Plant immunity suppression via PHR1-RALF-FERONIA shapes the root microbiome to alleviate phosphate starvation.

The microbiome plays an important role in shaping plant growth and immunity, but few plant genes and pathways impacting plant microbiome composition have been reported. In Arabidopsis thaliana, the phosphate starvation response (PSR) was recently found to modulate the root microbiome upon phosphate (Pi) starvation through the transcriptional regulator PHR1. Here, we report that A. thaliana PHR1 directly binds to the promoters of rapid alkalinization factor (RALF) genes, and activates their expression under phosphate-starvation conditions. RALFs in turn suppress complex formation of pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) receptor through FERONIA, a previously-identified PTI modulator that increases resistance to certain detrimental microorganisms. Suppression of immunity via the PHR1-RALF-FERONIA axis allows colonization by specialized root microbiota that help to alleviate phosphate starvation by upregulating the expression of PSR genes. These findings provide a new paradigm for coordination of host-microbe homeostasis through modulating plant innate immunity after environmental perturbations.

SKOR1 mediates FER kinase-dependent invasive growth of breast cancer cells.

High expression of the non-receptor tyrosine kinase FER is an independent prognostic factor that correlates with poor survival in breast cancer patients. To investigate whether the kinase activity of FER is essential for its oncogenic properties, we developed an ATP analogue-sensitive knock-in allele (FERASKI). Specific FER kinase inhibition in MDA-MB-231 cells reduces migration and invasion, as well as metastasis when xenografted into a mouse model of breast cancer. Using the FERASKI system, we identified Ski family transcriptional corepressor 1 (SKOR1) as a direct FER kinase substrate. SKOR1 loss phenocopies FER inhibition, leading to impaired proliferation, migration and invasion, and inhibition of breast cancer growth and metastasis formation in mice. We show that SKOR1 Y234, a candidate FER phosphorylation site, is essential for FER-dependent tumor progression. Finally, our work suggests that the SKOR1 Y234 residue promotes Smad2/3 signaling through SKOR1 binding to Smad3. Our study thus identifies SKOR1 as a mediator of FER-dependent progression of high-risk breast cancers.

Development of the nonreceptor tyrosine kinase FER-targeting PROTACs as a potential strategy for antagonizing ovarian cancer cell motility and invasiveness.

Aberrant overexpression of nonreceptor tyrosine kinase FER (Fps/Fes Related) has been reported in various ovarian carcinoma-derived tumor cells and is a poor prognosis factor for patient survival. It plays an essential role in tumor cell migration and invasion, acting concurrently in both kinase-dependent and -independent manners, which is not easily suppressed by conventional enzymatic inhibitors. Nevertheless, the PROteolysis-TArgeting Chimera (PROTAC) technology offers superior efficacy over traditional activity-based inhibitors by simultaneously targeting enzymatic and scaffold functions. Hence in this study, we report the development of two PROTAC compounds that promote robust FER degradation in a cereblon-dependent manner. Both PROTAC degraders outperform a Food and Drug Administration-approved drug, brigatinib, in ovarian cancer cell motility suppression. Importantly, these PROTAC compounds also degrade multiple oncogenic FER fusion proteins identified in human tumor samples. These results lay an experimental foundation to apply the PROTAC strategy to antagonize cell motility and invasiveness in ovarian and other types of cancers with aberrant expression of FER kinase and highlight PROTACs as a superior strategy for targeting proteins with multiple tumor-promoting functions.

Ferrostatin-1 ameliorates Cis-dichlorodiammineplatinum(II)-induced ovarian toxicity by inhibiting ferroptosis.

Cis-dichlorodiammineplatinum(II) (CDDP), while widely utilized in tumor therapy, results in toxic side effects that patients find intolerable. The specific mechanism by which CDDP inflicts ovarian damage remains unclear. This study aimed to explore the involvement of ferrostatin-1 (FER-1) and ferroptosis in CDDP-induced ovarian toxicity. This study established models of CDDP-induced injury in granulosa cells (GCs) and rat model of premature ovarian failure (POF). CCK-8 assessed the effects of CDDP and FER-1 on GC viability. FerroOrange and Mito-FerroGreen, DCFH-DA and MitoSox-Red, Rhodamine 123 and Transmission electron microscopy (TEM) measured Fe2+, reactive oxygen species (ROS), mitochondrial membrane potential and the mitochondrial morphology in GC cells, respectively. Serum hormone levels; organ indices; malondialdehyde, superoxide dismutase, and glutathione analyses; and western blotting were performed to examine ferroptosis's role in vitro. Molecular docking simulation was evaluated the interaction between FER-1 and GPX4 or FER-1 and NRF2. Molecular docking simulations were conducted to evaluate the interactions between FER-1 and GPX4, as well as FER-1 and NRF2. The findings revealed that CDDP-induced ovarian toxicity involved iron accumulation, increased ROS accumulation, and mitochondrial dysfunction, leading to endocrine disruption and tissue damage in rats. These changes correlated with NRF2, HO-1, and GPX4 levels. However, FER-1 decreased the extent of ferroptosis. Thus, ferroptosis appears to be a crucial mechanism of CDDP-induced ovarian injury, with GPX4 as potential protective targets.

HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer.

Ovarian cancer cells disseminate readily within the peritoneal cavity, which promotes metastasis, and are often resistant to chemotherapy. Ovarian cancer patients tend to present with advanced disease, which also limits treatment options; consequently, new therapies are required. The oncoprotein tyrosine kinase MET, which is the receptor for hepatocyte growth factor (HGF), has been implicated in ovarian tumorigenesis and has been the subject of extensive drug development efforts. Here, we report a novel ligand- and autophosphorylation-independent activation of MET through the nonreceptor tyrosine kinase feline sarcoma-related (FER). We demonstrated that the levels of FER were elevated in ovarian cancer cell lines relative to those in immortalized normal surface epithelial cells and that suppression of FER attenuated the motility and invasive properties of these cancer cells. Furthermore, loss of FER impaired the metastasis of ovarian cancer cells in vivo. Mechanistically, we demonstrated that FER phosphorylated a signaling site in MET: Tyr1349. This enhanced activation of RAC1/PAK1 and promoted a kinase-independent scaffolding function that led to recruitment and phosphorylation of GAB1 and the specific activation of the SHP2-ERK signaling pathway. Overall, this analysis provides new insights into signaling events that underlie metastasis in ovarian cancer cells, consistent with a prometastatic role of FER and highlighting its potential as a novel therapeutic target for metastatic ovarian cancer.

Vitamin D, Folate, Vitamin B12, and Iron Status in Pregnant/Postpartum Old Order Anabaptist Women in Southwestern Ontario.

Purpose: To assess vitamin D, folate, vitamin B12, and iron status in Old Order Anabaptist (OOA) pregnant/postpartum women.Methods: Blood was analyzed for plasma 25 hydroxy vitamin D (25(OH)D), red blood cell (RBC) folate, serum vitamin B12, and iron status indicators. Dietary intakes (food and supplements) from 3-day estimated records were compared to Dietary Reference Intakes and Canada's Food Guide (2007).Results: Fifty women participated in this descriptive cross-sectional study. Concentrations of 25(OH)D were low (<50 nmol/L for 20% and < 75 nmol/L for 63%); 42% had total vitamin D intakes < estimated average requirement (EAR). All women had RBC folate above the 1360 mmol/L cut-off. Nineteen percent had folate intakes upper limit. One woman had low serum vitamin B12 (<148 pmol/L); serum vitamin B12 was high (>652 pmol/L) for 24%. None had vitamin B12 intakes

The Fer tyrosine kinase protects sperm from spontaneous acrosome reaction.

The physiological acrosome reaction occurs after mammalian spermatozoa undergo a process called capacitation in the female reproductive tract. Only acrosome reacted spermatozoon can penetrate the egg zona-pellucida and fertilize the egg. Sperm also contain several mechanisms that protect it from undergoing spontaneous acrosome reaction (sAR), a process that can occur in sperm before reaching proximity to the egg and that abrogates fertilization. We previously showed that calmodulin-kinase II (CaMKII) and phospholipase D (PLD) are involved in preventing sAR through two distinct pathways that enhance F-actin formation during capacitation. Here, we describe a novel additional pathway involving the tyrosine kinase Fer in a mechanism that also prevents sAR by enhancing actin polymerization during sperm capacitation. We further show that protein-kinase A (PKA) and the tyrosine-kinase Src, as well as PLD, direct Fer phosphorylation/activation. Activated Fer inhibits the Ser/Thr phosphatase PP1, thereby leading to CaMKII activation, actin polymerization, and sAR inhibition.

The transcription factor POPEYE negatively regulates the expression of bHLH Ib genes to maintain iron homeostasis.

Iron (Fe) is an essential trace element for plants. When suffering from Fe deficiency, plants modulate the expression of Fe deficiency-responsive genes to promote Fe uptake. POPEYE (PYE) is a key bHLH (basic helix-loop-helix) transcription factor involved in Fe homeostasis. However, the molecular mechanism of PYE regulating the Fe deficiency response remains elusive in Arabidopsis. We found that the overexpression of PYE attenuates the expression of Fe deficiency-responsive genes. PYE directly represses the transcription of bHLH Ib genes (bHLH38, bHLH39, bHLH100, and bHLH101) by associating with their promoters. Although PYE contains an ethylene response factor-associated amphiphilic repression (EAR) motif, it does not interact with the transcriptional co-repressors TOPLESS/TOPLESS-RELATED (TPL/TPRs). Sub-cellular localization analysis indicated that PYE localizes in both the cytoplasm and nucleus. PYE contains a nuclear export signal (NES) which is required for the cytoplasmic localization of PYE. Mutation of the NES amplifies the repression function of PYE, resulting in down-regulation of Fe deficiency-responsive genes. Co-expression assays indicated that three bHLH IVc members (bHLH104, bHLH105/ILR3, and bHLH115) facilitate the nuclear accumulation of PYE. Conversely, PYE indirectly represses the transcription activation ability of bHLH IVc. Additionally, PYE directly negatively regulates its own transcription. This study provides new insights into the Fe deficiency response signalling pathway and enhances the understanding of PYE functions in Arabidopsis.

Fer-mediated activation of the Ras-MAPK signaling pathway drives the proliferation, migration, and invasion of endometrial carcinoma cells.

BACKGROUND: The role of Feline sarcoma-related protein (Fer) in various cancers has been extensively studied, but its specific involvement and underlying mechanisms in the progression of endometrial carcinoma (EC) are yet to be fully understood. METHODS: The expression levels of Fer were assessed in EC tissues and cell lines using real-time quantitative PCR and western blot analysis. CCK-8 assay, Edu staining, transwell assays, and flow cytometry, were conducted to evaluate the impact of Fer on EC cells. Furthermore, a mice xenograft model and immunohistochemistry (IHC) staining were utilized for in vivo analysis. The levels of Ras, pMek1/2, and pErk1/2 were determined by western blot assay. Ras-MAPK signaling pathway inhibitor was utilized to study the regulatory role of Fer on EC cells. RESULTS: Our findings revealed that Fer exhibited upregulation in both EC tissues and cell lines, concomitant with the activation of the Ras-MAPK signaling pathway. Silencing of Fer resulted in the suppression of cell proliferation, migration, invasion, and Ras-MAPK signaling pathway, while promoted hypoxia-induced apoptosis in RL95-2 and KLE cells. Fer overexpression stimulated cell proliferation, migration, invasion, and Ras-MAPK signaling pathway in Ishikawa and AN3-CA cells, which were reversed after treatment with either Ras or MAPK inhibitor. Moreover, silencing of Fer suppressed tumor growth and downregulated the expression of Ki-67, Ras, pMek1/2, and pErk1/2, but had no significant effect on Mek1/2 and Erk1/2, while upregulated caspase-3 expression in vivo. CONCLUSION: In summary, the upregulation of Fer in EC cells resulted in the enhancement of cell proliferation, migration, and invasion through the activation of the Ras-MAPK signaling pathway.

Antifungal activities of a novel triazole fungicide, mefentrifluconazole, against the major maize pathogen Fusarium verticillioides.

Fusarium ear rot (FER) is a serious fungal disease occurring the late growth stage of maize. FER not only reduces the yield of maize but also causes mycotoxin contamination, which affects the quality of maize and threatens human and animal health. Fusarium verticillioides is the predominant causative pathogen of FER worldwide. At present, there is no registered fungicide for use against maize FER in China. The novel isopropyl alcohol-triazole fungicide mefentrifluconazole (MFZ) has been shown to be effective against several Fusarium spp., but little is known about its specific activity against F. verticillioides. MFZ exhibited strong antifungal activities against 50 strains of F. verticillioides collected from the major maize-growing areas in China. MFZ inhibited mycelial growth, conidium production, germination and germ tube elongation of F. verticillioides. MFZ treatment significantly reduced fumonisin production and the expression levels of fumonisin biosynthetic genes. Genome-wide transcriptional profiling of F. verticillioides in response to MFZ indicated that the expression of genes involved in ergosterol biosynthesis, including fungicide target genes (cyp51 genes), was significantly downregulated by MFZ. MFZ treatment resulted in reduced ergosterol production and increased glycerol and malonaldehyde production as well as relative conductivity in F. verticillioides. A 2-year field experiment showed a significant reduction in FER severity in maize after spraying with MFZ at the tasseling stage. This study evaluated the potential of MFZ to control FER in maize and provides insights into its antifungal activities and mechanism of action against F. verticillioides.

Fer and FerT: A New Regulatory Link between Sperm and Cancer Cells.

Fer and its sperm and cancer specific variant, FerT, are non-receptor tyrosine kinases which play roles in cancer progression and metastasis. Recent studies have shed light on the regulatory role of these kinases in ensuring proper sperm function. Comparison of the regulatory cascades in which Fer and FerT are engaged in sperm and cancer cells presents an interesting picture, in which similar regulatory interactions of these enzymes are integrated in a similar or different regulatory context in the two cell types. These diverse compositions extend from the involvement of Fer in modulation of actin cytoskeleton integrity and function, to the unique regulatory interactions of Fer with PARP-1 and the PP1 phosphatase. Furthermore, recent findings link the metabolic regulatory roles of Fer and FerT in sperm and cancer cells. In the current review, we discuss the above detailed aspects, which portray Fer and FerT as new regulatory links between sperm and malignant cells. This perspective view can endow us with new analytical and research tools that will deepen our understanding of the regulatory trajectories and networks that govern these two multi-layered systems.

RALF22 promotes plant immunity and amplifies the Pep3 immune signal.

Rapid alkalinization factors (RALFs) in plants have been reported to dampen pathogen-associated molecular pattern (PAMP)-triggered immunity via suppressing PAMP-induced complex formation between the pattern recognition receptor (PRR) and its co-receptor BAK1. However, the direct and positive role of RALFs in plant immunity remains largely unknown. Herein, we report the direct and positive roles of a typical RALF, RALF22, in plant immunity. RALF22 alone directly elicited a variety of typical immune responses and triggered resistance against the devastating necrotrophic fungal pathogen Sclerotinia sclerotiorum in a FERONIA (FER)-dependent manner. LORELEI (LRE)-like glycosylphosphatidylinositol (GPI)-anchored protein 1 (LLG1) and NADPH oxidase RBOHD were required for RALF22-elicited reactive oxygen species (ROS) generation. The mutation of cysteines conserved in the C terminus of RALFs abolished, while the constitutive formation of two disulfide bridges between these cysteines promoted the RALF22-elicited ROS production and resistance against S. sclerotiorum, demonstrating the requirement of these cysteines in the functions of RALF22 in plant immunity. Furthermore, RALF22 amplified the Pep3-induced immune signal by dramatically increasing the abundance of PROPEP3 transcript and protein. Supply with RALF22 induced resistance against S. sclerotiorum in Brassica crop plants. Collectively, our results reveal that RALF22 triggers immune responses and augments the Pep3-induced immune signal in a FER-dependent manner, and exhibits the potential to be exploited as an immune elicitor in crop protection.

[The proper use of carboxymaltose iron and its economic impact in the geriatric wards of a French university hospital]. / Bon usage du fer carboxymaltose et impact économique dans les services gériatriques d'un CHU.

The proper use and economic impact of carboxymaltose iron were evaluated for patients hospitalized in the geriatric wards of a French university hospital from November 2019 to April 2020. Martial supplementation was recommended for 75.7% of the 173 patients who received carboxymaltose iron: 43.4% had a real indication for carboxymaltose iron, while 14.4% could have received sucrose iron and 17.9% could have received per os iron. Compliance with the recommendations would have generated savings of 10,345.80 euros (32.1%).

Single-cell RNA sequencing reveals a landscape and targeted treatment of ferroptosis in retinal ischemia/reperfusion injury.

BACKGROUND: The aim of this study was to establish a complete retinal cell atlas of ischemia-reperfusion injury by single-cell RNA sequencing, and to explore the underlying mechanism of retinal ischemia-reperfusion injury in mice. METHODS: Single-cell RNA sequencing was used to evaluate changes in the mouse retinal ischemia reperfusion model. In vivo and in vitro experiments were performed to verify the protective effect of inhibiting ferroptosis in retinal ischemia-reperfusion injury. RESULTS: After ischemia-reperfusion injury, retinal cells were significantly reduced, accompanied by the activation of myeloid and a large amount of blood-derived immune cell infiltration. The IFNG, MAPK and NFKB signaling pathways in retinal neuronal cells, together with the TNF signaling pathway in myeloid give rise to a strong inflammatory response in the I/R state. Besides, the expression of genes implicating iron metabolism, oxidative stress and multiple programed cell death pathways have changed in cell subtypes described above. Especially the ferroptosis-related genes and blocking this process could apparently alleviate the inflammatory immune responses and enhance retinal ganglion cells survival. CONCLUSIONS: We established a comprehensive landscape of mouse retinal ischemia-reperfusion injury at the single-cell level, revealing the important role of ferroptosis during this injury, and targeted inhibition of ferroptosis can effectively protect retinal structure and function.

Endothelin A receptor antagonist attenuated renal iron accumulation in iron overload heme oxygenase-1 knockout mice.

Progressive iron accumulation and renal impairment are prominent in both patients and mouse models of sickle cell disease (SCD). Endothelin A receptor (ETA) antagonism prevents this iron accumulation phenotype and reduces renal iron deposition in the proximal tubules of SCD mice. To better understand the mechanisms of iron metabolism in the kidney and the role of the ETA receptor in iron chelation and transport, we studied renal iron handling in a nonsickle cell iron overload model, heme oxygenase-1 (Hmox-1-/-) knockout mice. We found that Hmox-1-/- mice had elevated plasma endothelin-1 (ET-1), cortical ET-1 mRNA expression, and renal iron content compared with Hmox-1+/+ controls. The ETA receptor antagonist, ambrisentan, attenuated renal iron deposition, without any changes to anemia status in Hmox-1-/- mice. This was accompanied by reduced urinary iron excretion. Finally, ambrisentan had an important iron recycling effect by increasing the expression of the cellular iron exporter, ferroportin-1 (FPN-1), and circulating total iron levels in Hmox-1-/- mice. These findings suggest that the ET-1/ETA signaling pathway contributes to renal iron trafficking in a murine model of iron overload.

Identification of iron-responsive genes in Proteus vulgaris.

Iron is essential for almost all bacteria, and iron homeostasis is precisely controlled by the ferric uptake regulator (Fur). The Fur regulons have been well characterized in some model bacteria, yet little is known in the common opportunistic pathogen Proteus vulgaris. In this study, Fur regulon and iron-responsive genes in P. vulgaris were mainly defined by in silico and proteomic analyses. The results showed that about 250 potential Fur-regulated operons including 14 transcriptional factors were predicted, while 559 proteins exhibited differential expression in response to iron deficiency, not all being directly regulated by Fur, such as transcriptional factors lexA, recA, narL, and arcA. Collectively, these results demonstrated that Fur functioned as a global regulatory protein to repress or activate expression of a large repertoire of genes in P. vulgaris; besides, not all the iron-responsive genes were directly regulated by Fur, whereas indirectly regulated through other mechanisms such as additional transcriptional regulatory proteins.

SMaTE: A Segment-Level Feature Mixing and Temporal Encoding Framework for Facial Expression Recognition.

Despite advanced machine learning methods, the implementation of emotion recognition systems based on real-world video content remains challenging. Videos may contain data such as images, audio, and text. However, the application of multimodal models using two or more types of data to real-world video media (CCTV, illegally filmed content, etc.) lacking sound or subtitles is difficult. Although facial expressions in image sequences can be utilized in emotion recognition, the diverse identities of individuals in real-world content limits computational models of relationships between facial expressions. This study proposed a transformation model which employed a video vision transformer to focus on facial expression sequences in videos. It effectively understood and extracted facial expression information from the identities of individuals, instead of fusing multimodal models. The design entailed capture of higher-quality facial expression information through mixed-token embedding facial expression sequences augmented via various methods into a single data representation, and comprised two modules: spatial and temporal encoders. Further, temporal position embedding, focusing on relationships between video frames, was proposed and subsequently applied to the temporal encoder module. The performance of the proposed algorithm was compared with that of conventional methods on two emotion recognition datasets of video content, with results demonstrating its superiority.

Kids' Emotion Recognition Using Various Deep-Learning Models with Explainable AI.

Human ideas and sentiments are mirrored in facial expressions. They give the spectator a plethora of social cues, such as the viewer's focus of attention, intention, motivation, and mood, which can help develop better interactive solutions in online platforms. This could be helpful for children while teaching them, which could help in cultivating a better interactive connect between teachers and students, since there is an increasing trend toward the online education platform due to the COVID-19 pandemic. To solve this, the authors proposed kids' emotion recognition based on visual cues in this research with a justified reasoning model of explainable AI. The authors used two datasets to work on this problem; the first is the LIRIS Children Spontaneous Facial Expression Video Database, and the second is an author-created novel dataset of emotions displayed by children aged 7 to 10. The authors identified that the LIRIS dataset has achieved only 75% accuracy, and no study has worked further on this dataset in which the authors have achieved the highest accuracy of 89.31% and, in the authors' dataset, an accuracy of 90.98%. The authors also realized that the face construction of children and adults is different, and the way children show emotions is very different and does not always follow the same way of facial expression for a specific emotion as compared with adults. Hence, the authors used 3D 468 landmark points and created two separate versions of the dataset from the original selected datasets, which are LIRIS-Mesh and Authors-Mesh. In total, all four types of datasets were used, namely LIRIS, the authors' dataset, LIRIS-Mesh, and Authors-Mesh, and a comparative analysis was performed by using seven different CNN models. The authors not only compared all dataset types used on different CNN models but also explained for every type of CNN used on every specific dataset type how test images are perceived by the deep-learning models by using explainable artificial intelligence (XAI), which helps in localizing features contributing to particular emotions. The authors used three methods of XAI, namely Grad-CAM, Grad-CAM++, and SoftGrad, which help users further establish the appropriate reason for emotion detection by knowing the contribution of its features in it.

Hepcidin-to-Ferritin Ratio as an Early Diagnostic Index of Iron Overload in ß-Thalassemia Major Patients.

Hepcidin (HEPC) hormone production is expected to be elevated in cases accompanying iron overload, but the opposite impact of ineffective erythropoiesis in ß-thalassemia major (ß-TM) patients overrides this effect. The role of the HEPC-to-ferritin (FER) ratio and its components in iron metabolism along with their diagnostic cutoff values, sensitivity, specificity, and accuracy in ß-TM patients with iron overload, were examined in this study. This was a 1:1 case-control study with 120 participants, ages ranging from 2 to 30 years of both sexes, who were assigned into two groups: 60 ß-TM patients with iron overload, and a control group, comprising 60 healthy individuals matched by gender and age. In the present study, we found slightly elevated serum HEPC concentration (21.9 ng/mL) compared to the controls (9.9 ng/mL), which was not statistically significant (p =0.1), and the median HEPC-to-FER ratio of the cases was significantly lower than the controls, with the median case-control difference of (-0.366; p < 0.001). Our results revealed a statistically significant impact (p < 0.001) of mean age on the serum HEPC level with the inverse linear correlation of (-0.487, p < 0.001). The area under the curve of the HEPC-to-FER ratio was 0.999 and the optimum cutoff value was 0.046 ng/mL (p < 0.001) with 100.0% sensitivity and 98.3% specificity. In conclusion, we found that serum HEPC-to-FER ratio, with an accuracy of 99.2%, may serve as an excellent index for the diagnosis of iron overload in ß-TM patients differentiating them from nonthalassemic controls.

The Role of FER rs4957796 in the Risk of Developing and Dying from a Bloodstream Infection: A 23-Year Follow-up of the Population-based Nord-Trøndelag Health Study.

BACKGROUND: Bloodstream infection and sepsis are major causes of health loss worldwide, and it is important to identify patients at risk of developing and dying from these conditions. The single-nucleotide polymorphism most strongly associated with sepsis mortality is FER rs4957796. However, it is not known how this variant is associated with bloodstream infection incidence and mortality. METHODS: We used prospective data from 1995-2017 from the population-based HUNT Study. Genotypes were ascertained from blood samples, and additional genotypes were imputed. Information on bloodstream infection and diagnosis codes at hospitalization were collected through record linkage with all hospitals in the area. RESULTS: A total of 69 294 patients were included. Patients with the rs4957796 CC genotype had an increased risk of developing a bloodstream infection compared with the TT genotype (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.00-1.43). However, there was a protective additive effect of the C allele in terms of mortality in the total study population (HR, 0.77; 95% CI, .64-.92 per copy of the C allele) and among bloodstream infection patients (odds ratio, 0.70; 95% CI, .58-.85 per copy of the C allele). The results did not appear to be affected by selection bias. CONCLUSIONS: The rs4957796 CC genotype was associated with an increased risk of contracting a bloodstream infection but with a reduced risk of dying from one. The latter finding is in line with studies of sepsis case fatality, while the former expands our understanding of the immunoregulatory role of this polymorphism.