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To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

The significant morbidity and mortality resulted from the infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for urgent development of effective and safe vaccines. We report the immunogenicity and safety of an inactivated SARS-CoV-2 vaccine, KCONVAC, in healthy adults. Phase 1 and phase 2 randomized, double-blind, and placebo-controlled trials of KCONVAC were conducted in healthy Chinese adults aged 18 to 59 years. The participants in the phase 1 trial were randomized to receive two doses, one each on Days 0 and 14, of either KCONVAC (5 or 10 μg/dose) or placebo. The participants in the phase 2 trial were randomized to receive either KCONVAC (at 5 or 10 μg/dose) or placebo on Days 0 and 14 (0/14 regimen) or Days 0 and 28 (0/28 regimen). In the phase 1 trial, the primary safety endpoint was the proportion of participants experiencing adverse reactions/events within 28 days following the administration of each dose. In the phase 2 trial, the primary immunogenicity endpoints were neutralization antibody seroconversion and titer and anti-receptor-binding domain immunoglobulin G seroconversion at 28 days after the second dose. In the phase 1 trial, 60 participants were enrolled and received at least one dose of 5-μg vaccine (n = 24), 10-μg vaccine (n = 24), or placebo (n = 12). In the phase 2 trial, 500 participants were enrolled and received at least one dose of 5-μg vaccine (n = 100 for 0/14 or 0/28 regimens), 10-μg vaccine (n = 100 for each regimen), or placebo (n = 50 for each regimen). In the phase 1 trial, 13 (54%), 11 (46%), and seven (7/12) participants reported at least one adverse event (AE) after receiving 5-, 10-μg vaccine, or placebo, respectively. In the phase 2 trial, 16 (16%), 19 (19%), and nine (18%) 0/14-regimen participants reported at least one AE after receiving 5-, 10-μg vaccine, or placebo, respectively. Similar AE incidences were observed in the three 0/28-regimen treatment groups. No AEs with an intensity of grade 3+ were reported, expect for one vaccine-unrelated serious AE (foot fracture) reported in the phase 1 trial. KCONVAC induced significant antibody responses; 0/28 regimen showed a higher immune responses than that did 0/14 regimen after receiving two vaccine doses. Both doses of KCONVAC are well tolerated and able to induce robust immune responses in healthy adults. These results support testing 5-μg vaccine in the 0/28 regimen in an upcoming phase 3 efficacy trial. http://www.chictr.org.cn/index.aspx (No. ChiCTR2000038804, http://www.chictr.org.cn/showproj.aspx?proj=62350; No. ChiCTR2000039462, http://www.chictr.org.cn/showproj.aspx?proj=63353).

Dry eye disease (DED) is a common multifactorial disease affecting a substantial proportion of the population worldwide. Objective tests and subjective symptoms evaluation are necessary to assess DED. Although various treatments have been introduced, accurately evaluating the efficacy of those treatments is difficult because of the disparity between diagnostic tests and patient-reported symptoms. We reviewed the questionnaires used to evaluate DED and the improvements of quality of life with various treatments. In addition, we highlighted the importance of patient-reported outcomes (PRO) assessments for evaluating the effect of DED treatments. Given that the assessment of DED treatment effectiveness substantially relies on individual ocular experiences, acquiring qualitative PRO data is essential for comprehensive evaluation and optimal treatment management. Clinicians should not only focus on improving objective symptoms but also prioritize the well-being of patients in clinical management.

Kyphoplasty (KP) with intravertebral reduction devices (IRD) was reported to be associated with better radiological outcomes than KP with balloons (BK) for osteoporotic vertebral compression fractures (OVCFs). However, the mechanical factors that contribute to the radiological benefits of IRDs require further investigation. To probe the mechanical factors, this retrospective matched cohort study was designed, including the older patients with painful OVCFs and treated with KP. We compared the clinical and radiological outcomes between KP with an IRD and BK, where vertebral body height and kyphotic angle of the cemented vertebrae were measured pre- and postoperatively; clinical outcomes were collected by telephone interviews. The restoration and maintenance ratio suggested that IRDs were associated with favorable effects long-term wise in anterior to middle vertebral body and kyphosis than BK in patients. The gathered results concluded the radiological benefits of IRD regarding both its efficient restoration and maintenance in vertebrae.

An Escherichia coli-produced human papillomavirus (HPV) 16 and 18 bivalent vaccine (Cecolin) was prequalified by WHO in 2021. This study aimed to compare the immunogenicity of the E coli-produced HPV 9-valent vaccine Cecolin 9 (against HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) with Gardasil 9. This was a randomised, single-blind trial conducted in China. Healthy non-pregnant women aged 18–26 years, who were not breastfeeding and with no HPV vaccination history, were enrolled in the Ganyu Centre for Disease Control and Prevention (Lianyungang City, Jiangsu Province, China). Women were stratified by age (18–22 years and 23–26 years) and randomly assigned (1:1) using a permutated block size of eight to receive three doses of Cecolin 9 or Gardasil 9 at day 0, day 45, and month 6. All participants, as well as study personnel without access to the vaccines, were masked. Neutralising antibodies were measured by a triple-colour pseudovirion-based neutralisation assay. The primary outcomes, seroconversion rates and geometric mean concentrations (GMCs) at month 7, were analysed in the per-protocol set for immunogenicity (PPS-I). Non-inferiority was identified for the lower limit of the 95% CI of the GMC ratio (Cecolin 9 vs Gardasil 9) at a margin of 0·5 and a seroconversion rate difference (Cecolin 9–Gardasil 9) at a margin of –5%. This study was registered at ClinicalTrials.gov (NCT04782895) and is completed. From March 14 to 18, 2021, a total of 553 potential participants were screened, of which 244 received at least one dose of Cecolin 9 and 243 received at least one dose of Gardasil 9. The seroconversion rates for all HPV types in both groups were 100% in the PPS-I, with the values of the lower limits of 95% CIs for seroconversion rate differences ranging between –1·8% and –1·7%. The GMC ratios of five types were higher than 1·0, with the highest ratio, for HPV 58, at 1·65 (95% CI 1·38–1·97), and those of four types were lower than 1·0, with the lowest ratio, for HPV 11, at 0·79 (0·68–0·93). The incidence of adverse reactions in both groups was similar (43% [104/244] vs 47% [115/243]). Cecolin 9 induced non-inferior HPV type-specific immune responses compared with Gardasil 9 and is a potential candidate to accelerate the elimination of cervical cancer by allowing for global accessibility to 9-valent HPV vaccinations, especially in low-income and middle-income countries. National Natural Science Foundation, Fujian Provincial Natural Science Foundation, Xiamen Science and Technology Plan Project, Fundamental Research Funds for the Central Universities, CAMS Innovation Fund for Medical Sciences of China, and Xiamen Innovax.

Apocrine hidrocystomas are benign cystic tumors resulting from apocrine sweat glands’ proliferation. They typically present as solitary, slow-growing nodules at the head and neck, especially in the periorbital cutaneous region. We present a case of periorbital apocrine hidrocystoma in a 22-year-old woman that was treated as chalazion previously. Besides the hallmark histopathological findings of apocrine hidrocystoma, IgG4 plasma cell infiltration of the cystic wall was also found. The ratio of IgG4-to-IgG-positive plasma cells was high, whereas serum IgG4 was within the standard limit. This is, to date, the only probable IgG4-related ophthalmic disease associated with apocrine hidrocystoma.

This cranio-morphometric study emphasizes a “two-layer model” for eastern Eurasian anatomically modern human (AMH) populations, based on large datasets of 89 population samples including findings directly from ancient archaeological contexts. Results suggest that an initial “first layer” of AMH had related closely to ancestral Andaman, Australian, Papuan, and Jomon groups who likely entered this region via the Southeast Asian landmass, prior to 65–50 kya. A later “second layer” shared strong cranial affinities with Siberians, implying a Northeast Asian source, evidenced by 9 kya in central China and then followed by expansions of descendant groups into Southeast Asia after 4 kya. These two populations shared limited initial exchange, and the second layer grew at a faster rate and in greater numbers, linked with contexts of farming that may have supported increased population densities. Clear dichotomization between the two layers implies a temporally deep divergence of distinct migration routes for AMH through both southern and northern Eurasia.

Quantum discord is a measure of quantumness of correlations in bipartite states, which characterizes the difference between quantum mutual information and classical correlations. Based on the generators of Lie algebra su(d) , we study the quantum discord for two families of two-qudit states with maximally mixed marginals, and derive some upper bounds of quantum discord for such states by evaluating classical correlations. Furthermore, we make a comparison among total correlations, classical correlations and quantum discord for a class of special states in high-dimensional two-partite systems.

Background A significant number of infectious diseases affecting humans have been associated with zoonotic viruses. Wild small mammals, such as bats, rodents, and shrews, serve as natural reservoirs for a multitude of zoonotic viruses, particularly in Africa, where zoonosis is prevalent. Nevertheless, our knowledge of the virome composition within these hosts remains limited, impeding a more profound understanding of spillover events into human populations. Results We employed a viral metagenomics approach to characterize the virome in 846 wild small mammals sampled from Sierra Leone. Based on the complete RNA-dependent RNA polymerase genome, a total of 39 RNA viruses infecting mammals were identified, comprising 13 known viruses and 26 novel viruses. Notably, the Paramyxoviridae family exhibited the highest diversity of viral species across all three orders of wild mammal. The animal species Hipposideros jonesi and Lophuromys chrysopus were found to harbor the highest viral richness. Among these viral species, 15 were identified as cross-species transmitted viruses shared among different animal species, 3 were classified as zoonotic (Encephalomyocarditis virus, Rocahepevirus sp., and Lassa virus), while 3 others posed a potential risk for spillover (melian virus, Rodent hepacivirus, Hunnivirus A). Cross-species transmission analysis revealed that rodents played central roles in virus sharing, while cross-order viral transmission was less likely to occur in bats. Among 26 newly identified viruses, four viruses (Bat ledantevirus 2, Rattus rattus jeilongvirus, Miniopterus inflatus ribovirus, and Rat mamastrovirus) were predicted to have high zoonotic potential. Among them, Bat ledantevirus 2 exhibited the highest zoonotic potential and phylogenetic relatedness to the known human-infecting virus (Le Dantec virus). Further seroepidemiological analysis in patients, using single-round infectious virus particles as antigens, revealed the presence of neutralizing antibodies against Bat ledantevirus 2, a novel virus belonging to the Rhabdoviridae family. Conclusions These findings highlight the critical need for enhanced surveillance at the human-animal interface in order to identify viruses with cross-species transmission potential prior to their spillover into human population. 3jAdaZThBBPxLkCsTfWiSB Video Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a major impact on global human health. During the spread of SARS-CoV-2, weakened host immunity and the use of vaccines with low efficacy may result in the development of more-virulent strains or strains with resistance to existing vaccines and antibodies. The prevalence of SARS-CoV-2 mutant strains differs between regions, and this variation may have an impact on the effectiveness of vaccines. In this study, an epidemiological investigation of SARS-CoV-2 in Portugal was performed, and the VSV-ΔG-G* pseudovirus system was used to construct 12 spike protein epidemic mutants, D614G, A222V+D614G, B.1.1.7, S477N+D614G, P1162R+D614G+A222V, D839Y+D614G, L176F+D614G, B.1.1.7+L216F, B.1.1.7+M740V, B.1.258, B.1.258+L1063F, and B.1.258+N751Y. The mutant pseudoviruses were used to infect four susceptible cell lines (Huh7, hACE2-293T-293T, Vero, and LLC-MK2) and 14 cell lines overexpressing ACE2 from different species. Mutant strains did not show increased infectivity or cross-species transmission. Neutralization activity against these pseudoviruses was evaluated using mouse serum and 11 monoclonal antibodies. The neutralizing activity of immunized mouse serum was not significantly reduced with the mutant strains, but the mutant strains from Portugal could evade nine of the 11 monoclonal antibodies tested. Neutralization resistance was mainly caused by the mutations S477N, N439K, and N501Y in the spike-receptor binding domain. These findings emphasize the importance of SARS-CoV-2 mutation tracking in different regions for epidemic prevention and control.