Clin Kidney J. 2024 Oct 4;17(11):sfae299. doi: 10.1093/ckj/sfae299. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Obinutuzumab is a humanized and glycoengineered anti-CD20 monoclonal antibody that has been shown to induce more profound B-cell depletion than rituximab. The effectiveness and safety of obinutuzumab in the treatment of membranous nephropathy remain unclear.

METHODS: This was a retrospective study conducted in Huashan Hospital, Fudan University between 1 December 2021 and 30 November 2023. Patients with membranous nephropathy were included to assess the effectiveness and safety of obinutuzumab and prevalence of severe pneumonia during the outbreak of COVID-19 in China.

RESULTS: Eighteen patients were included in the study assessing the effectiveness of obinutuzumab. After a 12-month follow-up, 14 patients (78%) achieved remission, with six (33%) achieving complete remission and eight (44%) achieving partial remission. Among the 18 obinutuzumab-treated patients contracting COVID-19 for the first time, six (33%) developed severe pneumonia, and one died. By contrast, two of the 37 patients receiving glucocorticoids combined with cyclophosphamide, and none of the 44 patients on calcineurin inhibitors or the 46 patients on rituximab developed severe pneumonia. However, compared to patients receiving rituximab or glucocorticoids plus cyclophosphamide, the obinutuzumab-treated patients had a longer duration of membranous nephropathy and immunosuppressive therapy. Therefore, cardinal matching was employed to balance these baseline characteristics. Owing to small sample size for each regimen, patients receiving all the three non-obinutuzumab immunosuppressive regimens were grouped as a control cohort. After matching for age, gender, remission status, duration of membranous nephropathy, duration of immunosuppressive therapy, and ongoing immunosuppression, the obinutuzumab-treated patients still had a significantly higher incidence of severe pneumonia compared to those on other regimens (P = .019).

CONCLUSION: Obinutuzumab was an effective treatment option for patients with membranous nephropathy. On the other hand, it was associated with a higher incidence of severe pneumonia following COVID-19 infection compared to other immunosuppressive regimens.

PMID:39507289 | PMC:PMC11540158 | DOI:10.1093/ckj/sfae299

iScience. 2024 Sep 23;27(11):111017. doi: 10.1016/j.isci.2024.111017. eCollection 2024 Nov 15.

ABSTRACT

Homeostasis is necessary for epithelia to maintain barrier function and prevent the accumulation of defective cells. Unfit, excess, and dying cells in the larval zebrafish tail fin epidermis are removed via controlled cell death and extrusion. Extrusion coincides with oscillations of cell area, both in the extruding cell and its neighbors. Here, we develop a biophysical model of this process to explore the role of autonomous and non-autonomous mechanics. We vary biophysical properties and oscillatory behaviors of extruding cells and their neighbors along with tissue-wide cell density and viscosity. We find that cell autonomous processes are major contributors to the dynamics of extrusion, with the mechanical microenvironment providing a less pronounced contribution. We also find that some cells initially resist extrusion, influencing the duration of the expulsion process. Our model provides insights into the cellular dynamics and mechanics that promote elimination of unwanted cells from epithelia during homeostatic tissue maintenance.

PMID:39507245 | PMC:PMC11539584 | DOI:10.1016/j.isci.2024.111017

iScience. 2024 Oct 11;27(11):111156. doi: 10.1016/j.isci.2024.111156. eCollection 2024 Nov 15.

ABSTRACT

Inhibitory synaptic neurotransmission mediated by GABA requires a low concentration of chloride ions (Cl-) in neurons, which is established and maintained by the potassium-chloride co-transporter 2 (KCC2). While KCC2-interacting proteins are known to regulate KCC2 protein level and function, specific KCC2-interacting partners are still being identified and characterized. We asked whether SNAP25, an integral component of the SNARE-complex and a novel KCC2 interactor, regulates KCC2 protein and function in mice. We demonstrated that SNAP25 interacts with KCC2, and that this interaction is regulated by protein kinase C (PKC)-mediated phosphorylation. We also discovered that SNAP25 knockdown decreases total KCC2 in cortical neurons, and reduces the strength of synaptic inhibition, as demonstrated through a depolarization of the reversal potential for GABA (EGABA), indicating reduced KCC2 function. Our biochemical and electrophysiological data combined demonstrate that SNAP25 regulates KCC2 membrane expression and function, and in doing so, regulates inhibitory synaptic transmission.

PMID:39507243 | PMC:PMC11539599 | DOI:10.1016/j.isci.2024.111156

Transl Lung Cancer Res. 2024 Oct 31;13(10):2746-2760. doi: 10.21037/tlcr-24-716. Epub 2024 Oct 17.

ABSTRACT

BACKGROUND: Glycolysis proved to have a prognostic value in lung cancer; however, to identify glycolysis-related genomic markers is expensive and challenging. This study aimed at identifying glycolysis-related computed tomography (CT) radiomics features to develop a deep-learning prognostic model for non-small cell lung cancer (NSCLC).

METHODS: The study included 274 NSCLC patients from cohorts of The Second Affiliated Hospital of Soochow University (SZ; n=64), the Cancer Genome Atlas (TCGA)-NSCLC dataset (n=74), and the Gene Expression Omnibus dataset (n=136). Initially, the glycolysis enrichment scores were evaluated using a single-sample gene set enrichment analysis, and the cut-off values were optimized to investigate the prognostic potential of glycolysis genes. Radiomic features were then extracted using LIFEx software. The least absolute reduction and selection operator (LASSO) algorithm was employed to determine the glycolytic CT radiomics features. A deep-learning prognostic model was constructed by integrating CT radiomics and clinical features. The biological functions of the model were analyzed by incorporating RNA sequencing data.

RESULTS: Kaplan-Meier curves indicated that elevated glycolysis levels were associated with poorer survival outcomes. The LASSO algorithm identified 11 radiomic features that were then selected for inclusion in the deep-learning model. They have shown significant discrimination capability in assessing glycolysis status, achieving an area under the curve value of 0.8442. The glycolysis-based radiomics deep-learning model was named the DeepGR model. This model was able to effectively predict the clinical outcomes of NSCLC patients with AUCs of 0.8760 and 0.8259 in the SZ and TCGA cohorts, respectively. High-risk DeepGR scores were strongly associated with poor overall survival, resting memory CD4+ T cells, and a high response to programmed cell death protein 1 immunotherapy.

CONCLUSIONS: The DeepGR model effectively predicted the prognosis of NSCLC patients.

PMID:39507025 | PMC:PMC11535831 | DOI:10.21037/tlcr-24-716

Alzheimers Res Ther. 2024 Nov 6;16(1):245. doi: 10.1186/s13195-024-01611-8.

ABSTRACT

BACKGROUND: Facial aging, cognitive impairment, and dementia are all age-related conditions. However, the temporal relation between facial age and future risk of dementia was not systematically examined.

OBJECTIVES: To investigate the relationship between facial age (both subjective/perceived and objective) and cognitive impairment and/or dementia risk.

METHODS: The study included 195,329 participants (age ≥ 60 y) from the UK Biobank (UKB) with self-perceived facial age and 612 participants from the Nutrition and Health of Aging Population in China Project (NHAPC) study (age ≥ 56 y) with objective assessment of facial age. Cox proportional hazards model was used to prospectively examine the hazard ratios (HRs) and their 95% confidence intervals (CIs) of self-perceived facial age and dementia risk in the UKB, adjusting for age, sex, education, APOE ε4 allele, and other potential confounders. Linear and logistic regressions were performed to examine the cross-sectional association between facial age (perceived and objective) and cognitive impairment in the UKB and NHAPC, with potential confounders adjusted.

RESULTS: During a median follow-up of 12.3 years, 5659 dementia cases were identified in the UKB. The fully-adjusted HRs comparing high vs. low perceived facial age were 1.61 (95% CI, 1.33 ~ 1.96) for dementia (P-trend ≤ 0.001). Subjective facial age and cognitive impairment was also observed in the UKB. In the NHAPC, facial age, as assessed by three objective wrinkle parameters, was associated with higher odds of cognitive impairment (P-trend < 0.05). Specifically, the fully-adjusted OR for cognitive impairment comparing the highest versus the lowest quartiles of crow's feet wrinkles number was 2.48 (95% CI, 1.06 ~ 5.78).

CONCLUSIONS: High facial age was associated with cognitive impairment, dementia and its subtypes after adjusting for conventional risk factors for dementia. Facial aging may be an indicator of cognitive decline and dementia risk in older adults, which can aid in the early diagnosis and management of age-related conditions.

PMID:39506848 | DOI:10.1186/s13195-024-01611-8

BMC Proc. 2024 Nov 7;18(Suppl 20):25. doi: 10.1186/s12919-024-00307-z.

ABSTRACT

The Tri-Service Microbiome Consortium (TSMC) was founded to enhance collaboration, coordination, and communication of microbiome research among DoD organizations and to facilitate resource, material and information sharing among consortium members, which includes collaborators in academia and industry. The 2023 annual symposium was a hybrid meeting held in Washington DC on 26-27 September 2023 concurrent with the virtual attendance, with oral and poster presentations and discussions centered on microbiome-related topics within five broad thematic areas: 1) Environmental Microbiome Characterization; 2) Microbiome Analysis; 3) Human Microbiome Characterization; 4) Microbiome Engineering; and 5) In Vitro and In Vivo Microbiome Models. Collectively, the symposium provided an update on the scope of current DoD and DoD-affiliated microbiome research efforts and fostered collaborative opportunities. This report summarizes the presentations and outcomes of the 7th annual TSMC symposium.

PMID:39506745 | DOI:10.1186/s12919-024-00307-z

BMC Plant Biol. 2024 Nov 6;24(1):1050. doi: 10.1186/s12870-024-05713-1.

ABSTRACT

The physical appearance of date palm (Phoenix dactylifera) fruit (dates) is important for its market value. Many date-producing countries experience significant financial losses due to the poor appearance of the fruit, skin separation or puffiness being a major reason. Previous research showed evidence linking the skin separation phenotype to environmental conditions. To investigate this further, a genome-wide association study was conducted using genome data from 199 samples collected from 14 countries. Here, we identified nine genetic loci associated with this phenotype and investigated genes in these regions that may contribute to the phenotype overall. Multiple genes in the associated regions have functional responses to growth regulators and are involved in cell wall development and modification. Analysis of gene expression data shows many are expressed during fruit development. We show that there are both environmental and genetic contributions to the fruit skin separation phenotype. Our results indicate that different date cultivars exhibit varying degrees of skin separation despite genetic similarities or differences. However, genetically different cultivars show extreme differences compared to the phenotype variation between genetically similar cultivars. We demonstrate that beyond environmental factors, genetics is a strong contributor to the most extreme skin separation in some cultivars. Identifying the genetic factors may help better understand the biology and pathways that lead to the environmental effects on skin separation and improve commercial date production. In conclusion, our key finding is that both environmental and genetic factors contribute to skin separation variation, and improvements in environmental factors alone cannot overcome the extreme level of variation observed in some cultivars.

PMID:39506645 | DOI:10.1186/s12870-024-05713-1

Pediatrics. 2024 Nov 7:e2023064771. doi: 10.1542/peds.2023-064771. Online ahead of print.

ABSTRACT

CONTEXT: Mixed evidence exists on whether physical exercise interventions influence intelligence measures in children and adolescents.

OBJECTIVE: To determine the effect of exercise interventions on intelligence in children and adolescents.

DATA SOURCES: Relevant articles were identified in PubMed, Web of Science, PsycINFO, and Scopus (until February 22, 2024).

STUDY SELECTION: Randomized controlled trials assessing the effects of exercise interventions on intelligence in youth (≤19 years).

DATA EXTRACTION: A random-effects meta-analysis was performed for intelligence measures reported in ≥3 studies. Subanalyses examined the moderating effect of variables such as participants' intelligence quotient (IQ), age, or intervention duration.

RESULTS: Fourteen randomized controlled trials (n = 3203 participants; age range = 5-14 years) were included. Exercise interventions significantly improved general intelligence compared with control groups (standardized mean difference = 0.54, 95% confidence interval [CI] = 0.11-0.97, P = .01), which corresponded to a mean improvement in the IQ score of 4.0 points (95% CI = 1.44-6.64, P = .01). Significant benefits of exercise interventions were also observed for fluid intelligence (standard mean difference = 0.20, 95% CI = 0.06-0.34, P = .006). Crystallized intelligence could not be meta-analyzed because of a lack of studies. Subanalyses revealed similar benefits in participants with low/borderline versus normal IQ, children versus adolescents, and interventions with different durations.

LIMITATIONS: The heterogeneity observed in the characteristics of the exercise interventions and the populations included can be a potential confounding factor.

CONCLUSIONS: Exercise interventions are associated with improvements in intelligence (including both general and fluid intelligence) in youth.

PMID:39506553 | DOI:10.1542/peds.2023-064771

Nature. 2024 Nov 6. doi: 10.1038/s41586-024-08132-2. Online ahead of print.

ABSTRACT

The phosphorylation of synaptic proteins is a significant biochemical reaction that controls the sleep-wake cycle in mammals1-3. Protein phosphorylation in vivo is reversibly regulated by kinases and phosphatases. In this study, we investigate a pair of kinases and phosphatases that reciprocally regulate sleep duration. First, we perform a comprehensive screen of protein kinase A (PKA) and phosphoprotein phosphatase (PPP) family genes by generating 40 gene knockout mouse lines using prenatal and postnatal CRISPR targeting. We identify a regulatory subunit of PKA (Prkar2b), a regulatory subunit of protein phosphatase 1 (PP1; Pppr1r9b) and catalytic and regulatory subunits of calcineurin (also known as PP2B) (Ppp3ca and Ppp3r1) as sleep control genes. Using adeno-associated virus (AAV)-mediated stimulation of PKA and PP1-calcineurin activities, we show that PKA is a wake-promoting kinase, whereas PP1 and calcineurin function as sleep-promoting phosphatases. The importance of these phosphatases in sleep regulation is supported by the marked changes in sleep duration associated with their increased and decreased activities, ranging from approximately 17.3 h per day (PP1 expression) to 4.3 h per day (postnatal CRISPR targeting of calcineurin). Localization signals to the excitatory post-synapse are necessary for these phosphatases to exert their sleep-promoting effects. Furthermore, the wake-promoting effect of PKA localized to the excitatory post-synapse negated the sleep-promoting effect of PP1-calcineurin. These findings indicate that PKA and PP1-calcineurin have competing functions in sleep regulation at excitatory post-synapses.

PMID:39506111 | DOI:10.1038/s41586-024-08132-2

Nature. 2024 Nov 6. doi: 10.1038/s41586-024-08124-2. Online ahead of print.

ABSTRACT

Persister cells, rare phenotypic variants that survive normally lethal levels of antibiotics, present a major barrier to clearing bacterial infections1. However, understanding the precise physiological state and genetic basis of persister formation has been a longstanding challenge. Here we generated a high-resolution single-cell2 RNA atlas of Escherichia coli growth transitions, which revealed that persisters from diverse genetic and physiological models converge to transcriptional states that are distinct from standard growth phases and instead exhibit a dominant signature of translational deficiency. We then used ultra-dense CRISPR interference3 to determine how every E. coli gene contributes to persister formation across genetic models. Among critical genes with large effects, we found lon, which encodes a highly conserved protease4, and yqgE, a poorly characterized gene whose product strongly modulates the duration of post-starvation dormancy and persistence. Our work reveals key physiologic and genetic factors that underlie starvation-triggered persistence, a critical step towards targeting persisters in recalcitrant bacterial infections.

PMID:39506104 | DOI:10.1038/s41586-024-08124-2

Nat Cell Biol. 2024 Nov 6. doi: 10.1038/s41556-024-01548-y. Online ahead of print.

ABSTRACT

RNA modification has emerged as an important epigenetic mechanism that controls abnormal metabolism and growth in acute myeloid leukaemia (AML). However, the roles of RNA N4-acetylcytidine (ac4C) modification in AML remain elusive. Here, we report that ac4C and its catalytic enzyme NAT10 drive leukaemogenesis and sustain self-renewal of leukaemic stem cells/leukaemia-initiating cells through reprogramming serine metabolism. Mechanistically, NAT10 facilitates exogenous serine uptake and de novo biosynthesis through ac4C-mediated translation enhancement of the serine transporter SLC1A4 and the transcription regulators HOXA9 and MENIN that activate transcription of serine synthesis pathway genes. We further characterize fludarabine as an inhibitor of NAT10 and demonstrate that pharmacological inhibition of NAT10 targets serine metabolic vulnerability, triggering substantial anti-leukaemia effects both in vitro and in vivo. Collectively, our study demonstrates the functional importance of ac4C and NAT10 in metabolism control and leukaemogenesis, providing insights into the potential of targeting NAT10 for AML therapy.

PMID:39506072 | DOI:10.1038/s41556-024-01548-y

Sci Rep. 2024 Nov 6;14(1):26951. doi: 10.1038/s41598-024-77575-4.

ABSTRACT

Compounds that can induce oxidative stress in cancer cells while remaining nontoxic to healthy cells are extremely promising for potential anticancer drugs. 2,2':6',2''-terpyridine-metal complexes possess these properties. The high level of activity (IC50 = 0.605 µM) of 2,2':6',2''-terpyridine-metal complexes on lung, breast, pancreatic, and glioblastoma multiforme cancer lines and their selectivity (SI > 41.32) on human normal fibroblasts were confirmed and presented in this paper. The mechanism of action of these compounds is associated with the generation of reactive oxygen species, which affects several cellular pathways and signals. The results demonstrate that 2,2':6',2''-terpyridine-metal complexes affect cell cycle inhibition in the G0/G1 phase as well as the activation of apoptosis and autophagy cell death. These results were confirmed in several independent studies, including experiments measuring the fluorescence levels of reactive oxygen species, flow cytometry, and gene and protein analysis.

PMID:39505960 | DOI:10.1038/s41598-024-77575-4

NPJ Vaccines. 2024 Nov 6;9(1):211. doi: 10.1038/s41541-024-01007-7.

ABSTRACT

Rotaviruses pose a significant threat to young children. To identify novel pro- and anti-rotavirus host factors, we performed genome-wide CRISPR/Cas9 screens using rhesus rotavirus and African green monkey cells. Genetic deletion of either SERPINB1 or TMEM236, the top two antiviral factors, in MA104 cells increased virus titers in a rotavirus strain independent manner. Using this information, we optimized the existing rotavirus reverse genetics systems by combining SERPINB1 knockout MA104 cells with a C3P3-G3 helper plasmid. We improved the recovery efficiency and rescued several low-titer rotavirus reporter and mutant strains that prove difficult to rescue otherwise. Furthermore, we demonstrate that TMEM236 knockout in Vero cells supported higher yields of two live-attenuated rotavirus vaccine strains than the parental cell line and represents a more robust vaccine-producing cell substrate. Collectively, we developed a third-generation optimized rotavirus reverse genetics system and generated gene-edited Vero cells as a new substrate for improving rotavirus vaccine production.

PMID:39505878 | DOI:10.1038/s41541-024-01007-7

Cell Mol Neurobiol. 2024 Nov 6;44(1):74. doi: 10.1007/s10571-024-01504-2.

ABSTRACT

The global public health addiction crisis has been stark, with over 932,400 deaths in the USA and Canada from opioid overdose since 1999-2020, surpassing the mortality rates at the top of the HIV/AIDS epidemic. Both nations exhibit opioid consumption rates significantly above the norm for developed countries. Analgesic type of opioids present both therapeutic benefits and substantial health risks, necessitating balanced drug regulation, careful prescribing, and dedicated opioid stewardship. The role of the cytochrome P450 2D6 (CYP2D6) system (Enzymatic functions) in metabolizing opioids highlights the potential of genotype-guided analgesia. By integrating Pharmacogenomics (PGx), this approach aims to optimize pain management, enhance safety, and reduce addiction risks. This understanding prompted the utilization of multifactor dimensionality reduction (MDR) to explore a range of phenotypes including PGx and gene-gene interactions (GGI) in a healthy cohort, thereby personalizing pain management strategies. The study sampled 100 unrelated healthy Western Iranians and 100 individuals from the 1000 Genome Project. Pre-testing involved searching for PGx annotations (variants associated with drug-gene-diseases) related to pain sensitivity and inflammation using the PharmGKB database, which identified 128 relevant genes. A questionnaire helped select 100 participants who had never used potent opioids but also other psychoactive agents (e.g., nicotine, amphetamines, etc.) and disease-related drugs. Whole-exome sequencing (WES) was then employed to analyze these genes in an Iranian cohort. Further analyses included MDR for identifying synergistic gene annotations and GGI for exploring complex gene interactions through the Visualization of Statistical Epistasis Networks (ViSEN). The study identified a Pain, Anti-Inflammatory, and Immunomodulating agents (PAIma) panel from the 128 genes, resulting in 55,590 annotations across 21 curated pathways. After filtering, 54 significant structural or regulatory variants were identified. This research also highlighted novel gene relationships involving the CYP3A5 gene, hsa-miR-355-5p, Paliperidone, and CYP2D6, which warrant further investigation. This study offers a novel pharmacogenetic framework that could potentially transform opioid prescribing practices to mitigate misuse and enhance personalized pain management. Further validation of these findings from multi countries and ethnic groups could guide clinicians in implementing DNA-based opioid prescribing, aligning treatment more closely with individual genetic profiles.

PMID:39505757 | DOI:10.1007/s10571-024-01504-2

J Adv Res. 2024 Nov 4:S2090-1232(24)00494-6. doi: 10.1016/j.jare.2024.11.002. Online ahead of print.

ABSTRACT

BACKGROUND: Roots perform multifaceted functions in plants including the movement of nutrients and water, sensing stressors, shaping microbiome, and providing structural support. How roots perceive and respond above traits at the molecular level remains largely unknown. Although crop development has greatly advanced, most current efforts have concentrated on above-ground traits leaving significant knowledge gaps in root biology. Also, studying root system architecture (RSA) is more difficult due to its intricacy and the difficulties of observing them during plant life cycle. However, with the aid of high throughput phenotyping and genotyping tools many developmental and stress-mediated regulation of RSA has emerged in both model and crop plants leading to new insights in root biology. Our current understanding of upstream signaling events (cell wall, apoplast) in roots and how they are interconnected with downstream signaling cascades has largely been constrained by the fact that most research in plant systems concentrates on cytosolic signal transduction pathways while ignoring the early perception by cells' exterior parts. In this regard, we discussed the role of FERONIA (FER) a cell wall receptor-like kinase (RLK) which acts as a sensor and a bridge between apoplast and cytosolic signaling pathways in root biology.

AIM OF THE REVIEW: The goal of this study is to provide valuable insights into present understanding and future research perspectives on how FER regulates distinct root responses related to growth and adaptation.

KEY SCIENTIFIC CONCEPTS OF REVIEW: In plants, FER is a unique RLK because it can act as a multitasking sensor regulate diverse growth, and adaptive traits. In this review, we mainly highlighted its role in root biology like how it modulates distinct root responses such as root development, sensing abiotic stressors, mechanical stimuli, nutrient transport, and shaping microbiome. Further, we provided an update on how FER controls root traits by involving RALF peptides, calcium, ROS and hormones. We also highlight number of outstanding questions in FER mediated root responses that warrant future investigation. We believe that FER can provide novels insights for the development of future climate resilient and high yielding crops based on the modified root system.

PMID:39505145 | DOI:10.1016/j.jare.2024.11.002

Eur J Med Chem. 2024 Nov 2;281:117027. doi: 10.1016/j.ejmech.2024.117027. Online ahead of print.

ABSTRACT

Tumors and angiogenesis are connected through a complex interplay. VEGF165, generated from both tumor and vascular endothelial cells, serves as a mutual benefit for both cell types. Therapeutic approaches modulating VEGF165 have been proposed as promising antitumor therapies. PROTACs are bifunctional molecules that exploit the intracellular ubiquitin-proteasome system to degrade specific proteins. To date, there are no targeted PROTACs designed to degrade VEGF165 in both tumor and vascular endothelial cells. The aptamer AS1411 is notable for its ability to selectively recognize and enter both tumor and vascular endothelial cells by targeting the cell surface nucleolin (NCL). Moreover, AS1411 has also been repurposed as an intracellular recruiter of E3 ligase MDM2 via leveraging NCL as a molecular bridge. In this study, we conjugated AS1411 with a VEGF165-specific aptamer V7t1, creating hybrid aptamers-engineered PROTACs. The PROTACs demonstrate remarkable selectivity for both tumor and vascular endothelial cells and facilitate the ubiquitination and proteasomal degradation of VEGF165. The PROTACs inhibit the growth of tumor cells and also impede angiogenesis, without causing toxicity to normal tissues. The hybrid aptamers-engineered PROTACs provide an avenue for disrupting the tumor-angiogenesis interplay through modulation of VEGF165 in both tumor and vascular endothelial cells.

PMID:39504794 | DOI:10.1016/j.ejmech.2024.117027

Biophys Chem. 2024 Oct 29;316:107346. doi: 10.1016/j.bpc.2024.107346. Online ahead of print.

ABSTRACT

Repression of msl-2 mRNA translation is essential for viability of Drosophila melanogaster females to prevent hypertranscription of both X chromosomes. This translational control event is coordinated by the female-specific protein Sex-lethal (Sxl) which recruits the RNA binding proteins Unr and Hrp48 to the 3' untranslated region (UTR) of the msl-2 transcript and represses translation initiation. The mechanism exerted by Hrp48 during translation repression and its interaction with msl-2 are not well understood. Here we investigate the RNA binding specificity and affinity of the tandem RNA recognition motifs of Hrp48. Using NMR spectroscopy, molecular dynamics simulations and isothermal titration calorimetry, we identified the exact region of msl-2 3' UTR recognized by Hrp48. Additional biophysical experiments and translation assays give further insights into complex formation of Hrp48, Unr, Sxl and RNA. Our results show that Hrp48 binds independent of Sxl and Unr downstream of the E and F binding sites of Sxl and Unr to msl-2.

PMID:39504588 | DOI:10.1016/j.bpc.2024.107346

Sci Adv. 2024 Nov 8;10(45):eadm8212. doi: 10.1126/sciadv.adm8212. Epub 2024 Nov 6.

ABSTRACT

Mitochondrial dynamics orchestrate many essential cellular functions, including metabolism, which is instrumental in promoting cancer growth and metastatic progression. However, how mitochondrial dynamics influences metastatic progression remains poorly understood. Here, we show that breast cancer cells with low metastatic potential exhibit a more fused mitochondrial network compared to highly metastatic cells. To study the impact of mitochondrial dynamics on metastasis, we promoted mitochondrial elongation in metastatic breast cancer cells by individual genetic deletion of three key regulators of mitochondrial fission (Drp1, Fis1, Mff) or by pharmacological intervention with leflunomide. Omics analyses revealed that mitochondrial elongation causes substantial alterations in metabolic pathways and processes related to cell adhesion. In vivo, enhanced mitochondrial elongation by loss of mitochondrial fission mediators or treatment with leflunomide notably reduced metastasis formation. Furthermore, the transcriptomic signature associated with elongated mitochondria correlated with improved clinical outcome in patients with breast cancer. Overall, our findings highlight mitochondrial dynamics as a potential therapeutic target in breast cancer.

PMID:39504368 | DOI:10.1126/sciadv.adm8212

Cell Rep. 2024 Nov 5;43(11):114913. doi: 10.1016/j.celrep.2024.114913. Online ahead of print.

ABSTRACT

Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic clock that predicts biological age. Network analysis of the age-associated metabolites reveals a critical role of essential fatty acids to connect lipids with other metabolic processes. These results characterize many metabolites involved in aging and point to nutrition as a source of intervention for healthy aging therapeutics.

PMID:39504246 | DOI:10.1016/j.celrep.2024.114913

Cell Rep. 2024 Nov 5;43(11):114930. doi: 10.1016/j.celrep.2024.114930. Online ahead of print.

ABSTRACT

Immunomodulatory variants that lead to the loss or gain of specific protein interactions often manifest only as organismal phenotypes in infectious disease. Here, we propose a network-based approach to integrate genetic variation with a structurally resolved human protein interactome network to prioritize immunomodulatory variants in COVID-19. We find that, in addition to variants that pass genome-wide significance thresholds, variants at the interface of specific protein-protein interactions, even though they do not meet genome-wide thresholds, are equally immunomodulatory. The integration of these variants with single-cell epigenomic and transcriptomic data prioritizes myeloid and T cell subsets as the most affected by these variants across both the peripheral blood and the lung compartments. Of particular interest is a common coding variant that disrupts the OAS1-PRMT6 interaction and affects downstream interferon signaling. Critically, our framework is generalizable across infectious disease contexts and can be used to implicate immunomodulatory variants that do not meet genome-wide significance thresholds.

PMID:39504244 | DOI:10.1016/j.celrep.2024.114930