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Proteomic characterization and comparison of the infective and adult life stage secretomes from Necator americanus and Ancylostoma ceylanicum
Full text linkMore than 470 million people globally are infected with the hookworms Ancylostoma ceylanicum and Necator americanus, resulting in an annual loss of 2.1 to 4 million disability-adjusted-life-years. Current infection management approaches are limited by modest drug efficacy, the costs associated with frequent mass drug administration campaigns, and the risk of reinfection and burgeoning drug resistance. Subunit vaccines based on proteins excreted and secreted (ES) by hookworms that reduce worm numbers and associated disease burden are a promising management strategy to overcome these limitations. However, studies on the ES proteomes of hookworms have mainly described proteins from the adult life stage which may preclude the opportunity to target the infective larva. Here, we employed high resolution mass spectrometry to identify 103 and 57 ES proteins from the infective third larvae stage (L3) as well as 106 and 512 ES proteins from the adult N. americanus and A. ceylanicum respectively. Comparisons between these developmental stages identified 91 and 41 proteins uniquely expressed in the L3 ES products of N. americanus and A. ceylanicum, respectively. We characterized these proteins based on functional annotation, KEGG pathway analysis, InterProScan signature and gene ontology. We also performed reciprocal BLAST analysis to identify orthologs across species for both the L3 and adult stages and identified five orthologous proteins in both life stages and 15 proteins that could be detected only in the L3 stage of both species. Last, we performed a three-way reciprocal BLAST on the L3 proteomes from both hookworm species together with a previously reported L3 proteome from the rodent hookworm Nippostrongylus brasiliensis, and identified eight L3 proteins that could be readily deployed for testing using well established rodent models. This novel characterization of L3 proteins and taxonomic conservation across hookworm species provides a raft of potential candidates for vaccine discovery for prevention of hookworm infection and disease
N-glycosylation in the SERPIN domain of the C1-esterase inhibitor in hereditary angioedema
Full text linkHereditary angioedema is an autosomal dominant disorder caused by defects in C1-esterase inhibitor (C1-INH), resulting in poorly controlled activation of the kallikrein-kinin system and bradykinin overproduction. C1-INH is a heavily glycosylated protein in the serine protease inhibitor (SERPIN) family, yet the role of these glycosylation sites remains unclear. To elucidate the functional impact of N-glycosylation in the SERPIN domain of C1-INH, we engineered 4 sets consisting of 26 variants at or near the N-linked sequon (NXS/T). Among these, 6 are reported in patients with hereditary angioedema and 5 are known C1-INH variants without accessible clinical histories. We systematically evaluated their expression, structure, and functional activity with C1s̄, FXIIa, and kallikrein. Our findings showed that of the 11 reported variants, 7 were deleterious. Deleting N at the 3 naturally occurring N-linked sequons (N238, N253, and N352) resulted in pathologic consequences. Altering these sites by substituting N with A disrupted N-linked sugar attachment, but preserved protein expression and function. Furthermore, an additional N-linked sugar generated at N272 impaired C1-INH function. These findings highlight the importance of N-linked sequons in modulating the expression and function of C1-INH. Insights gained from identifying the pathological consequences of N-glycan variants should assist in defining more tailored therapy
Triacylglycerol mobilization underpins mitochondrial stress recovery
Full text linkMitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction
The Stomach
No full textEsther Ochoa is medical student. She presented artwork in the form of photography.
The Stomach emphasizes the importance of community within the holistic healthcare experience. The use of local wood symbolizes the transformative aspects of her future career field, plastic and reconstructive surgery. Just as PRS surgeons manipulate tissue- moving, reusing, shaping- the artist turned a tree into a cutting board, just as WashU is shaping the artist into a doctor.
This design choice also underscores the importance of humor and nutrition in healthcare—both essential for maintaining mental health and preventing burnout among healthcare professionals. The Stomach is an allegory of her view on healthcare which highlights the essential role teamwork plays in medical care. Just as a breadboard brings people together during social gatherings, effective healthcare relies on collaborative efforts amongst various professionals and shared decision-making with patients. Patients should be given a seat at the table when decisions about their treatment plans are made. Many patients also require multidisciplinary care, including primary care physicians, OT, PT, nurses, and pharmacists, and all these facets of the care team must move in tandem to produce ideal medical outcomes. The Stomach serves as a reminder of the value of every team member and the collective effort required in patient care
Association of hyponatremia with outcomes after geriatric trauma: A systematic review and meta-analysis
Full text linkBACKGROUND: Trauma is a major cause of mortality in the elderly population. Hyponatremia is the most common electrolyte imbalance in geriatric patients and has been demonstrated to be a risk factor for altered cognition, low bone density, falls, and death. We systematically and critically reviewed the literature to ascertain the association between hyponatremia and geriatric trauma outcomes.
METHODS: We searched seven databases for articles published from inception to October 2023. Studies included reported on geriatric trauma, hyponatremia, and clinical outcomes. Two investigators independently reviewed 6535 abstracts, 235 full-text articles, and critically appraised each study. Study details, patient characteristics, and outcomes were independently extracted by two reviewers. Data quality assessment was performed using the Grading of Recommendations Assessment, Development, and Evaluation approach. Publication bias was assessed using funnel plot-based methods. A meta-analysis of risk ratios (RR) was performed using the random effects method.
RESULTS: Four retrospective cohort studies involving 11 894 geriatric patients were included. Among these, 492 (21.4%) were classified as trauma patients due to a fall and 1806 (78.6%) were classified as a trauma patient due to the presence of a fracture. In total, 2298 (19.3%) patients were classified as hyponatremic (125-135 mmol/L) while 9596 (80.7%) were classified as normonatremic. The pooled RR for in-hospital mortality for hyponatremic patients was 2.23 (95% CI 1.51 to 3.74) with high heterogeneity across the studies (I
CONCLUSIONS: Geriatric trauma patients presenting with hyponatremia appear to have an increased risk of in-hospital mortality. Given this association, national trauma registries should consider collecting serum sodium values for geriatric patients and providers should work to address hyponatremia as a possible contribution to falls. Given the paucity of published literature on this topic, there is a need for prospective studies evaluating the association between hyponatremia and geriatric trauma outcomes.
LEVEL OF EVIDENCE: Level III, systematic review with meta-analysis
MRN-CtIP, EXO1, and DNA2-WRN/BLM act bidirectionally to process DNA gaps in PARPi-treated cells without strand cleavage
No full textSingle-stranded DNA (ssDNA) gaps impact genome stability and PARP inhibitor (PARPi) sensitivity, especially in BRCA1/2-deficient tumors. Using single-molecule DNA fiber analysis, electron microscopy, and biochemical methods, we found that MRN, CtIP, EXO1, and DNA2-WRN/BLM resect ssDNA gaps through a mechanism different from their actions at DNA ends. MRN resects ssDNA gaps in the 3\u27-to-5\u27 direction using its pCtIP-stimulated exonuclease activity. Unlike at DNA ends, MRN does not use its endonucleolytic activity to cleave the 5\u27-terminated strand flanking the gap or the ssDNA. EXO1 and DNA2-WRN/BLM specifically resect the 5\u27 end of the gap independent of MRN-CtIP. This resection process alters ssDNA gap repair kinetics in BRCA1-proficient and -deficient cells. In BRCA1-deficient cells treated with PARPis, excessive resection results in larger ssDNA gaps, hindering their repair and leading to DNA breaks in subsequent cell cycle stages due to ssDNA gaps colliding with DNA replication forks. These findings broaden our understanding of the role of human nucleases in DNA metabolism and have significant implications for defining the mechanisms driving PARPi sensitivity in BRCA-deficient tumors
Female mice lacking GluA3 show early onset of hearing loss, cochlear synaptopathy, and afferent terminal swellings in ambient sound levels
No full textAMPA-type glutamate receptors (AMPARs) mediate excitatory cochlear transmission. However, unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3
Developing a novel index for individual-level social determinants and cardiovascular diseases in the Coronary Artery Risk Development in Young Adults (CARDIA) study
No full textBACKGROUND: Social determinants of health (SDH) have been found to contribute to cardiovascular risk and the development of cardiovascular disease (CVD). However, few studies have examined early-life exposure to SDH and the combined effect of multiple SDH measures on CVD. There is an urgent need to develop an SDH index for use in practice and clinical settings.
METHODS: A total of 3189 participants from the CARDIA Study who had chest CT scans at the year-25 (Y25) visit were included in this study. Personal and parental SDH measures, including education, occupation, income, financial strain, and childhood family environment, were obtained through interviews. The participants\u27 coronary artery calcification (CAC) was measured using chest CT scans, and left-ventricular mass (LVM) was measured using M-mode echocardiography. The values of the individual social determinants of health (iSDH) index were determined based on individual-level measures and CAC using a supervised learning method-the Boosted Regression Tree (BRT) model. This index\u27s association with the LVM index (LVMI) was evaluated as an external validation using linear regression models adjusting for race, sex, BMI, smoking status, alcohol intake, and physical activity.
RESULTS: Each one-standard-deviation (SD) increase in the iSDH index was associated with an increase in LVMI ranging from 0.376 (95% CI -0.016, 0.767) at year 0 to 0.468 (95% CI 0.115, 0.821) at year 20. The association between the iSDH index and the LVMI was more pronounced as the participants aged. Also, the iSDH indices were more strongly associated with LVMI among Black participants (β = 0.969, 95% CI = 0.081, 1.858) than White participants (β = 0.202, 95% CI = -0.228, 0.633) at year 5.
CONCLUSIONS: Higher iSDH indices in early adulthood were associated with increased LVMI values in midlife. The association between the iSDH index and CVD was stronger among Black adults than with White adults
Location and extent of disease predicts outcome of neurofibromatosis type 1-related pediatric low-grade gliomas
No full textFiber- and acetate-mediated modulation of MHC-II expression on intestinal epithelium protects from Clostridioides difficile infection
No full textHere, we explore the relationship between dietary fibers, colonic epithelium major histocompatibility complex class II (MHC-II) expression, and immune cell interactions in regulating susceptibility to Clostridioides difficile infection (CDI). We find that a low-fiber diet increases MHC-II expression in the colonic epithelium, which, in turn, worsens CDI by promoting the development of pathogenic CD