Novel functions of circulating Klotho

A significant portion of the key biological functions of αKlotho (αKL) and its cognate ligand Fibroblast growth factor-23 (FGF23) have been revealed through the study of rare diseases of mineral metabolism. These findings have far reaching implications for common disorders such as chronic kidney disease-mineral bone disorder (CKD-MBD). αKL’s predominant effect on mineral homeostasis is through its actions in the kidney as a co-receptor for FGF23, however emerging data has shed light on its capacity to act as a circulating factor through the cleavage of the transmembrane form of αKL (‘mKL’) to produce ‘cleaved KL’ or ‘cKL’. This review summarizes new findings from studies using extended delivery of cKL to mouse models with phenotypes reflecting those arising in CKD-MBD

Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho

αKlotho (αKL) regulates mineral metabolism, and diseases associated with αKL deficiency are characterized by hyperphosphatemia and vascular calcification (VC). αKL is expressed as a membrane-bound protein (mKL) and recognized as the coreceptor for fibroblast growth factor-23 (FGF23) and a circulating soluble form (cKL) created by endoproteolytic cleavage of mKL. The functions of cKL with regard to phosphate metabolism are unclear. We tested the ability of cKL to regulate pathways and phenotypes associated with hyperphosphatemia in a mouse model of CKD-mineral bone disorder and αKL-null mice. Stable delivery of adeno-associated virus (AAV) expressing cKL to diabetic endothelial nitric oxide synthase-deficient mice or αKL-null mice reduced serum phosphate levels. Acute injection of recombinant cKL downregulated the renal sodium-phosphate cotransporter Npt2a in αKL-null mice supporting direct actions of cKL in the absence of mKL. αKL-null mice with sustained AAV-cKL expression had a 74%-78% reduction in aorta mineral content and a 72%-77% reduction in mineral volume compared with control-treated counterparts (P<0.01). Treatment of UMR-106 osteoblastic cells with cKL + FGF23 increased the phosphorylation of extracellular signal-regulated kinase 1/2 and induced Fgf23 expression. CRISPR/Cas9-mediated deletion of fibroblast growth factor receptor 1 (FGFR1) or pretreatment with inhibitors of mitogen-activated kinase kinase 1 or FGFR ablated these responses. In summary, sustained cKL treatment reduced hyperphosphatemia in a mouse model of CKD-mineral bone disorder, and it reduced hyperphosphatemia and prevented VC in mice without endogenous αKL. Furthermore, cKL stimulated Fgf23 in an FGFR1-dependent manner in bone cells. Collectively, these findings indicate that cKL has mKL-independent activity and suggest the potential for enhancing cKL activity in diseases of hyperphosphatemia with associated VC

Sustained Klotho delivery reduces serum phosphate in a model of diabetic nephropathy

Diabetic nephropathy (DN) is a primary cause of end-stage renal disease and is becoming more prevalent because of the global rise in type 2 diabetes. A model of DN, the db/db uninephrectomized (db/db-uni) mouse, is characterized by obesity, as well as compromised renal function. This model also manifests defects in mineral metabolism common in DN, including hyperphosphatemia, which leads to severe endocrine disease. The FGF23 coreceptor, α-Klotho, circulates as a soluble, cleaved form (cKL) and may directly influence phosphate handling. Our study sought to test the effects of cKL on mineral metabolism in db/db-uni mice. Mice were placed into either mild or moderate disease groups on the basis of the albumin-to-creatinine ratio (ACR). Body weights of db/db-uni mice were significantly greater across the study compared with lean controls regardless of disease severity. Adeno-associated cKL administration was associated with increased serum Klotho, intact, bioactive FGF23 (iFGF23), and COOH-terminal fragments of FGF23 (P < 0.05). Blood urea nitrogen was improved after cKL administration, and cKL corrected hyperphosphatemia in the high- and low-ACR db/db-uni groups. Interestingly, 2 wk after cKL delivery, blood glucose levels were significantly reduced in db/db-uni mice with high ACR (P < 0.05). Interestingly, several genes associated with stabilizing active iFGF23 were also increased in the osteoblastic UMR-106 cell line with cKL treatment. In summary, delivery of cKL to a model of DN normalized blood phosphate levels regardless of disease severity, supporting the concept that targeting cKL-affected pathways could provide future therapeutic avenues in DN

Predictors of long-term neutralizing antibody titers following COVID-19 vaccination by three vaccine types: the BOOST study

Abstract As concerns related to the COVID-19 pandemic continue, it is critical to understand the impact of vaccination type on neutralizing antibody response durability as well as to identify individual difference factors related to decline in neutralization. This was a head-to-head comparison study following 498 healthy, community volunteers who received the BNT162b2 (n = 287), mRNA-1273 (n = 149), and Ad26.COV2.S (n = 62). Participants completed questionnaires and underwent blood draws prior to vaccination, 1 month, and 6 months after the vaccination series, and neutralizing antibody (nAB) titers at 1- and 6-months post vaccination were quantified using a high-throughput pseudovirus assay. Over 6 months of follow-up, nABs declined in recipients of BNT162b2 and mRNA-1273, while nABs in recipients of Ad26.COV2.S showed a significant increase. At the 6-month time point, nABs to Ad26.COV2.S were significantly higher than nABs to BNT162b2 and equivalent to mRNA-1273. Irrespective of follow-up timing, being older was associated with lower nAB for participants who received BNT162b2 and Ad26.COV2.S but not for those who received mRNA-1273. A higher baseline BMI was associated with a lower nAB for Ad26.COV2.S recipients but not for recipients of other vaccines. Women and non-smokers showed higher nAB compared to men and current smokers, respectively. The durability of neutralizing antibody responses differed by vaccine type and several sociodemographic factors that predicted response. These findings may inform booster recommendations in the future

Predictors of long-term neutralizing antibody titers following COVID-19 vaccination by three vaccine types: the BOOST study

As concerns related to the COVID-19 pandemic continue, it is critical to understand the impact of vaccination type on neutralizing antibody response durability as well as to identify individual difference factors related to decline in neutralization. This was a head-to-head comparison study following 498 healthy, community volunteers who received the BNT162b2 (n = 287), mRNA-1273 (n = 149), and Ad26.COV2.S (n = 62). Participants completed questionnaires and underwent blood draws prior to vaccination, 1&nbsp;month, and 6&nbsp;months after the vaccination series, and neutralizing antibody (nAB) titers at 1- and 6-months post vaccination were quantified using a high-throughput pseudovirus assay. Over 6&nbsp;months of follow-up, nABs declined in recipients of BNT162b2 and mRNA-1273, while nABs in recipients of Ad26.COV2.S showed a significant increase. At the 6-month time point, nABs to Ad26.COV2.S were significantly higher than nABs to BNT162b2 and equivalent to mRNA-1273. Irrespective of follow-up timing, being older was associated with lower nAB for participants who received BNT162b2 and Ad26.COV2.S but not for those who received mRNA-1273. A higher baseline BMI was associated with a lower nAB for Ad26.COV2.S recipients but not for recipients of other vaccines. Women and non-smokers showed higher nAB compared to men and current smokers, respectively. The durability of neutralizing antibody responses differed by vaccine type and several sociodemographic factors that predicted response. These findings may inform booster recommendations in the future

Age distribution of all snakebite victims.

BackgroundSnakebite is a neglected disease that disproportionally affects the rural poor. There is a dearth of evidence regarding incidence and risk factors in snakebite-endemic countries. Without this basic data, it will be impossible to achieve the target of a 50% reduction of snakebite morbidity and mortality by 2030 as set by the World Health Organization.MethodsThis was a descriptive analysis nested in a 2021 community-based demographic survey of over 70,000 individuals conducted in Mopeia, Mozambique, in preparation for a cluster randomized trial to test an intervention for malaria. We describe the incidence rate, demographics, socioeconomic indicators and outcomes of snakebite in this population.FindingsWe found the incidence of self-reported snakebite in Mopeia to be 393 bites per 100,000 person-years at risk, with 2% of households affected in the preceding 12 months. Whilst no fatalities were recorded, over 3,000 days of work or school days were lost with an individual household economic impact higher than that of uncomplicated malaria. 1 in 6 of those affected did not fully recover at the time of the study. We found significant relationships between age older than 15, use of firewood for household fuel, and animal possession with snakebite.ConclusionsThis study exposes higher than expected incidence and burden of snakebite in rural Mozambique. Whilst snakebite elimination in Mozambique seems unattainable today, it remains a preventable disease with manageable sequelae. We have shown that snakebite research is particularly easy to nest in larger studies, making this a practical and cost-effective way of estimating its incidence.</div

The nine questions about snakebite embedded in the larger demography questionnaire.

Beyond these, one question about livestock morbidity/mortality also allowed for the answer “killed by a snake” but there were zero answers with that option. “Loss of limb” was operationally defined as amputation (medical or necrosis) or loss of function.</p

Medically significant snake species likely to be found in Mopeia [13–15].

Medically significant snake species likely to be found in Mopeia [13–15].</p

Self-reported recovery after snakebite by age group.

Self-reported recovery after snakebite by age group.</p

Sex and age of all snakebite victims and all participants.

Sex and age of all snakebite victims and all participants.</p