COVID-19 Breakthrough Infections and Transmission Risk: Real-World Data Analyses from Germany's Largest Public Health Department (Cologne).

BACKGROUND AND METHODS: Vaccination is currently considered the most successful strategy for combating the SARS-CoV-2 virus. According to short-term clinical trials, protection against infection is estimated to reach up to 95% after complete vaccination (≥14 days after receipt of all recommended COVID-19 vaccine doses). Nevertheless, infections despite vaccination, so-called breakthrough infections, are documented. Even though they are more likely to have a milder or even asymptomatic course, the assessment of further transmission is highly relevant for successful containment. Therefore, we calculated the real-world transmission risk from fully vaccinated patients (vaccination group, VG) to their close contacts (CP) compared with the risk from unvaccinated reference persons matched according to age, sex, and virus type (control group = CG) utilizing data from Cologne's health department. RESULTS: A total of 357 breakthrough infections occurred among Cologne residents between 27 December 2020 (the date of the first vaccination in Cologne) and 6 August 2021. Of the 979 CPs in VG, 99 (10.1%) became infected. In CG, 303 of 802 CPs (37.8%) became infected. Factors promoting transmission included non-vaccinated status (ß = 0.237; p < 0.001), male sex (ß = 0.079; p = 0.049), the presence of symptoms (ß = -0.125; p = 0.005), and lower cycle threshold value (ß = -0.125; p = 0.032). This model explained 14.0% of the variance (corr. R2). CONCLUSION: The number of transmissions from unvaccinated controls was three times higher than from fully vaccinated patients. These real-world data underscore the importance of vaccination in enabling the relaxation of stringent and restrictive general pandemic control measures.

Lhx2 regulates the timing of ß-catenin-dependent cortical neurogenesis.

The timing of cortical neurogenesis has a major effect on the size and organization of the mature cortex. The deletion of the LIM-homeodomain transcription factor Lhx2 in cortical progenitors by Nestin-cre leads to a dramatically smaller cortex. Here we report that Lhx2 regulates the cortex size by maintaining the cortical progenitor proliferation and delaying the initiation of neurogenesis. The loss of Lhx2 in cortical progenitors results in precocious radial glia differentiation and a temporal shift of cortical neurogenesis. We further investigated the underlying mechanisms at play and demonstrated that in the absence of Lhx2, the Wnt/ß-catenin pathway failed to maintain progenitor proliferation. We developed and applied a mathematical model that reveals how precocious neurogenesis affected cortical surface and thickness. Thus, we concluded that Lhx2 is required for ß-catenin function in maintaining cortical progenitor proliferation and controls the timing of cortical neurogenesis.

TEX11 modulates germ cell proliferation by competing with estrogen receptor ß for the binding to HPIP.

Klinefelter syndrome (KS), characterized by the presence of more than one X-chromosome in men, is a major genetic cause of male infertility. Germ cell degeneration in KS patients is thought to be the consequences of overexpression of some genes on the X-chromosome. However, the identity of these genes and the underlying mechanisms remain unclear. Testis-expressed 11 (TEX11) is an X-chromosome-encoded germ-cell-specific protein that is expressed most abundantly in spermatogonia and early spermatocytes in the testes. In our search for TEX11-interacting partners using the yeast two-hybrid system, we identified hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP), which anchors estrogen receptors (ER) to the cytoskeleton and modulates their functions. We found that mouse spermatogonial stem cells expressed Tex11, Hpip, and Esr2 but not Esr1. In cultured cells, TEX11 competed with ERß for binding to HPIP. Upon treatment with 17ß-estradiol or an ERß agonist diarylpropionitrile, TEX11 promoted the nuclear translocation of ERß and enhanced its transcriptional activities. On the other hand, TEX11 suppressed the nongenomic activities of ERß in the cytoplasm, as indicated by reduced phosphorylation of AKT and ERK signaling molecules. Overexpression of TEX11 in mouse germ-cell-derived GC-1 and GC-2 cells suppressed the cell proliferation and the expression of cFos, Ccnd1, and Ccnb1 that were stimulated by 17ß-estradiol or diarylpropionitrile and elevated the expression level of the proapoptotic Bax gene. The negative effect of TEX11 on cell proliferation suggests that increased expression of TEX11 in the germ cells may partially contribute to the spermatogenic defect observed in KS patients.

DAZAP1, an hnRNP protein, is required for normal growth and spermatogenesis in mice.

DAZAP1 (Deleted in Azoospermia Associated Protein 1) is a ubiquitous hnRNP protein that is expressed most abundantly in the testis. Its ability to shuttle between the nucleus and the cytoplasm and its exclusion from the transcriptionally inactive XY body in pachytene spermatocytes implicate it in mRNA transcription and transport. We generated Dazap1 mutant alleles to study the role of DAZAP1 in mouse development. Most mice homozygous for the null allele as well as a hypomorphic Fn allele died soon after birth. The few Dazap1(Fn/Fn) mice that survived could nonetheless live for more than a year. They appeared and behaved normally but were much smaller in size compared to their wild-type and heterozygous littermates. Both male and female Dazap1(Fn/Fn) mice were sterile. Males had small testes, and the seminiferous tubules were atrophic with increased numbers of apoptotic cells. The tubules contained many germ cells, including pachytene spermatocytes with visible XY-bodies and diplotene spermatocytes, but no post-meiotic cells. FACS analyses confirmed the absence of haploid germ cells, indicating spermatogenesis arrested right before the meiotic division. Female Dazap1(Fn/Fn) mice had small ovaries that contained normal-appearing follicles, yet their pregnancy produced no progeny due to failure in embryonic development. The phenotypes of Dazap1 mutant mice indicate that DAZAP1 is not only essential for spermatogenesis, but also required for the normal growth and development of mice.

Partial duplication at AZFc on the Y chromosome is a risk factor for impaired spermatogenesis in Han Chinese in Taiwan.

The Azoospermia Factor c (AZFc) region on the Y chromosome long arm is one of the least stable regions in the human genome. It consists almost entirely of very long repeats and is prone to rearrangement. Numerous structures at AZFc have been identified, and some of them have been reported to be associated with male infertility. We screened 580 Han Chinese in Taiwan for AZFc deletion and duplication using three PCR assays, and characterized the DAZ genes in selected subjects with additional Southern analyses. About 9.5% of our subjects have AZFc partial deletion, 2.8% have partial deletion followed by duplication, and 1.7% have partial duplication. The overall rearrangement frequencies vary significantly between different Y chromosome haplogroups (Yhgs), ranging from 2.9% in O3e to 100% in N and Q. All individuals in Yhg-N lack the sY1191 marker, but one out of three of them actually have four DAZ genes, indicating further duplication after the b2/b3 deletion. Our additional screening of 142 oligospermic men and 107 fertile controls found no significant difference in the frequencies of the gr/gr and the b2/b3 deletion. However, the frequency of AZFc partial duplication in the infertile group (7.0%) was significantly higher than that in the fertile control group (0.9%) and the general Taiwanese population (1.7%). Our results indicate that AZFc partial deletion and partial duplication are common polymorphisms in Han Chinese, and that the AZFc partial duplication, but not the AZFc partial deletion, is a risk factor for male infertility in the Taiwanese population.