Specification and development of the pars intercerebralis and pars lateralis, neuroendocrine command centers in the Drosophila brain

The central neuroendocrine system in the Drosophila brain includes two centers, the pars intercerebralis (PI) and pars lateralis (PL). The PI and PL contain neurosecretory cells (NSCs) which project their axons to the ring gland, a complex of peripheral endocrine glands flanking the aorta. We present here a developmental and genetic study of the PI and PL. The PI and PL are derived from adjacent neurectodermal placodes in the dorso-medial head. The placodes invaginate during late embryogenesis and become attached to the brain primordium. The PI placode and its derivatives express the homeobox gene Dchx1 and can be followed until the late pupal stage. NSCs labeled by the expression of Drosophila insulin-like peptide (Dilp), FMRF, and myomodulin form part of the Dchx1 expressing PI domain. NSCs of the PL can be followed throughout development by their expression of the adhesion molecule FasII. Decapentaplegic (Dpp), secreted along the dorsal midline of the early embryo, inhibits the formation of the PI and PL placodes; loss of the signal results in an unpaired, enlarged placodeal ectoderm. The other early activated signaling pathway, EGFR, is positively required for the maintenance of the PI placode. Of the dorso-medially expressed head gap genes, only tailless (tll) is required for the specification of the PI. Absence of the corpora cardiaca, the endocrine gland innervated by neurosecretory cells of the PI and PL, does not affect the formation of the PI/PL, indicating that inductive stimuli from their target tissue are not essential for early PI/PL development.     

A rangewide herbarium‐derived dataset indicates high levels of gene flow in black cherry (Prunus serotina)

Isolation by Distance (IBD) is a genetic pattern in which populations geographically closer to one another are more genetically similar to each other than populations which are farther apart. Black cherry (Prunus serotina Ehrh.) (Rosaceae) is a forest tree species widespread in eastern North America, and found sporadically in the southwestern United States, Mexico, and Guatemala. IBD has been studied in relatively few North American plant taxa, and no study has rigorously sampled across the range of such a widespread species. In this study, IBD and overall genetic structure were assessed in eastern black cherry (P. serotina Ehrh. var. serotina), the widespread variety of eastern North America. Eastern North America. Prunus serotina Ehrh. var. serotina (Rosaceae). Dense sampling across the entire range of eastern black cherry was made possible by genotyping 15 microsatellite loci in 439 herbarium samples from all portions of the range. Mantel tests and STRUCTURE analyses were performed to evaluate the hypothesis of IBD and genetic structure. Mantel tests demonstrated significant but weak IBD, while STRUCTURE analyses revealed no clear geographic pattern of genetic groups. The modest geographic/genetic structure across the eastern black cherry range suggests widespread gene flow in this taxon. This is consistent with P. serotina's status as a disturbance‐associated species. Further studies should similarly evaluate IBD in species characteristic of low‐disturbance forests.     

Antibody responses against SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines in health care workers in the Netherlands: A prospective cohort study

BackgroundEmerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants.Methods and findingsIn a prospective cohort of 165 SARS-CoV-2 naive health care workers in the Netherlands, vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S), we performed a head-to-head comparison of the ability of sera to recognize and neutralize SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma, Delta and Omicron). Repeated serum sampling was performed 5 times during a year (from January 2021 till January 2022), including before and after booster vaccination with BNT162b2. Four weeks after completing the initial vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of mRNA-1273, followed by recipients of BNT162b2 (geometric mean titers (GMT) of 358 [95% CI 231–556] and 214 [95% CI 153–299], respectively; p<0.05), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (GMT of 18 [95% CI 11–30] and 14 [95% CI 8–25] IU/ml, respectively; p<0.001). VOCs neutralization was reduced in all vaccine groups, with the greatest reduction in neutralization GMT observed against the Omicron variant (fold change 0.03 [95% CI 0.02–0.04], p<0.001). The booster BNT162b2 vaccination increased neutralizing antibody titers for all groups with substantial improvement against the VOCs including the Omicron variant. We used linear regression and linear mixed model analysis. All results were adjusted for possible confounding of age and sex. Study limitations include the lack of cellular immunity data.ConclusionsOverall, this study shows that the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after initial vaccination and after booster vaccination, which implies the use of mRNA vaccines for both initial and booster vaccination.

Marit J. van Gils and colleagues investigate antibody responses against diverse emerging SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines in health care workers in the Netherlands.     

Secundum atrial septal defect in adults: a practical review and recent developments

Secundum atrial septal defect (ASDII) is a common congenital heart defect that causes shunting of blood between the systemic and pulmonary circulations. Patients with an isolated ASDII often remain asymptomatic during childhood and adolescence. If the defect remains untreated, however, the rates of exercise intolerance, supraventricular arrhythmias, right ventricular dysfunction and pulmonary arterial hypertension (PAH) increase with patient age, and life expectancy is reduced. Transcatheter and surgical techniques both provide valid options for ASDII closure, the former being the preferred method. With the exception of those with severe and irreversible PAH, closure is beneficial to, and thus indicated in all patients with significant shunts, regardless of age and symptoms. The symptomatic and survival benefits conferred by defect closure are inversely related to patient age and the presence of PAH, supporting timely closure after diagnosis. In this paper we review the management of adult patients with an isolated ASDII, with a focus on aspects of importance to the decision regarding defect closure and medical follow-up.     

Comparative proteome analyses of host protein expression in response to Enterovirus 71 and Coxsackievirus A16 infections

Enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) are the main etiological agents of Hand, Foot and Mouth Disease (HFMD), a common disease among children and had caused several outbreaks in the Asia-Pacific region. Although being genetically close to each other, EV71 infection can cause serious and fatal neurological complications like encephalitis, myocarditis, acute flaccid paralysis (AFP) and aseptic meningitis, but not in CA16 infections. In this study, the cellular response of host cells infected with EV71 and CA16 was characterized and compared by 2-dimensional proteome analyses. A total of 16 proteins were identified to be differentially expressed in EV71 and CA16-infected host cells. Desmin and HSP27, both indirectly regulate the contraction of muscle cells, were significantly downregulated as a result of EV71 infection, suggesting a link to acute flaccid paralysis. The ability of EV71 to evade host immune system may be due to the downregulation of MHC-I synthesis proteins like protein disulfide isomerase A3 and calreticulin. Proteins such as nucleophosmin, nuclear ribonucleoprotein C, and eukaryotic translation initiation factor 2 were all downregulated significantly, suggesting the rapid shutting down of host translation machinery by EV71. These findings provide insight into the nature of high virulent EV71 infection as compared to CA16.     

Fate of stem cell transplants in peripheral nerves

While damaged peripheral nerves demonstrate some potential to regenerate, complete functional recovery remains infrequent, owing to a functional loss of supportive Schwann cells distal to the injury. An emerging solution to improve upon this intrinsic regenerative capacity is to supplement injured nerves with stem cells derived from various tissues. While many of these strategies have proven successful in animal models, few studies have examined the behavior of transplanted stem cells in vivo, including whether they survive and differentiate. In previous work, we demonstrated that cells derived from neonatal rodent dermis (skin-derived precursor cells, or SKPs) could improve regenerative parameters when transplanted distal to both acute and chronic nerve injuries in Lewis rats. The aim of this work was to track the fate of these cells in various nerve injury paradigms and determine the response of these cells to a known glial growth factor. Here, we report that SKPs survive, respond to local cues, differentiate into myelinating Schwann cells, and avoid complete clearance by the host's immune defenses for a minimum of 10 weeks. Moreover, the ultimate fate of SKPs in vivo depends on the nerve environment into which they are injected and can be modified by inclusion of heregulin-1β.     

Triazoloamides as potent γ-secretase modulators with reduced hERG liability

Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Aβ42 IC(50) in cell-based assays and reduced affinity for the hERG channel.     

Ice Templated Free‐Standing Hierarchically WS2/CNT‐rGO Aerogel for High‐Performance Rechargeable Lithium and Sodium Ion Batteries

A hybrid nanoarchitecture aerogel composed of WS₂ nanosheets and carbon nanotube‐reduced graphene oxide (CNT‐rGO) with ordered microchannel three‐dimensional (3D) scaffold structure was synthesized by a simple solvothermal method followed by freeze‐drying and post annealing process. The 3D ordered microchannel structures not only provide good electronic transportation routes, but also provide excellent ionic conductive channels, leading to an enhanced electrochemical performance as anode materials both for lithium‐ion batteries (LIBs) and sodium‐ion batteries (SIBs). Significantly, WS₂/CNT‐rGO aerogel nanostructure can deliver a specific capacity of 749 mA h g^?1 at 100 mA g^?1 and a high first‐cycle coulombic efficiency of 53.4% as the anode material of LIBs. In addition, it also can deliver a capacity of 311.4 mA h g^?1 at 100 mA g^?1, and retain a capacity of 252.9 mA h g^?1 at 200 mA g^?1 after 100 cycles as the anode electrode of SIBs. The excellent electrochemical performance is attributed to the synergistic effect between the WS₂ nanosheets and CNT‐rGO scaffold network and rational design of 3D ordered structure. These results demonstrate the potential applications of ordered CNT‐rGO aerogel platform to support transition‐metal‐dichalcogenides (i.e., WS₂) for energy storage devices and open up a route for material design for future generation energy storage devices.     

Design of selective PI3Kδ inhibitors using an iterative scaffold-hopping workflow

PI3Kδ mediates key immune cell signaling pathways and is a target of interest for multiple indications in immunology and oncology. Here we report a structure-based scaffold-hopping strategy for the design of chemically diverse PI3Kδ inhibitors. Using this strategy, we identified several scaffolds that can be combined to generate new PI3Kδ inhibitors with high potency and isoform selectivity. In particular, an oxindole-based scaffold was found to impart exquisite selectivity when combined with several hinge binding motifs.