Reflecting on the health effects of chronic stress| editor's selection of the April issue of eBioMedicine

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The Lancet Discovery Science is a group of open access academic journals, including Lancet's eBioMedicine, Part of The Lancet Discovery Science and eClinicalMedicine, covering areas including basic medical research, Translational medicine research, clinical research and health system research. This group of journals publishes important initial studies that help researchers and clinicians discover new opportunities that may improve the health and well-being of people around the world. The Lancet has launched a compilation of selected papers from eBioMedicine to share with readers.

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Selected papers

1

Telomere length-dependent T cell clonal expansion: a model of senescence associated with lymphopenia and mortality in COVID-19 T cells

Severe COVID-19 T-cell lymphopenia is more common in older adults and has a poor prognosis. Counteracting the decline in the number of T cells during COVID-19 infection requires rapid and large number of T cell clone expansions, a process that is telomere length (TL) dependent.

James J. Anderson and his team at the University of Washington developed a model of telomere length-dependent T cell clonal expansion capacity with age, and actually examined the relationship between T cell clonal amplification and COVID-19 mortality in the general population. The model showed that individuals with average hematopoietic cell telomeres maintained maximum T cell clonal expansion capacity at age 20, and until age 60, this ability rapidly declined by more than 90% over 10 years. The decline in the capacity of T cell clones to expand coincides with a sharp increase in COVID-19 mortality with age. Short hematopoietic cell telomere length may increase the susceptibility of many older adults and some young adults to T-cell lymphopenia and serious diseases caused by COVID-19.

2

Induction of SARS-CoV-2 neutralizing antibodies with CoronaVac and BNT162b2 vaccines in uninfected COVID-19 populations and previously infected people

One of the main challenges of the COVID-19 pandemic is to better define "protection thresholds" to guide the global response. Nicole D. Tischler, Rafael A. Medina and their team from the Chilean Catholic University and the Albert Einstein School of Medicine in the United States studied the dynamic antibody responses of naturally infected individuals in Chile and compared them with humoral responses caused by coronavirus immunization based on inactivated viruses or BNT162b2 vaccines. The authors also compared them with data on the effectiveness and availability of the two vaccines, respectively.

The study measured and compared changes in neutralizing and antinucleocapsid antibody responses in 74 patients with COVID-19 (37 outpatients and 37 inpatients) during the acute and convalescent phases. They also assessed antibody changes in 36 patients who were vaccinated against CoronaVac (n = 30) or BNT162b2 (n = 6) after rehabilitation. Antibody titers were measured simultaneously on 50 individuals who were not infected but were vaccinated with two doses of coronaVac (n = 35) or BNT162b2 (n = 15) vaccines. They compared the neutralization level after vaccination with the neutralization level of the convalescent individual and estimated the predicted efficacy.

SarS-CoV-2 infection was found to induce a strong neutralizing antibody and anti-N antibody response lasting greater than 9 months, but the neutralizing antibody showed rapid decay. After the recovery period, CoronaVac or BNT162b2 vaccination significantly improves neutralizing antibody titers. In uninfected individuals, calculating the mean titers induced by the two doses of CoronaVac or BNT162b2 were 0.2-fold and 5.2-fold, respectively, for convalescent individuals, and were recommended as protective thresholds. CoronaVac does not or induces only a small number of anti-N antibody reactions. Using a logistic model established by the two authors, the predicted efficacy of BNT162b2 was estimated at 97%, closely consistent with the Phase 3 efficacy study, while coronaVac's predicted efficacy was about 50%, corresponding to the lowest range of clinical trials, lower than the true data for the Gamma variant during the Chilean epidemic (February 2 to May 1, 2021), when vaccine efficacy against COVID-19 was estimated to be 62.8% to 64.6%.

In individuals with past infections, the attenuation of neutralizing antibody titers over time suggests the need for vaccination to enhance humoral memory responses. Two doses of CoronaVac-induced neutralizing antibody titers were given to uninfected individuals significantly lower than those in convalescent patients, similar to one dose of BTN162b2. The actual life effectiveness of CoronaVac in Chile was higher than expected, suggesting that the low titers and additional cellular immune responses caused by the coronavirus may provide protection for highly immune populations. Nonetheless, the two doses of CoronaVac vaccine induce lower neutralizing antibody titers in uninfected individuals compared to the BTN162b2 vaccine, highlighting the need for enhanced immunity over time, especially when new SARS-CoV-2 variants emerge, to maintain protective levels of antibodies.

3

Human tau protein accumulation promotes glycogen synthase kinase-3β acetylation: a vicious cycle of Alzheimer's neurodegenerative degeneration

Glycogen synthase kinase-3β (GSK-3β) is one of the most effective kinases to promote hyperphosphorylation and accumulation of the Alzheimer's disease (AD) tau protein. Scholars from Huazhong University of Science and Technology and Zhengzhou University published an article in this issue of eBioMedicine to discuss the regulatory mechanism in the development of AD. The authors identified the acetylation site of GSK-3β by mass spectrometry, then established a cell and animal model of GSK-3β acetylation and conducted studies at the molecular, cell biology, and behavioral levels. They found that GSK-3β protein levels were elevated in the brains of AD patients and transgenic mice. Overexpression of tau protein can increase GSK-3β protein and its acetylation levels while reducing ubiquitination-associated proteolysis levels. Tau protein directly acetylizes GSK-3β at the K15 site, both in vitro and in vivo. K15-acetylation inhibits the proteolysis of Ubiquitination-associated GSK-3β, altering its activity-dependent phosphorylation, leading to over-activation of kinases. Activation of K15-acetylated GSK-3β in turn exacerbates AD-like lesions. Competitive inhibition of GSK-3β k15-acetylation by a newly designed peptide significantly improved cognitive impairment and AD-like pathology in 3xTg-AD mice. The results of the study showed that Tau can be acetylated directly at the K15 site of GSK-3β, revealing a vicious cycle between Tau hyperphosphorylation and GSK-3β activation.

4

In acute pancreatitis, keto acts as an endogenous protective program to inhibit the activation of inflammatory macrophages

Innate immunity and its metabolites are associated with the pathogenesis and severity of acute pancreatitis (AP). However, liver metabolism and its role in immune response and AP progression remain unclear. In this issue, eBioMedicine published a collaborative study by Shanghai Jiao Tong University School of Medicine and West China Hospital to explore the role of liver metabolism in the pathogenesis of AP.

The authors first measured circulating ketone body β-hydroxybutyric acid (βOHB) levels in the AP clinical cohort and rain frog peptide-induced AP (Cer-AP) mouse models and compared their liver transcriptomics and metabolomics. They inhibited fatty acid β oxidation (FAO) ketogenicity in mouse models or supplemented with βOHB, and then explored the role and mechanism of βOHB through in vitro studies.

The authors found that circulating betaOHB was elevated in patients with non-severe AP (SAP), but not in SAP patients. This result is consistent with the mouse model, which manifests as a limited and overactive immune response. In animals that received 7 injections of rain frog peptide per hour, FAO-ketogenesis was activated, while in animals that received 12 injections of rain frog peptide per hour, long-chain FAO and mitochondrial function were impaired. βOHB has a significant effect on pancreatic acinar cell damage, which has the potential to inhibit the activation of pro-inflammatory macrophages through class I histone deacetylase.

5

The science of stress reduction

In 2016, WHO listed mental stress as a modern health epidemic. Today, 6 years later, it is clear that the various events that have taken place around the world have not alleviated the pressure on people. A WHO report released in March 2022 estimated that the COVID-19 pandemic has led to a 25% increase in the global prevalence of anxiety and depression, largely due to the pressures of prolonged social distancing. The UK has designated April as Stress Awareness Month, hoping to provide an important opportunity to reflect on the health effects of chronic stress and the scientific evidence behind popular stress reduction interventions and coping strategies. This issue of eBioMedicine editorials explores topics related to stress reduction. END

Cover image by Séverine Urfer

*Chinese translation is for reference only, and all content is subject to the original English text.