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Context The calcium-sensing receptor (CaSR) is essential to maintain a stable calcium concentration in serum. Spermatozoa are exposed to immense changes in concentrations of CaSR ligands such as calcium, magnesium, and spermine during epididymal maturation, in the ejaculate, and in the female reproductive environment. However, the role of CaSR in human spermatozoa is unknown. Objective This work aimed to investigate the role of CaSR in human spermatozoa. Methods We identified CaSR in human spermatozoa and characterized the response to CaSR agonists on intracellular calcium, acrosome reaction, and 3′,5′-cyclic adenosine 5′-monophosphate (cAMP) in spermatozoa from men with either loss-of-function or gain-of-function mutations in CASR and healthy donors. Results CaSR is expressed in human spermatozoa and is essential for sensing extracellular free ionized calcium (Ca2+) and Mg2+. Activators of CaSR augmented the effect of sperm-activating signals such as the response to HCO3– and the acrosome reaction, whereas spermatozoa from men with a loss-of-function mutation in CASR had a diminished response to HCO3–, lower progesterone-mediated calcium influx, and were less likely to undergo the acrosome reaction in response to progesterone or Ca2+. CaSR activation increased cAMP through soluble adenylyl cyclase (sAC) activity and increased calcium influx through CatSper. Moreover, external Ca2+ or Mg2+ was indispensable for HCO3– activation of sAC. Two male patients with a CASR loss-of-function mutation in exon 3 presented with normal sperm counts and motility, whereas a patient with a loss-of-function mutation in exon 7 had low sperm count, motility, and morphology. Conclusion CaSR is important for the sensing of Ca2+, Mg2+, and HCO3– in spermatozoa, and loss-of-function may impair male sperm function.

The coronavirus disease 2019 (COVID‐19) pandemic is declared a global health emergency. COVID‐19 is triggered by a novel coronavirus: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV2). Baseline characteristics of admitted patients with COVID‐19 show that adiposity, diabetes and hypertension are risk factors for developing severe disease, but so far immunosuppressed patients that are listed as high‐risk patients have not been more susceptible to severe COVID‐19 than the rest of the population. Multiple clinical trials are currently being conducted, which hopefully can identify more drugs that can lower mortality, morbidity and burden on the society. Several independent studies have convincingly shown that cyclosporine inhibit replication of several different coronaviruses in vitro. The cyclosporine‐analog Alisporivir has recently been shown to inhibit SARS‐CoV2 in vitro. These findings are intriguing, although there is no clinical evidence for a protective effect to reduce the likelihood of severe COVID‐19 or to treat the immune storm or adult respiratory distress syndrome (ARDS) that often causes severe morbidity. Here, we review the putative link between COVID‐19 and cyclosporine, while we await more robust clinical data.

Currently, no treatment exists to improve semen quality in most infertile men. Here, we demonstrate systemic and direct effects of Fibroblast growth factor 23 (FGF23) and Klotho, which normally regulate vitamin D and mineral homeostasis, on testicular function. Direct effects are plausible because KLOTHO is expressed in both germ cells and spermatozoa and forms with FGFR1 a specific receptor for the bone-derived hormone FGF23. Treatment with FGF23 increased testicular weight in wild-type mice, while mice with global loss of either FGF23 or Klotho had low testicular weight, reduced sperm count, and sperm motility. Mice with germ cell-specific Klotho (gcKL) deficiency neither had a change in sperm count nor sperm motility. However, a tendency toward fewer pregnancies was detected, and significantly fewer Klotho heterozygous pups originated from gcKL knockdown mice than would be expected by mendelian inheritance. Moreover, gcKL mice had a molecular phenotype with higher testicular expression of Slc34a2 and Trpv5 than wild-type littermates, which suggests a regulatory role for testicular phosphate and calcium homeostasis. KLOTHO and FGFR1 were also expressed in human germ cells and spermatozoa, and FGF23 treatment augmented the calcium response to progesterone in human spermatozoa. Moreover, cross-sectional data revealed that infertile men with the highest serum Klotho levels had significantly higher serum Inhibin B and total sperm count than men with the lowest serum Klotho concentrations. In conclusion, this translational study suggests that FGF23 and Klotho influence gonadal function and testicular mineral ion homeostasis both directly and indirectly through systemic changes in vitamin D and mineral homeostasis.

Background Several animal studies, and one inoculation study in adult asthmatics have shown that interleukin-33 (IL-33) is a major contributor to type-2 inflammation in acute asthma. However, the link between IL-33 and type-2 inflammation has not been shown in naturally occurring asthma exacerbations. Objectives To determine if airway IL-33 is associated with type-2 inflammation measured by type-2 cytokines, FeNO and sputum eosinophils in patients presenting to the Emergency Department with an asthma exacerbations. Methods Adult patients hospitalized due to acute asthma were enrolled. Upper airways were sampled with nasal swabs and lower airways with induced sputum. Cytokines were measured at protein level using a Luminex® assay and mRNA expression level using droplet-digital-PCR. Airway sampling was repeated four weeks after exacerbation. Results At the time of exacerbation, upper airway IL-33 correlated with upper airway IL-5 and IL-13 (R = 0.84, p, Highlights • IL-33 correlates to type 2 cytokines in hospitalized patients with acute asthma. • Airway IL-13 and IL-33 positively correlate with fractional exhaled nitric oxide. • Airway IL-5 correlates to blood eosinophils in naturally occurring acute asthma.

INTRODUCTION Animal studies, and in vivo inoculation with rhinovirus, have shown that the epithelial-derived cytokine interleukin-33 (IL-33) is a major contributor to Th2-inflammation in acute asthma. However the link between IL-33 and Th2-inflammation has never been shown in naturally occurring cases of acute asthma. AIMS AND OBJECTIVES To determine whether IL-33 plays a role in driving Th2-inflammation in hospitalised acute asthma patients, we aimed to investigate whether the level of IL-33 in the nasal epithelium correlated with levels of Th2 cytokines in upper and lower airways. METHODS Patients admitted to hospital with an acute asthma exacerbation were recruited. Nasal swabs were used to sample nasal fluid representing upper airways, and induced sputum were collected, representing lower airways. Sampling was repeated after 4 weeks, and all samples analysed using Droplet Digital PCR for IL-33, IL-5 and IL-13. RESULTS Nineteen patients were recruited. Nasal IL-33 correlated with IL-5 in both upper and lower airways during acute asthma (0.75, p=0.008 and 0.74, p=0.010, respectively). Similar correlations were found with IL-13 (0.64, p=0.018 and 0.65, p=0.017, respectively). These associations were not significant at the 4-week follow-up. Sputum IL-33 was not associated with IL-5 or IL-13 in either sputum or in the nasal epithelium. CONCLUSION Nasal, but not sputum IL-33 is associated with Th2-promoting cytokines IL-5 and IL-13 in naturally occurring acute asthma cases. These findings support the role of IL-33 as an initiator of Th2-inflammation in acute asthma.