Spread of Mutant Middle East Respiratory Syndrome Coronavirus with Reduced Affinity to Human CD26 during the South Korean Outbreak

The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe respiratory infection with a high mortality rate (similar to 35%). MERS-CoV has been a global threat due to continuous outbreaks in the Arabian peninsula and international spread by infected travelers since 2012. From May to July 2015, a large outbreak initiated by an infected traveler from the Arabian peninsula swept South Korea and resulted in 186 confirmed cases with 38 deaths (case fatality rate, 20.4%). Here, we show the rapid emergence and spread of a mutant MERS-CoV with reduced affinity to the human CD26 receptor during the South Korean outbreak. We isolated 13 new viral genomes from 14 infected patients treated at a hospital and found that 12 of these genomes possess a point mutation in the receptor-binding domain (RBD) of viral spike (S) protein. Specifically, 11 of these genomes have an I529T mutation in RBD, and 1 has a D510G mutation. Strikingly, both mutations result in reduced affinity of RBD to human CD26 compared to wild-type RBD, as measured by surface plasmon resonance analysis and cellular binding assay. Additionally, pseudotyped virus bearing an I529T mutation in S protein showed reduced entry into host cells compared to virus with wild-type S protein. These unexpected findings suggest that MERS-CoV adaptation during human-to-human spread may be driven by host immunological pressure such as neutralizing antibodies, resulting in reduced affinity to host receptor, and thereby impairs viral fitness and virulence, rather than positive selection for a better affinity to CD26. IMPORTANCE Recently, a large outbreak initiated by an MERS-CoV-infected traveler from the Middle East swept South Korea and resulted in 186 confirmed cases with 38 deaths. This is the largest outbreak outside the Middle East, and it raised strong concerns about the possible emergence of MERS-CoV mutations. Here, we isolated 13 new viral genomes and found that 12 of them possess a point mutation in the receptor-binding domain of viral spike protein, resulting in reduced affinity to the human cognate receptor, CD26, compared to the wild-type virus. These unexpected findings suggest that MERS-CoV adaptation in humans may be driven by host immunological pressure.111819Ysciescopu

Ell3 Enhances Differentiation of Mouse Embryonic Stem Cells by Regulating Epithelial-Mesenchymal Transition and Apoptosis

Ell3 is a testis-specific RNA polymerase II elongation factor whose cellular function is not clear. The present study shows that Ell3 is activated during the differentiation of mouse embryonic stem cells (mESCs). Furthermore, Ell3 plays a critical role in stimulating lineage differentiation of mESCs by promoting epithelial-mesenchymal transition (EMT) and suppressing apoptosis. Mouse ESCs engineered to stably express Ell3 were rapidly differentiated compared with control cells either under spontaneous differentiation or neural lineage-specific differentiation conditions. Gene expression profile and quantitative RT-PCR analysis showed that the expression of EMT markers, such as Zeb1 and Zeb2, two major genes that regulate EMT, was upregulated in Ell3-overexpressing mESCs. Remarkably, knockdown of Zeb1 attenuated the enhanced differentiation capacity of Ell3-overexpressing mESCs, which indicates that Ell3 plays a role in the induction of mESC differentiation by inducing EMT. In contrast to Ell3-overexpressing mESCs, Ell3-knock down mESCs could not differentiate under differentiation conditions and, instead, underwent caspase-dependent apoptosis. In addition, apoptosis of differentiating Ell3-knock out mESCs was associated with enhanced expression of p53. The present results suggest that Ell3 promotes the differentiation of mESCs by activating the expression of EMT-related genes and by suppressing p53 expression

Novel roles of the chemorepellent axon guidance molecule RGMa in cell migration and adhesion

The repulsive guidance molecule A (RGMa) is a contact-mediated axon guidance molecule that has significant roles in central nervous system (CNS) development. Here we have examined whether RGMa has novel roles in cell migration and cell adhesion outside the nervous system. RGMa was found to stimulate cell migration from Xenopus animal cap explants in a neogenin-dependent and BMP-independent manner. RGMa also stimulated the adhesion of Xenopus animal cap cells, and this adhesion was dependent on neogenin and independent of calcium. To begin to functionally characterize the role of specific domains in RGMa, we assessed the migratory and adhesive activities of deletion mutants. RGMa lacking the partial von Willebrand factor type D (vWF) domain preferentially perturbed cell adhesion, while mutants lacking the RGD motif affected cell migration. We also revealed that manipulating the levels of RGMa in vivo caused major migration defects during Xenopus gastrulation. We have revealed here novel roles of RGMa in cell migration and adhesion and demonstrated that perturbations to the homeostasis of RGMa expression can severely disrupt major morphogenetic events. These results have implications for understanding the role of RGMa in both health and disease

Knockdown of Midgut Genes by dsRNA-Transgenic Plant-Mediated RNA Interference in the Hemipteran Insect Nilaparvata lugens

BACKGROUND: RNA interference (RNAi) is a powerful technique for functional genomics research in insects. Transgenic plants producing double-stranded RNA (dsRNA) directed against insect genes have been reported for lepidopteran and coleopteran insects, showing potential for field-level control of insect pests, but this has not been reported for other insect orders. METHODOLOGY/PRINCIPAL FINDINGS: The Hemipteran insect brown planthopper (Nilaparvata lugens Stål) is a typical phloem sap feeder specific to rice (Oryza sativa L.). To analyze the potential of exploiting RNAi-mediated effects in this insect, we identified genes (Nlsid-1 and Nlaub) encoding proteins that might be involved in the RNAi pathway in N. lugens. Both genes are expressed ubiquitously in nymphs and adult insects. Three genes (the hexose transporter gene NlHT1, the carboxypeptidase gene Nlcar and the trypsin-like serine protease gene Nltry) that are highly expressed in the N. lugens midgut were isolated and used to develop dsRNA constructs for transforming rice. RNA blot analysis showed that the dsRNAs were transcribed and some of them were processed to siRNAs in the transgenic lines. When nymphs were fed on rice plants expressing dsRNA, levels of transcripts of the targeted genes in the midgut were reduced; however, lethal phenotypic effects after dsRNA feeding were not observed. CONCLUSIONS: Our study shows that genes for the RNAi pathway (Nlsid-1 and Nlaub) are present in N. lugens. When insects were fed on rice plant materials expressing dsRNAs, RNA interference was triggered and the target genes transcript levels were suppressed. The gene knockdown technique described here may prove to be a valuable tool for further investigations in N. lugens. The results demonstrate the potential of dsRNA-mediated RNAi for field-level control of planthoppers, but appropriate target genes must be selected when designing the dsRNA-transgenic plants

Angiogenesis and chronic kidney disease

The number of patients requiring renal replacement therapy due to end-stage renal disease (ESRD) is increasing worldwide. The prevalence of chronic kidney disease (CKD), and the importance of CKD as a risk factor in development of ESRD and in complicating cardiovascular disease (CVD) have been confirmed. In recent years, the involvement of angiogenesis-related factors in the progression of CKD has been studied, and the potential therapeutic effects on CKD of modulating these factors have been identified. Vascular endothelial growth factor (VEGF)-A, a potent pro-angiogenic factor, is involved in the development of the kidney, in maintenance of the glomerular capillary structure and filtration barrier, and in the renal repair process after injury. VEGF-A is also involved in the development of early diabetic nephropathy, demonstrated by the therapeutic effects of anti-VEGF-A antibody. Angiopoietin (Ang)-1 induces the maturation of newly formed blood vessels, and the therapeutic effects of Ang-1 in diabetic nephropathy have been described. In experimental models of diabetic nephropathy, the therapeutic effects of angiogenesis inhibitors, including angiostatin, endostatin and tumstatin peptides, the isocoumarin NM-3, and vasohibin-1, have been reported

Opioid-free anesthesia with lidocaine for improved postoperative recovery in hysteroscopy: a randomized controlled trial

Abstract Background Anesthesia with opioids negatively affects patients’ quality of recovery. Opioid-free anesthesia attempts to avoid these effects. This study aimed to evaluate the effect of opioid-free anesthesia on the quality of recovery, using lidocaine on patients undergoing hysteroscopy. Methods A parallel-group, randomized, double-blind, controlled trial was conducted in Yichang Central Peoples’ Hospital, Hubei Province, China, from January to April, 2022. We included 90 female patients (age: 18–65 years, American Society of Anesthesiologists Physical Status Class I–II) scheduled for elective hysteroscopy, 45 of whom received lidocaine (Group L), and 45 received sufentanil (Group S). Patients were randomly allocated to receive either lidocaine or sufentanil perioperatively. The primary outcome was the quality of postoperative recovery, which was assessed using the QoR-40 questionnaire (a patient-reported outcome questionnaire measuring the quality of recovery after surgery). Results The two groups were similar in age, American Society of Anesthesiology physical status, height, weight, body mass index, and surgical duration. The QoR scores were significantly higher in Group L than Group S. The incidence of postoperative nausea and vomiting, as well as the time to extubation were significantly lower in Group L than Group S. Conclusion Opioid-free anesthesia with lidocaine achieves a better quality of recovery, faster recovery, and a shorter time to extubation than general anesthesia with sufentanil. Trial registration The trial was registered on January 15, 2022 in the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/showprojen.aspx?proj=149386 ), registration number ChiCTR2200055623.(15/01/2022)

Tunable threshold voltage of an n-type Si nanowire ferroelectric-gate field effect transistor for high-performance nonvolatile memory applications.

We successfully fabricated ferroelectric-gate field effect transistor (FEFET)-based nonvolatile memory devices using an n-type Si nanowire coated with omega-shaped-gate organic ferroelectric poly(vinylidene fluoride-trifluoroethylene) via a low-temperature fabrication process. Our FEFET memory devices with controllable threshold voltage via adjustment of the doping concentration exhibit excellent memory characteristics with ultra-low ON state power dissipation (≤3 nW), a large modulation in channel conductance between the ON and OFF states exceeding 10(5), a long retention time of over 3 × 10(4) s and a high endurance of over 10(5) programming cycles whilst maintaining an I ON/I OFF ratio higher than 10(3). This result may be promising for next-generation nonvolatile memory on flexible substrate applications

High performance Si nanowire field-effect-transistors based on a CMOS inverter with tunable threshold voltage.

We successfully fabricated nanowire-based complementary metal-oxide semiconductor (NWCMOS) inverter devices by utilizing n- and p-type Si nanowire field-effect-transistors (NWFETs) via a low-temperature fabrication processing technique. We demonstrate that NWCMOS inverter devices can be operated at less than 1 V, a significantly lower voltage than that of typical thin-film based complementary metal-oxide semiconductor (CMOS) inverter devices. This low-voltage operation was accomplished by controlling the threshold voltage of the n-type Si NWFETs through effective management of the nanowire (NW) doping concentration, while realizing high voltage gain (>10) and ultra-low static power dissipation (≤3 pW) for high-performance digital inverter devices. This result offers a viable means of fabricating high-performance, low-operation voltage, and high-density digital logic circuits using a low-temperature fabrication processing technique suitable for next-generation flexible electronics