Serum resistance is a poorly understood but common trait of some difficult-to-treat pathogenic strains of bacteria. Here, we report that glycine, serine and threonine catabolic pathway is ...down-regulated in serum-resistant Escherichia coli, whereas exogenous glycine reverts the serum resistance and effectively potentiates serum to eliminate clinically-relevant bacterial pathogens in vitro and in vivo. We find that exogenous glycine increases the formation of membrane attack complex on bacterial membrane through two previously unrecognized regulations: 1) glycine negatively and positively regulates metabolic flux to purine biosynthesis and Krebs cycle, respectively. 2) α-Ketoglutarate inhibits adenosine triphosphate synthase, which in together promote the formation of cAMP/CRP regulon to increase the expression of complement-binding proteins HtrE, NfrA, and YhcD. The results could lead to effective strategies for managing the infection with serum-resistant bacteria, an especially valuable approach for treating individuals with weak acquired immunity but a normal complement system.
Branched selectivity in asymmetric allylic C−H alkylation is enabled by using 2‐acylimidazoles as nucleophiles in the presence of a chiral phosphoramidite‐palladium catalyst. A wide range of terminal ...alkenes, including 1,4‐dienes and allylarenes, are nicely tolerated and provide chiral 2‐acylimidazoles in moderate to high yields and with high levels of regio‐, and enantio‐, and E/Z‐selectivities. Mechanistic studies using density‐functional theory calculations suggest a nucleophile‐coordination‐enabled inner‐sphere attack mode for the enantioselective carbon–carbon bond‐forming event.
Branching out: Palladium‐chiral phosphoramidite catalysis is used for an unprecedented branched‐selective asymmetric allylic C−H alkylation by using 2‐acylimidazoles as model coordinating nucleophiles. Density‐functional theory calculations suggest an unusual inner‐sphere mechanism for the carbon–carbon bond‐forming process.
Fangcang shelter hospitals were established in China during the coronavirus disease 2019 (COVID-19) pandemic as a countermeasure to stop the spread of the disease. To our knowledge, no research has ...been conducted on mental health problems among patients in Fangcang shelter hospitals. This study aimed to determine the prevalence and major influencing factors of anxiety and depressive symptoms among COVID-19 patients admitted to Fangcang shelter hospitals. From February 23, 2020, to February 26, 2020, we obtained sociodemographic and clinical characteristics information of COVID-19 patients in Jianghan Fangcang Shelter Hospital (Wuhan, China) and assessed their mental health status and sleep quality. Data were obtained with an online questionnaire. The questionnaire consisted of a set of items on demographic characteristics, a set of items on clinical characteristics, the Self-Rating Anxiety Scale, Self-Rating Depression Scale, and Pittsburgh Sleep Quality Index. Three hundred seven COVID-19 patients who were admitted to Jianghan Fangcang Shelter Hospital participated in this study. The prevalence of anxiety and depressive symptoms were 18.6% and 13.4%, respectively. Poor sleep quality and having ≥ two current physical symptoms were independent risk factors for anxiety symptoms. Female sex, having a family member with confirmed COVID-19, and having ≥ two current physical symptoms were independent risk factors for depressive symptoms. Anxiety and depressive symptoms were found to be common among COVID-19 patients in Fangcang Shelter Hospital, with some patients being at high risk.
The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C–H alkylation is principally more atom- and ...step-economic than the classical allylic functionalizations and thus can be considered a transformative variant. However, asymmetric allylic C–H alkylation reactions are still scarce and yet underdeveloped. Herein, we have found that Z/E- and regioselectivities in the Pd-catalyzed asymmetric allylic C–H alkylation of 1,4-dienes are highly dependent on the type of nucleophiles. A highly stereoselective allylic C–H alkylation of 1,4-dienes with azlactones has been established by palladium-chiral phosphoramidite catalysis. The protocol proceeds under mild conditions and can accommodate a wide scope of substrates, delivering structurally divergent α,α-disubstituted α-amino acid surrogates in high yields and excellent levels of diastereo-, Z/E-, regio-, and enantioselectivities. Notably, this method provides key chiral intermediates for an efficient synthesis of lepadiformine marine alkaloids. Experimental and computational studies on the reaction mechanism suggest a novel concerted proton and two-electron transfer process for the allylic C–H cleavage and reveal that the Z/E- and regioselectivities are governed by the geometry and coordination pattern of nucleophiles.
Abstract
The physical composition of the ejecta of gamma-ray bursts (GRBs) remains an open question. The radiation mechanism of the prompt gamma rays is also in debate. This problem can be solved for ...the bursts hosting distinct thermal radiation. However, the events with dominant thermal spectral components are still rare. In this work, we focus on GRB 220426A, a recent event detected by the Fermi Gamma-ray Burst Monitor. The time-resolved and time-integrated data analyses yield very hard low-energy spectral indices and rather soft high-energy spectral indices. This means that the spectra of GRB 220426A are narrowly distributed. And the Bayesian inference results are in favor of the multicolor blackbody model. The physical properties of the relativistic outflow are calculated. Assuming a redshift
z
= 1.4, the bulk Lorentz factors Γ of the shells are found to be between
274
−
18
+
24
and
827
−
71
+
100
, and the corresponding photosphere radii
R
ph
are in the range of
1.83
−
0.50
+
0.52
×
10
11
and
2.97
−
0.15
+
0.14
×
10
12
cm. Similar to GRB 090902B, the time-resolved properties of GRB 220426A satisfy the observed Γ–
L
and
E
p
–
L
correlations, where
L
is the luminosity of the prompt emission and
E
p
is the spectral peak energy.
The prevalence of multidrug-resistant bacteria has been increasing rapidly worldwide, a trend that poses great risk to human and animal health and creates urgent need for pharmaceutical and ...nonpharmaceutical approaches to stop the spread of disease due to antimicrobial resistance. Here, we found that alanine, aspartate, and glutamate metabolism was inactivated, and glutamine was repressed in multidrug-resistant uropathogenic
using a comparative metabolomics approach. Exogenous glutamine promoted β-lactam–, aminoglycoside-, quinolone-, and tetracycline-induced killing of uropathogenic
and potentiated ampicillin to eliminate multidrug-resistant
,
,
,
,
, and
. Glutamine-potentiated ampicillin-mediated killing was effective against biofilms of these bacteria in a mouse urinary tract infection model and against systemic infection caused by
,
,
, or
in a mouse model. Exogenous glutamine stimulated influx of ampicillin, leading to the accumulation of intracellular antibiotic concentrations that exceeded the amount tolerated by the multidrug-resistant bacteria. Furthermore, we demonstrated that exogenous glutamine promoted the biosynthesis of nucleosides including inosine, which in turn interacted with CpxA/CpxR and up-regulated OmpF. We validated the physiological relevance of the mechanism by showing that loss of
,
,
, or
elevated antibiotic resistance in antibiotic-sensitive strains. In addition, glutamine retarded the development of ampicillin resistance. These results may facilitate future development of effective approaches for preventing or managing chronic, multidrug-resistant bacterial infections, bacterial persistence, and difficult-to-treat bacterial biofilms.
Asymmetric functionalization of the C(sp3)–H bond is an attractive yet challenging strategy to achieve versatile bond-forming events, enabling the precise assembly of molecular complexity with ...minimal manipulation of functional groups. Here, we report an asymmetric C(sp3)–H/C(sp3)–H umpolung coupling of N-allylimine and coordinating α-aryl carbonyls by using chiral phosphoramidite-palladium catalysis. A wide variety of α-heteroaryl ketones and 2-acylimidazoles are nicely tolerated to open a convenient and tunable avenue for efficient synthesis of enantioenriched β-amino-γ,δ-unsaturated carbonyl derivatives with high levels of regio- and stereoselectivities, capable of providing a key intermediate for asymmetric synthesis of Focalin. This protocol showcases an umpolung reactivity of the N-allylimines through a concerted proton and two-electron transfer process to cleave the allylic C–H bond, effectively complementing established methodology for allylic C–H functionalization. An inner-sphere allylation pathway for both α-heteroaryl carbonyls and 2-acylimidazoles to attack the π-allylpalladium species is suggested by computational studies and experimental facts, wherein the nitrogen coordination to the palladium center enables the preference of branched regioselectivity.
Abstract A stellar-mass black hole (BH) or a millisecond magnetar is believed to be born as the central engine of gamma-ray bursts (GRBs). The presence of plateaus in the X-ray extended emission or ...afterglow of GRBs is widely accepted as an indicator of a magnetar central engine, particularly those with a sharp decay (faster than t −3 ), the so-called internal plateau. However, an alternative model, by taking the evolution of the magnetic flux at the BH horizon into account, suggests that an internal plateau can also arise from a jet powered by the Blandford–Znajek (BZ) mechanism (hereafter, a BZ jet). In this study, we propose that a precessional BZ jet would manifest a quasiperiodic oscillation (QPO) signature on the internal plateau and the subsequent sharp decay. Such lightcurves cannot be readily explained by the activity of a short-lived, supermassive magnetar, thus favoring a Kerr BH as the central engine. The X-ray afterglow of GRB 050904, comprising nine flares, is characterized by a QPO-modulated plateau and sharp decay, which can be well reproduced by a precessional BZ jet model. Therefore, one potential clue for distinguishing between these two engines lies in whether the QPO signature is present throughout the entire plateau and the subsequent sharp decay, as the magnetar scenario suggests a collapse at the end of the plateau.
An asymmetric allylic C–H alkylation of allyl ethers has been established by chiral phosphoramidite-palladium catalysis, affording a wide variety of functionalized chiral 2-acylimidazoles in moderate ...to high yields and with high levels of enantioselectivity. Moreover, this protocol could be applied to a concise asymmetric synthesis of a tachykinin receptor antagonist.
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