoplasmic activity in its individualized fractions. The13C-NMR based dereplication of the produced fractions and the purification of one of them highlighted the presence of saccharides, terpenes, flavonoids, cardanols and aliphatic acids. The obtained clusters of13C chemical shifts were assigned to their corresponding molecular structures with the help of open online databases, resulting in nine unambiguously identified compounds, whereas the purification of one of these fractions led to the identification of palmitic acid (10), palmitic acid methyl ester (11), 3-[12(E)-pentadecenyl]phenol (12), 3-[14(E)-heptadecenyl]phenol (13), ursolic acid (14) and stigmasta-4,24(28)-dien-3-one (15). A synergistic effect between these metabolites is thought to be responsible for the anti-Toxoplasma activity.
An Investigation of Parameter-Dependent Cell-Type Specific Effects of Transcranial Focused Ultrasound Stimulation Using an Awake Head-Fixed Rodent Model
Authors: Ramachandran Sandhya , Gao Huan , Yttri Eric , Yu Kai , He Bin
Published: June 2024

Transcranial focused ultrasound (tFUS) is a promising neuromodulation technique able to target shallow and deep brain structures with high precision. Previous studies have demonstrated that tFUS stimulation responses are both cell-type specific and controllable through altering stimulation parameters. Specifically, tFUS can elicit time-locked neural activity in regular spiking units (RSUs) that is sensitive to increases in pulse repetition frequency (PRF), while time-locked responses are not seen in fast spiking units (FSUs). These findings suggest a unique capability of tFUS to alter circuit network dynamics with cell-type specificity; however, these results could be biased by the use of anesthesia, which significantly modulates neural activities. In this study, we develop an awake head-fixed rat model specifically designed for tFUS study, and address a key question if tFUS still has cell-type specificity under awake conditions. Using this novel animal model, we examined a series of PRFs and burst duty cycles (DCs) to determine their effects on neuronal subpopulations without anesthesia. We conclude that cell-type specific time-locked and delayed responses to tFUS as well as PRF and DC sensitivity are present in the awake animal model and that despite some differences in response, isoflurane anesthesia is not a major confound in studying the cell-type specificity of ultrasound neuromodulation. We further determine that, in an awake, head-fixed setting, the preferred PRF and DC for inducing time-locked excitation with our pulsed tFUS paradigm are 1500 Hz and 60%, respectively.
The DivisionCounter, a method for counting large ranges of cell divisionsin vivo,reveals cell dynamics of leukemic cell killing via CAR-T therapy
Authors: Hustin Lucie S P , Conrad Cecile , Liu Chang , Fuentealba Jaime , Menegatti Silvia , Shneer Seva , Battistella Aude , Tabarin Fanny , Weber Tom S , Amigorena Sebastian , Duffy Ken R , Perié Leïla
Published: June 2024

Cell division drives multicellular growth and its dysregulation can cause disease. While approximately 44 divisions are needed to produce without death all 1013cells in the human body, current methods are limited to count 10 cell divisionsin vivoacross diverse mammalian cell types. Here we introduce the DivisionCounter, a method to count cell divisionin vivoover large division ranges (∼70 divisions) using an easy fluorescence readout. We demonstrate that the DivisionCounter accurately measures the average cell division count of cells bothin vitroandin vivo. Its use revealed that leukemia tumor division rates are independent of the organ’s specific microenvironment and CAR-T cell treatment, providing an estimate of tumor death ratesin vivo. The DivisionCounter method holds unique potential for quantifying contributions of cell division, death, and migration to the growth of healthy and pathological mammalian tissues.