Objective This study aimed to conduct a systematic review of the current literature to determine estimates of vertical transmission of coronavirus disease 2019 based on early RNA detection of severe acute respiratory syndrome coronavirus 2 after birth from various neonatal or fetal sources and neonatal serology. Data Sources Eligible studies published until May 28, 2020, were retrieved from PubMed, EMBASE, medRxiv, and bioRxiv collection databases. Study Eligibility Criteria This systematic review included cohort studies, case series, and case reports of pregnant women who received a coronavirus disease 2019 diagnosis using severe acute respiratory syndrome coronavirus 2 viral RNA test and had reported data regarding the testing of neonates or fetuses for severe acute respiratory syndrome coronavirus 2 immediately after birth and within 48 hours of birth. A total of 30 eligible case reports describing 43 tested neonates and 38 cohort or case series studies describing 936 tested neonates were included. Study Appraisal and Synthesis Methods The methodological quality of all included studies was evaluated by a modified version of the Newcastle-Ottawa scale. Quantitative synthesis was performed on cohort or case series studies according to the neonatal biological specimen site to reach pooled proportions of vertical transmission. Results Our quantitative synthesis revealed that of 936 neonates from mothers with coronavirus disease 2019, 27 neonates had a positive result for severe acute respiratory syndrome coronavirus 2 viral RNA test using nasopharyngeal swab, indicating a pooled proportion of 3.2% (95% confidence interval, 2.2–4.3) for vertical transmission. Of note, the pooled proportion of severe acute respiratory syndrome coronavirus 2 positivity in neonates by nasopharyngeal swab in studies from China was 2.0% (8/397), which was similar to the pooled proportion of 2.7% (14/517) in studies from outside of China. Severe acute respiratory syndrome coronavirus 2 viral RNA testing in neonatal cord blood was positive in 2.9% of samples (1/34), 7.7% of placenta samples (2/26), 0% of amniotic fluid (0/51), 0% of urine samples (0/17), and 9.7% of fecal or rectal swabs (3/31). Neonatal serology was positive in 3 of 82 samples (3.7%) (based on the presence of immunoglobulin M). Conclusion Vertical transmission of severe acute respiratory syndrome coronavirus 2 is possible and seems to occur in a minority of cases of maternal coronavirus disease 2019 infection in the third trimester. The rates of infection are similar to those of other pathogens that cause congenital infections. However, given the paucity of early trimester data, no assessment can yet be made regarding the rates of vertical transmission in early pregnancy and potential risk for consequent fetal morbidity and mortality.

6-Deoxyerythronolide B, the macrocyclic aglycone of the antibiotic erythromycin, is synthesized by a polyketide synthase (PKS) that has emerged as the prototypical modular megasynthase. A variety of molecular biological, protein chemical, and biosynthetic experiments over the past two decades have yielded insights into its mechanistic features. More recently, high-resolution structural images of portions of the 6-deoxyerythronolide B synthase have provided a platform for interpreting this wealth of biochemical data, while at the same time presenting a fundamentally new basis for the design of more detailed investigations into this remarkable enzyme. For example, the critical roles of domain-domain interactions and nonconserved linkers, as well as large interdomain movements in the structure and function of modular PKSs, have been highlighted. In turn, these insights point the way forward for more sophisticated and efficient biosynthetic engineering of complex polyketide natural products.

We report the 2.6 A X-ray crystal structure of a 190 kDa homodimeric fragment from module 3 of the 6-deoxyerthronolide B synthase covalently bound to the inhibitor cerulenin. The structure shows two well-organized interdomain linker regions in addition to the full-length ketosynthase (KS) and acyltransferase (AT) domains. Analysis of the substrate-binding site of the KS domain suggests that a loop region at the homodimer interface influences KS substrate specificity. We also describe a model for the interaction of the catalytic domains with the acyl carrier protein (ACP) domain. The ACP is proposed to dock within a deep cleft between the KS and AT domains, with interactions that span both the KS homodimer and AT domain. In conjunction with other recent data, our results provide atomic resolution pictures of several catalytically relevant protein interactions in this remarkable family of modular megasynthases.

Polyketide synthases (PKSs) catalyze the production of numerous biologically important natural products via repeated decarboxylative condensation reactions. Modular PKSs, such as the 6-deoxyerythronolide B synthase (DEBS), consist of multiple catalytic modules, each containing a unique set of covalently linked catalytic domains. To better understand the engineering opportunities of these assembly lines, the extender unit and acyl carrier protein (ACP) specificity of ketosynthase (KS) domains from modules 3 and 6 of DEBS were analyzed. These studies were undertaken with a newly developed didomain [KS][AT] construct, which lacks its own ACP domain and can therefore be interrogated with homologous or heterologous ACP or acyl-ACP substrates. By substituting the natural methylmalonyl extender unit with a malonyl group, a modest role was demonstrated for the KS in recognition of the nucleophilic substrate. The KS domain from module 3 of DEBS was found to exhibit a distinct ACP-recognition profile from the KS domain of module 6. Based on the above kinetic insights, a hybrid module was constructed ([TE]) which displayed substrate recognition and elongation capabilities consistent with the natural module 3 protein. Unlike module 3 however, which lacks a ketoreductase (KR) domain, the hybrid module was able to catalyze reduction of the β-ketothioester product of chain elongation. The high expression level and functionality of this hybrid protein demonstrates the usefulness of kinetic analysis for hybrid module design.