Kodamaea ohmeri: A rare yeast causing invasive infections in immunocompromised patients.

INTRODUCTION: Kodamaea ohmeri is a rare, recognized pathogen that has previously been isolated from environmental sources. The patients commonly affected by this yeast include immunocompromised as well as immunocompetent patients having several associated risk factors. METHODOLOGY: We report three cases in which K. ohmeri was isolated from blood using Bact T/ALERT. Identification was carried out by MALDI-TOF MS (Vitek-MS, BioMérieux, Marcy-l'Etoile, France) in addition to color characteristics on chromogenic media. The patients had diminished immune response on account of a multitude of comorbidities. RESULTS: K. ohmeri can be misidentified as Candida tropicalis, Candida albicans, or Candida hemolounii by conventional methods; correct and timely identification can be achieved by MALDI-TOF MS. Antifungal susceptibility breakpoints for K. ohmeri are currently not defined. An Echinocandin was added to the treatment regimen of all three of the cases. CONCLUSIONS: Identification of K. ohmeri using conventional methods is difficult and unusual yeasts should be carefully observed, especially upon prolonged incubation.

Functional characterization of QT interval associated SCN5A enhancer variants identify combined additive effects.

Several empirical and theoretical studies suggest presence of multiple enhancers per gene that collectively regulate gene expression, and that common sequence variation impacting on the activities of these enhancers is a major source of inter-individual variability in gene expression. However, for vast majority of genes, enhancers and the underlying regulatory variation remains unknown. Even for the genes with well-characterized enhancers, the nature of the combined effects from multiple enhancers and their variants, when known, on gene expression regulation remains unexplored. Here, we have evaluated the combined effects from five SCN5A enhancers and their regulatory variants that are known to collectively correlate with SCN5A cardiac expression and underlie QT interval association in the general population. Using small deletions centered at the regulatory variants in episomal reporter assays in a mouse cardiomyocyte cell line we demonstrate that the variants and their flanking sequences play critical role in individual enhancer activities, likely being a transcription factor (TF) binding site. By performing oligonucleotide-based pulldown assays on predicted TFs we identify the TFs likely driving allele-specific enhancer activities. Using all 32 possible allelic synthetic constructs in reporter assays, representing the five biallelic enhancers in tandem in their genomic order, we demonstrate combined additive effects on overall enhancer activities. Using transient enhancer assays in developing zebrafish embryos we demonstrate the four out the five enhancer elements act as enhancers in vivo . Together, these studies extend the previous findings to uncover the TFs driving the enhancer activities of QT interval associated SCN5A regulatory variants, reveal the additive effects from allelic combinations of these regulatory variants, and prove their potential to act as enhancers in vivo .

Correction: Advances in metal-organic frameworks for water remediation applications.

[This corrects the article DOI: 10.1039/D3RA07982A.].

Advances in metal-organic frameworks for water remediation applications.

Rapid industrialization and agricultural development have resulted in the accumulation of a variety of harmful contaminants in water resources. Thus, various approaches such as adsorption, photocatalytic degradation and methods for sensing water contaminants have been developed to solve the problem of water pollution. Metal-organic frameworks (MOFs) are a class of coordination networks comprising organic-inorganic hybrid porous materials having organic ligands attached to inorganic metal ions/clusters via coordination bonds. MOFs represent an emerging class of materials for application in water remediation owing to their versatile structural and chemical characteristics, such as well-ordered porous structures, large specific surface area, structural diversity, and tunable sites. The present review is focused on recent advances in various MOFs for application in water remediation via the adsorption and photocatalytic degradation of water contaminants. The sensing of water pollutants using MOFs via different approaches, such as luminescence, electrochemical, colorimetric, and surface-enhanced Raman spectroscopic techniques, is also discussed. The high porosity and chemical tunability of MOFs are the main driving forces for their widespread applications, which have huge potential for their commercial use.

Caesarean scar ectopic pregnancy: A case series.

Caesarean scar ectopic pregnancy (CSEP) is a uncommon presentation of pregnancy with incidence of nearly 1 in 2000 pregnancies. We present this case series of scar pregnancy with a objective to help obstetricians in early diagnosis and appropriate management to prevent its catastrophic complications.

Identification of Candida auris by PCR and assessment of biofilm formation by crystal violet assay.

INTRODUCTION: Candida auris is a notorious pathogen capable of forming biofilms on devices as well as host tissues, often culminating in infections. We evaluated characteristics of infections and the methods to diagnose C. auris over a period of three years in a tertiary care hospital. METHODS: Patients admitted between 2018 and 2020, who had candidemia due to C. auris were included in the study. Identification was performed using HiCrome™ Candida Differential Agar, Vitek 2 (BioMérieux, Inc., Marcy-l'Etoile, France) and MALDI-TOF, Vitek-MS. Identification was confirmed by detection of rDNA region covering part of 5.8S, entire of ITS2, and part of 28S by polymerase chain reaction (PCR). Biofilm formation was assessed by crystal violet staining. RESULTS: Presence of central line and broad spectrum antimicrobials were noted in all patients whereas total parenteral nutrition was given in 82.1% of these patients. Identification by Vitek2 v8.1 correlated with MALDI-TOF MS. PCR products of length 163 â€‹bp were obtained in all isolates as visualized by agarose gel electrophoresis. The biofilm quantity measured as A560 of the twenty-eight C. auris isolates ranged from 0.16 to 0.80 compared to C. albicans. CONCLUSIONS: C. auris can be identified by PCR targeting specific rDNA region. Biofilm formation and quantification can be achieved by growing C. auris isolates in Mueller-Hinton broth over a duration of 48 â€‹h.

Unveiling the dynamics of the breast milk microbiome: impact of lactation stage and gestational age.

BACKGROUND: Breast milk (BM) provides complete nutrition for infants for the first six months of life and is essential for the development of the newborn's immature immune and digestive systems. While BM was conventionally believed to be sterile, recent advanced high throughput technologies have unveiled the presence of diverse microbial communities in BM. These insights into the BM microbiota have mainly originated from uncomplicated pregnancies, possibly not reflecting the circumstances of mothers with pregnancy complications like preterm birth (PTB). METHODS: In this article, we investigated the BM microbial communities in mothers with preterm deliveries (before 37 weeks of gestation). We compared these samples with BM samples from healthy term pregnancies across different lactation stages (colostrum, transitional and mature milk) using 16S rRNA gene sequencing. RESULTS: Our analysis revealed that the microbial communities became increasingly diverse and compositionally distinct as the BM matured. Specifically, mature BM samples were significantly enriched in Veillonella and lactobacillus (Kruskal Wallis; p < 0.001) compared to colostrum. The comparison of term and preterm BM samples showed that the community structure was significantly different between the two groups (Bray Curtis and unweighted unifrac dissimilarity; p < 0.001). Preterm BM samples exhibited increased species richness with significantly higher abundance of Staphylococcus haemolyticus, Propionibacterium acnes, unclassified Corynebacterium species. Whereas term samples were enriched in Staphylococcus epidermidis, unclassified OD1, and unclassified Veillonella among others. CONCLUSION: Our study underscores the significant influence of pregnancy-related complications, such as preterm birth (before 37 weeks of gestation), on the composition and diversity of BM microbiota. Given the established significance of the maternal microbiome in shaping child health outcomes, this investigation paves the way for identifying modifiable factors that could optimize the composition of BM microbiota, thereby promoting maternal and infant health.

Role of the vaginal microbiome in miscarriage: exploring the relationship.

Miscarriage is a devastating pregnancy loss that affects many women worldwide. It is characterized as a spontaneous miscarriage that occurs before 20 weeks of gestation which affects more than 25% of pregnancies. While the causes of miscarriage are complex and multifactorial, recent research has suggested a potential role of the vaginal microbiota. The vaginal microbiome is a dynamic ecosystem of microbes that are essential for preserving vaginal health and avoiding infections. Vaginal dysbiosis has been accompanied with numerous adverse pregnancy complications, such as preterm birth. However, the effect of the vaginal microbiome in miscarriage is not fully understood. This review aims to investigate the link between vaginal microbiota and miscarriage. Also, we investigate the various mechanisms through which the vaginal microbiota may affect miscarriage. Additionally, we examine the implications of these research findings, specifically the possibility of vaginal microbiome screening and targeted interventions to prevent miscarriage.

Exploring Kinnow mandarin's hidden potential: Nature's key to antimicrobial and antidiabetic gold nanoparticles (K-AuNPs).

This pioneering study aims to address the paradox of the highly regarded Kinnow mandarin fruit, whose valuable peels have been considered undesired remnants from industrial fruit juice production. The study proposes the utilization of these discarded peels to synthesize ecologically safe gold nanoparticles (K-AuNPs) through a one-pot method. The objectives of this research are to synthesize K-AuNPs using an ecologically safe single-step approach, utilizing discarded Kinnow mandarin fruit peels, and to assess their antibacterial and antidiabetic potential. The validation of K-AuNPs involved various techniques including UV-visible spectroscopy, TEM, DLS, and zeta-potential investigations. The antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, and Bacillus subtilis was compared to levofloxacin and Kinnow mandarin aqueous peel extract (KAPE). Furthermore, the anti-diabetic efficacy was evaluated through α-amylase and α-glucosidase experiments, comparing K-AuNPs to pure KAPE and the standard inhibitor acarbose. The results confirmed the successful synthesis of K-AuNPs from KAPE, as evidenced by UV-spectral profiles (527 nm), TEM micrographs (∼21 d. nm), dynamic light scattering (65 d.nm), and zeta-potential (-12 mV). The K-AuNPs demonstrated a superior zone of inhibition and lower MIC values against Escherichia coli, Pseudomonas aeruginosa, and Bacillus subtilis, surpassing levofloxacin and KAPE alone. Additionally, the K-AuNPs exhibited potent anti-diabetic efficacy, outperforming both pure KAPE and acarbose at a lower dosage. To sum up, the process of producing K-AuNPs utilizing Kinnow mandarin peel extracts demonstrates a powerful antibacterial and antidiabetic remedy sourced from previously discarded materials. These findings signify a significant leap forward in the domain of natural product exploration, with the potential to fundamentally reshape modern healthcare approaches.

Mature white adipocyte plasticity during mammary gland remodelling and cancer.

Mammary gland growth and differentiation predominantly rely on stromal-epithelial cellular communication. Specifically, mammary adipocytes play a crucial role in ductal morphogenesis, as well as in the proliferation and differentiation of mammary epithelial cells. The process of lactation entails a reduction in the levels of white adipose tissue associated with the MG, allowing for the expansion of milk-producing epithelial cells. Subsequently, during involution and the regression of the milk-producing unit, adipocyte layers resurface, occupying the vacated space. This dynamic phenomenon underscores the remarkable plasticity and expansion of adipose tissue. Traditionally considered terminally differentiated, adipocytes have recently been found to exhibit plasticity in certain contexts. Unraveling the significance of this cell type within the MG could pave the way for novel approaches to reduce the risk of breast cancer and enhance lactation performance. Moreover, a comprehensive understanding of adipocyte trans- and de-differentiation processes holds promise for the development of innovative therapeutic interventions targeting cancer, fibrosis, obesity, type 2 diabetes, and other related diseases. Additionally, adipocytes may find utility in the realm of regenerative medicine. This review article provides a comprehensive examination of recent advancements in our understanding of MG remodelling, with a specific focus on the tissue-specific functions of adipocytes and their role in the development of cancer. By synthesizing current knowledge in this field, it aims to consolidate our understanding of adipocyte biology within the context of mammary gland biology, thereby fostering further research and discovery in this vital area.

CRISPR-Cas9 based knockout of S100A8 in mammary epithelial cells enhances cell proliferation and triggers oncogenic transformation via the PI3K-Akt pathway: Insights from a deep proteomic analysis.

S100A8 is a calcium-binding protein with multiple functions, including being a chemoattractant for phagocytes and playing a key role in the inflammatory response. Its expression has been shown to influence epithelial-mesenchymal transition (EMT) and metastasis in colorectal cancer. However, the role of S100A8 in cell proliferation and differentiation remains unknown. In this study, we used the CRISPR-Cas9 system to knock out S100A8 in healthy mammary epithelial cells and investigated the resulting changes in proteome profiling and signaling pathways. Our results showed that S100A8 knockout led to an increase in cell proliferation and migration, reduced cell-cell adhesion, and increased apoptosis compared to wildtype cells. Proteomics data indicated that S100A8 significantly affects cell cycle progression, cell proliferation, and cell survival through the PI3K-Akt pathway. Furthermore, our findings suggest that S100A8 function is associated with Pten expression, a negative regulator of the PI3K-Akt pathway. These results indicate that S100A8 dysregulation in healthy cells can lead to altered cellular physiology and higher proliferation, similar to cancerous growth. Therefore, maintaining S100A8 expression is critical for preserving healthy cell physiology. This study provides novel insights into the role of S100A8 in cell proliferation and differentiation and its potential relevance to cancer biology. SIGNIFICANCE: The study suggests that maintaining S100A8 expression is critical for preserving healthy cell physiology, and dysregulation of S100A8 in healthy cells can lead to altered cellular physiology and higher proliferation, similar to cancerous growth. Therefore, targeting the PI3K-Akt pathway or regulating Pten expression, a negative regulator of the PI3K-Akt pathway, may be potential strategies for cancer treatment by controlling S100A8 dysregulation. Additionally, S100A8 and S100A9 have been shown to promote metastasis of breast carcinoma by forming a metastatic milieu. However, the differential expression of S100A8 in tumors and its dual effects of antitumor and protumor make the relationship between S100A8 and tumors complicated. Currently, most research focuses on the function of S100A8 as a secretory protein in the microenvironment of tumors, and its function inside healthy cells without forming dimers remains unclear. Furthermore, the study provides insight into the role of S100A8 in cell proliferation and differentiation, which may have implications for other diseases beyond cancer. The functional role of S100A8 in normal mammary epithelial cells remains completely uncertain. Therefore, the objective of this study is to investigate the function of S100A8 on proliferation in mammary epithelial cells after its deletion and to elucidate the underlying proteins involved in downstream signaling. Our findings indicate that the deletion of S100A8 leads to excessive proliferation in normal mammary epithelial cells, reduces apoptosis, and affects cell-cell adhesion molecules required for cellular communication, resulting in a cancer-like phenotype.

Cohesin contributes to transcriptional repression of stage-specific genes in the human malaria parasite.

The complex life cycle of the human malaria parasite, Plasmodium falciparum, is driven by specific transcriptional programs, but it is unclear how most genes are activated or silenced at specific times. There is an association between transcription and spatial organization; however, the molecular mechanisms behind genome organization are unclear. While P. falciparum lacks key genome-organizing proteins found in metazoans, it has all core components of the cohesin complex. To investigate the role of cohesin in P. falciparum, we functionally characterize the cohesin subunit Structural Maintenance of Chromosomes protein 3 (SMC3). SMC3 knockdown during early stages of the intraerythrocytic developmental cycle (IDC) upregulates a subset of genes involved in erythrocyte egress and invasion, which are normally expressed at later stages. ChIP-seq analyses reveal that during the IDC, SMC3 enrichment at the promoter regions of these genes inversely correlates with gene expression and chromatin accessibility. These data suggest that SMC3 binding contributes to the repression of specific genes until their appropriate time of expression, revealing a new mode of stage-specific gene repression in P. falciparum.

MSMEG_5850, a stress-induced TetR protein, involved in global transcription regulation in Mycobacterium smegmatis.

Aim: To decipher the role of MSMEG_5850 in the physiology of mycobacteria. Methods: MSMEG_5850 was knocked out and RNA sequencing was performed. MSMEG_5850 protein was purified from the Escherichia coli pET28a system. Electrophoretic mobility shift assay and size exclusion chromatography were used to determine the binding of MSMEG_5850 to its motif and binding stoichiometry. The effect of nutritional stress was monitored. Results: Transcriptome analysis revealed the differential expression of 148 genes in an MSMEG_5850 knockout strain. MSMEG_5850 had control over 50 genes because those genes had a binding motif upstream of their sequence. The electrophoretic mobility shift assay showed MSMEG_5850 bound to its motif as a monomer. MSMEG_5850 was upregulated under nutritional stress and promoted the survival of mycobacteria. Conclusion: The study confirms the role of MSMEG_5850 in global transcriptional regulation.

Maternal microbiota and gestational diabetes: impact on infant health.

Gestational diabetes mellitus (GDM) is a common complication of pregnancy that has been associated with an increased risk of obesity and diabetes in the offspring. Pregnancy is accompanied by tightly regulated changes in the endocrine, metabolic, immune, and microbial systems, and deviations from these changes can alter the mother's metabolism resulting in adverse pregnancy outcomes and a negative impact on the health of her infant. Maternal microbiomes are significant drivers of mother and child health outcomes, and many microbial metabolites are likely to influence the host health. This review discusses the current understanding of how the microbiota and microbial metabolites may contribute to the development of GDM and how GDM-associated changes in the maternal microbiome can affect infant's health. We also describe microbiota-based interventions that aim to improve metabolic health and outline future directions for precision medicine research in this emerging field.

Netarsudil monotherapy as the initial treatment for open-angle glaucoma and ocular hypertension in Indian patients: A real-world evaluation of efficacy and safety.

Purpose: Glaucoma is the second leading cause of blindness worldwide, affecting more than 64 million people aged 40-80. The best way to manage primary open-angle glaucoma (POAG) is by lowering the intraocular pressure (IOP). Netarsudil is a Rho kinase inhibitor, the only class of antiglaucoma medications that reorganizes the extracellular matrix to improve the aqueous outflow through the trabecular pathway. Methods: An open-label, real-world, multicentric, observation-based 3-month study was performed for assessing the safety and ocular hypotensive efficacy of netarsudil ophthalmic solution (0.02% w/v) in patients with elevated IOP. Patients were given netarsudil ophthalmic solution (0.02% w/v) as a first-line therapy. Diurnal IOP measurements, best-corrected visual acuity, and adverse event assessments were recorded at each of the five visits (Day-1: screening day and first dosing day; subsequent observations were taken at 2 weeks, 4 weeks, 6 weeks, and 3 months). Results: Four hundred and sixty-nine patients from 39 centers throughout India completed the study. The mean IOP at baseline of the affected eyes was 24.84 ± 6.39 mmHg (mean ± standard deviation). After the first dose, the IOP was measured after 2, 4, and 6 weeks, with the final measurement taken at 3 months. The percentage reduction in IOP in glaucoma patients after 3 months of once-daily netarsudil 0.02% w/v solution use was 33.34%. The adverse effects experienced by patients were not severe in the majority of cases. Some adverse effects observed were redness, irritation, itching, and others, but only a small number of patients experienced severe reactions, as reported in a decreasing order: redness > irritation > watering > itching > stinging > blurring. Conclusion: We found that netarsudil 0.02% w/v solution monotherapy when used as the first-line treatment in primary open-angle glaucoma and ocular hypertension was both safe and effective.

The SMC-like RecN protein is at the crossroads of several genotoxic stress responses in Escherichia coli.

Introduction: DNA damage repair (DDR) is an essential process for living organisms and contributes to genome maintenance and evolution. DDR involves different pathways including Homologous recombination (HR), Nucleotide Excision Repair (NER) and Base excision repair (BER) for example. The activity of each pathway is revealed with particular drug inducing lesions, but the repair of most DNA lesions depends on concomitant or subsequent action of the multiple pathways. Methods: In the present study, we used two genotoxic antibiotics, mitomycin C (MMC) and Bleomycin (BLM), to decipher the interplays between these different pathways in E. coli. We combined genomic methods (TIS and Hi-SC2) and imaging assays with genetic dissections. Results: We demonstrate that only a small set of DDR proteins are common to the repair of the lesions induced by these two drugs. Among them, RecN, an SMC-like protein, plays an important role by controlling sister chromatids dynamics and genome morphology at different steps of the repair processes. We further demonstrate that RecN influence on sister chromatids dynamics is not equivalent during the processing of the lesions induced by the two drugs. We observed that RecN activity and stability requires a pre-processing of the MMC-induced lesions by the NER but not for BLM-induced lesions. Discussion: Those results show that RecN plays a major role in rescuing toxic intermediates generated by the BER pathway in addition to its well-known importance to the repair of double strand breaks by HR.

An integrated tumor, immune and microbiome atlas of colon cancer.

The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcus bromii, associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches.

Interpretation of Antimicrobial Susceptibility Testing Using European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) Breakpoints: Analysis of Agreement.

OBJECTIVES: Breakpoints provided by European Committee on Antimicrobial Susceptibility Testing (EUCAST) are now being used in many countries. This study was planned to ascertain the agreement in antimicrobial susceptibility using the Clinical and Laboratory Standards Institute (CLSI) and EUCAST breakpoints during the Kirby-Bauer disk diffusion method. METHODS:  This was a prospective observational study. Clinical isolates belonging to the family Enterobacteriaceae recovered between January and December, 2022, were included in the analysis. The diameter of the zone of inhibition of the 14 antimicrobials (viz. amoxicillin/clavulanic acid, cefazolin, ceftriaxone, cefuroxime, cefixime, aztreonam, meropenem, gentamicin, amikacin, ciprofloxacin, levofloxacin, norfloxacin, trimethoprim/sulfamethoxazole and fosfomycin) was analysed. Antimicrobial susceptibility was interpreted using CLSI 2022 and EUCAST 2022 guidelines.  Results: Susceptibility data from a total of 356 isolates showed a slight increase in the percentage of resistant isolates with most of the drugs using EUCAST guidelines. The level of agreement varied from almost perfect to slight. For two drugs, i.e., fosfomycin and cefazolin, the agreement was least among the drug analysed (kappa (κ) value < 0.5, p < 0.001). For Ceftriaxone and Aztreonam, with EUCAST, susceptible (S) isolates would have been categorised in the newly redefined "I" category. It would have indicated the use of higher dosages of drugs.  Conclusion: Change in the breakpoints impacts the interpretation of the susceptibility. It can also lead to a change in the dosage of the drug used for treatment. Therefore, there is an urgent need to see the impact of recent modifications "I" category of EUCAST on the clinical outcome and usage of antimicrobials.

Infection Trends, Susceptibility Pattern, and Treatment Options for Stenotrophomonas maltophilia Infections in Trauma Patients: A Retrospective Study.

Introduction Stenotrophomonas maltophilia is an emerging environmental, gram-negative, multidrug-resistant organism, associated with risk factors such as prolonged hospitalization, invasive procedures, admission to the intensive care unit, mechanical ventilation, use of indwelling catheters, administration of immunosuppressants or corticosteroids, human immunodeficiency virus infection, underlying malignancy, and organ transplantation. The organism, despite being of low invasiveness in immune-competent individuals, is difficult to treat because of intrinsic resistance to several antimicrobial agents. Materials and Methods This study focuses on commonly encountered resistance from among the isolates over a duration of 7 years from 2012 to 2018, analyzed retrospectively. Identification and susceptibility testing were performed using Vitek 2 (BioMérieux, Marcy-l'Etoile, France). Results Bloodstream infections were found to be most common (52.02%), followed by respiratory infections (35.83%). The median age of the patients was 36 years, and male to female ratio was 143:27. The median duration of hospital stay was 18 days, and mortality was seen in 18.82% of patients. Susceptibility to cotrimoxazole and levofloxacin was seen in 97.1% of isolates (168 out of 173) and 90.1% of isolates (156 out of 173), respectively. Conclusion Despite being effective in a majority of S . maltophilia isolates, both cotrimoxazole and levofloxacin have their shortcomings. Cotrimoxazole is bacteriostatic and can cause bone marrow suppression and resistance to levofloxacin sometimes develops during therapy. Thus, the therapy should be decided considering the characteristics of both of these drugs.

Complement, complosome, and complotype: A perspective.

Recent rapid progress in key technological advances, including the broader accessibility of single-cell "omic" approaches, have allowed immunologists to gain important novel insights into the contributions of individual immune cells in protective immunity and immunopathologies. These insights also taught us that there is still much to uncover about the (cellular) networks underlying immune responses. For example, in the last decade, studies on a key component of innate immunity, the complement system, have defined intracellularly active complement (the complosome) as a key orchestrator of normal cell physiology. This added an unexpected facet to the biology of complement, which was long considered fully explored. Here, we will summarize succinctly the known activation modes and functions of the complosome and provide a perspective on the origins of intracellular complement. We will also make a case for extending assessments of the complotype, the individual inherited landscape of common variants in complement genes, to the complosome, and for reassessing patients with known serum complement deficiencies for complosome perturbations. Finally, we will discuss where we see current opportunities and hurdles for dissecting the compartmentalization of complement activities toward a better understanding of their contributions to cellular function in health and disease.