Risk factors for corticosteroid insufficiency during the sub-acute phase of acute traumatic brain injury

Hypothalamic-pituitary-adrenal axis dysfunction may lead to the occurrence of critical illness-related corticosteroid insufficiency.Critical illness-related corticosteroid insufficiency can easily occur after traumatic brain injury,but few studies have examined this occurrence.A multicenter,prospective,cohort study was performed to evaluate the function of the hypothalamic-pituitary-adrenal axis and the incidence of critical illness-related corticosteroid insufficiency during the sub-acute phase of traumatic brain injury.One hundred and forty patients with acute traumatic brain injury were enrolled from the neurosurgical departments of three tertiary-level hospitals in China,and the critical illness-related corticosteroid insufficiency incidence,critical-illness-related corticosteroid insufficiency-related risk factors,complications,and 28-day mortality among these patients was recorded.Critical illness-related corticosteroid insufficiency was diagnosed in patients with plasma total cortisol levels less than 10μg/dL(275.9 nM)on post-injury day 4 or when serum cortisol was insufficiently suppressed(less than 50%)during a dexamethasone suppression test on post-injury day 5.The results demonstrated that critical illness-related corticosteroid insufficiency occurred during the sub-acute phase of traumatic brain injury in 5.6%of patients with mild injury,22.5%of patients with moderate injury,and 52.2%of patients with severe injury.Traumatic brain injury-induced critical illness-related corticosteroid insufficiency was strongly correlated to injury severity during the sub-acute stage of traumatic brain injury.Traumatic brain injury patients with critical illness-related corticosteroid insufficiency frequently presented with hemorrhagic cerebral contusions,diffuse axonal injury,brain herniation,and hypotension.Differences in the incidence of hospital-acquired pneumonia,gastrointestinal bleeding,and 28-day mortality were observed between patients with and without critical illness-related corticosteroid insufficiency during the sub-acute phase of traumatic brain injury.Hypotension,brain-injury severity,and the types of traumatic brain injury were independent risk factors for traumatic brain injury-induced critical illness-related corticosteroid insufficiency.These findings indicate that critical illness-related corticosteroid insufficiency is common during the sub-acute phase of traumatic brain injury and is strongly associated with poor prognosis.The dexamethasone suppression test is a practical assay for the evaluation of hypothalamic-pituitary-adrenal axis function and for the diagnosis of critical illness-related corticosteroid insufficiency in patients with traumatic brain injury,especially those with hypotension,hemorrhagic cerebral contusions,diffuse axonal injury,and brain herniation.Sub-acute infection of acute traumatic brain injury may be an important factor associated with the occurrence and development of critical illness-related corticosteroid insufficiency.This study protocol was approved by the Ethics Committee of General Hospital of Tianjin Medical University,China in December 2011(approval No.201189).

Structural characterization of SARS-CoV-2 dimeric ORF9b reveals potential fold-switching trigger mechanism

The constant emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants indicates the evolution and adaptation of the virus.Enhanced innate immune evasion through increased expression of viral antagonist proteins,including ORF9b,contributes to the improved transmission of the Alpha variant;hence,more attention should be paid to these viral proteins.ORF9b is an accessory protein that suppresses innate immunity via a monomer conformation by binding to Tom70.Here,we solved the dimeric structure of SARS-CoV-2 ORF9b with a long hydrophobic tunnel containing a lipid molecule that is crucial for the dimeric conformation and determined the specific lipid ligands as monoglycerides by conducting a liquid chromatography with tandem mass spectrometry analysis,suggesting an important role in the viral life cycle.Notably,a long intertwined loop accessible for host factor binding was observed in the structure.Eight phosphorylated residues in ORF9b were identified,and residues S50 and S53 were found to contribute to the stabilization of dimeric ORF9b.Additionally,we proposed a model of multifunctional ORF9b with a distinct conformation,suggesting that ORF9b is a fold-switching protein,while both lipids and phosphorylation contribute to the switching.Specifically,the ORF9b monomer interacts with Tom70 to suppress the innate immune response,whereas the ORF9b dimer binds to the membrane involving mature virion assembly.Our results provide a better understanding of the multiple functions of ORF9b.

A pan-coronavirus peptide inhibitor prevents SARS-CoV-2 infection in mice by intranasal delivery

Coronaviruses(Co Vs)have brought serious threats to humans,particularly severe acute respiratory syndrome coronavirus 2(SARS-Co V-2),which continually evolves into multiple variants.These variants,especially Omicron,reportedly escape therapeutic antibodies and vaccines,indicating an urgent need for new antivirals with pan-SARS-Co V-2 inhibitory activity.We previously reported that a peptide fusion inhibitor,P3,targeting heptad repeated-1(HR1)of SARS-Co V-2 spike(S)protein,could inhibit viral infections.Here,we further designed multiple derivatives of the P3 based on structural analysis and found that one derivative,the P315V3,showed the most efficient antiviral activity against SARS-Co V-2 variants and several other sarbecoviruses,as well as other human-Co Vs(HCo Vs).P315V3 also exhibited effective prophylactic efficacy against the SARS-Co V-2 Delta and Omicron variants in mice via intranasal administration.These results suggest that P315V3,which is in PhaseⅡclinical trial,is promising for further development as a nasal pan-SARS-Co V-2 or pan-Co Vs inhibitor to prevent or treat CoV diseases.

Corrosion behavior of Fe–Cr–Ni based alloys exposed to molten MgCl_(2)–KCl–NaCl salt with over-added Mg corrosion inhibitor

MgCl_(2)–NaCl–KCl salts mixture shows great potential as a high-temperature(>700°C)thermal energy storage material in next-generation concentrated solar power plants.Adding Mg into molten MgCl_(2)–NaCl–KCl salt as a corrosion inhibitor is one of the most effective and cost-effective methods to mitigate the molten salt corrosion of commercial Fe–Cr–Ni alloys.However,it is found in this work that both stainless steel 310 and Incoloy 800H samples were severely corroded after 500 h immersion test at 700°C when the alloy samples directly contacted with the over-added Mg in the liquid form.The corrosion attack is different from the classical impurity-driven corrosion in molten chloride salts found in previous work.Microscopic analysis indicates that Ni preferentially leaches out of alloy matrix due to the tendency to form MgNi_(2)/Mg_(2)Ni compounds.The Ni-depletion leads to the formation of a porous corrosion layer on both alloys,with the thickness around 204μm(stainless steel 310)and 1300μm(Incoloy 800H),respectively.These results suggest that direct contact of liquid Mg with Ni-containing alloys should be avoided during using Mg as a corrosion inhibitor for MgCl_(2)–NaCl–KCl or other chlorides for high temperature heat storage and transfer.

Structural basis of Semliki Forest virus entry using the very-low-density lipoprotein receptor

Alphaviruses are a group of important viruses that cause significant diseases in humans.Among them,Semliki Forest vi-rus(SFV)not only causes symptoms such as joint pain but also infects neuron cells and induces encephalitis in rodents.Recently,the very-low-density lipoprotein receptor(VLDLR)was identified as the cellular receptor for SFV entry.In this study,we present the cryo-electron microscopy structure of SFV bound to human VLDLR.VLDLR targets E1-DIII region of SFV using its membrane-distal LDLR class A(LA)repeats.Structural and functional analyses emphasize the synergistic role of multiple VLDLR repeats in the SFV entry.Remarkably,VLDLR’s binding mode to SFV closely mirrors that of minor group human rhinoviruses but differs significantly from other alphaviruses’interactions with receptors in the canyon re-gion of the E protein.We also assessed SFV binding to VLDLR or apolipoprotein E receptor 2(ApoER2)proteins in horses and mosquitoes and revealed their use of multiple but different LA repeats for binding.Our findings illuminate SFV’s cross-species infectivity,offering insights into potential antiviral strategies against alphavirus infections.

A protective human antibody against respiratory syncytial virus by targeting a prefusion epitope across sites IV and V of the viral fusion glycoprotein

Respiratory syncytial virus(RSV)is one of the leading pathogens that cause lower respiratory tract infections in infants and the elderly.Passive immunoprophylaxis with monoclonal antibody(mAb)has been approved to prevent morbidity and mortality from RSV infection in infants.Here we report the isolation of two neutralizing mAbs against RSV from convalescent children by prefusion form of fusion(F)glycoprotein as bait.One mAb RV11 exhibited good potency in neutralization of RSV strains from both A and B subtypes in cell-based assay,and protected mice from RSV infection in vivo.An RV11 escape mutant was identified,which contains an S443P mutation in F protein.Crystal structure showed the RV11 bound to a conserved prefusion epitope across the antigenic sites IV and V of the F glycoprotein.RV11 showed a strong synergistic effect when combined with two RSV antivirals,an F-targeting small molecular inhibitor ziresovir and a siteØneutralizing mAb D25(the parental mAb for nirsevimab).The study extended our knowledge to the neutralizing and protective epitopes of RSV,and the mAb RV11 deserves further development for clinical translation.

Crystal structure of the African swine fever virus core shell protein p15

African swine fever virus(ASFV)is the causative agent of African swine fever,a highly fatal hemorrhagic disease of pigs,which has resulted in great economic losses to the global pork industry,especially in Asia.ASFV particles are comprised ofmultiple layers encompassing the genomic DNA.Though the capsid structure has been determined,very little is known about the structure of the core shell.The precursor polyprotein pp62 is the structural component of the core shell that gives rise to the p35 and p15 proteins.Herein,we describe the crystal structure of p15 at a resolution of 2.2Å.The structure of p15 exhibits as a trimeric conformation that is mainly mediated by intermolecular disulfide bonds and supported bymultiple hydrogen bond interactions.The button conformation on the surface of adjacentmolecules may also play a role in trimeric formation of the ASFV p15.The center of the p15 trimer exhibits opposite electrostatic characteristics on each side.These findings benefit our understanding of ASFV core shell assembly and will aid in the design of antiviral drugs and vaccines.

A neutralizing-protective supersite of human monoclonal antibodies for yellow fever virus

The yellow fever virus(YFV)is a life-threatening human pathogen.Owing to the lack of available therapeutics,non-vaccinated individuals are at risk.Here,we isolated eight human monoclonal antibodies that neutralize YFV infection.Five recognized overlapping epitopes and exhibited potent neutralizing activity.Two(YD6 and YD73)were ultra-potent and conferred complete protection against the lethal challenge of YFV as both prophylactics and therapeutics in a mouse model.Crystal structures revealed that YD6 engaged the YFV envelope protein in both pre-and post-fusion states,suggesting viral inhibition by a“double-lock”mechanism.The recognition determinants for YD6 and YD73 are clustered at the premembrane(prM)-binding site.Notably,antibodies targeting this site were present in minute traces in YFV-infected individuals but contributed significantly to neutralization,suggesting a vulnerable supersite of YFV.We provide two promising candidates for immunotherapy against YFV,and the supersite represents an ideal target for epitope-based vaccine design.

Distinct PD-L1 binding characteristics of therapeutic monoclonal antibody durvalumab

Dear Editor,Blockade of PD-1/PD-L1 signaling pathway by monoclonal antibodies(MAbs)to release the anti-tumor activity of pre-existing tumor specific T cell immunity has initiated a new era for tumor immunotherapy.Administration of anti-PD-1 MAbs(nivolumab and pembrolizumab)in either monotherapy or in combination with anti-CTLA-4 MAbs or traditional chemother-apy has achieved a tumor regression rate of 30%-50%in dealing with melanoma,non-small cell lung cancer,etc.(Larkin et al.,2015).

Structural and functional insights into MCR-2 mediated colistin resistance

Dear Editor,The spread of antibiotic resistance genes among bacteria is a serious and growing threat to global health (Peleg and Hoopet,2010).One emerging case is transferable genes found in bacteria-encoding enzymes resistant to colistin.Colistin is a cationic polypeptide antibiotic with broadspectrum activity against Gram-negative bacteria through interactions with the lipid A moiety of bacterial lipopoly-saccharide(LPS),subsequently destroying the cell envelope.During late 2015,a plasmid-mediated gene,mcr-1,was first reported from Escherichia coli(E.coli)in China to confer resistance to colistin(Liu et a1.,2016),and detected world-wide soon afterwards(Gao et a1.,2016;Hu et a1.,2016).

Use of a compact high-definition two-dimensional exoscope in surgical treatment of large vestibular schwannoma

Background::Extra-corporeal video telescope operating monitor system provides a necessary instrument to perform high-precision neurosurgical procedures that could substitute or supplement the traditional surgical microscope.The present study was designed to evaluate a compact high-definition two-dimensional exoscope system for assisting in surgical removal of large vestibular schwannoma(VS),as an alternative to a binocular surgical microscope.Methods::Patients with Koos grade 3 and grade 4 VS undergoing surgery were enrolled in this prospective cohort study between January 2013 and June 2018.The demographics and tumor characteristics(size,Koos grade,composition[cystic or solid mass])were matched between the two groups of patients.The following outcome measurements were compared between the two groups:duration of surgery,volume of blood loss,extent of tumor resection,number of operating field adjustments,pre-and post-operative facial and cochlear nerve function evaluated at 3 months post-surgery,complications and surgeons’comfortability.Results::A total of 81 patients received tumor resection through the retrosigmoid approach under either an exoscope(cases,n=39)or a surgical microscope(control,n=42).Patients in the two groups had comparable tumor location(P=0.439),Koos grading(P=0.867),and composition(P=0.891).While no significant differences in the duration of surgery(P=0.172),extent of tumor resection(P=0.858),facial function(P=0.838),and hearing ability(P=1.000),patients operated on under an exoscope had less blood loss(P=0.036)and a fewer field adjustments(P<0.001).Both primary and assistant surgeons reported a high level of comfort operating under the exoscope(P=0.001 and P<0.001,respectively).Conclusions::The compact high-definition two-dimensional exoscope system provides a safe and efficient means to assist in removing large VSs,as compared to a surgical microscope.After the acquaintance with a visual perception through a dynamic hint and stereoscopically viewing corresponding to the motion parallax,the exoscope system provided a comfortable,high-resolution visualization without compromising operational efficiency and patient safety.

The identification of a CD47-blocking“hotspot”and design of a CD47/PD-L1 dual-specific antibody with limited hemagglutination

Dear Editor,By targeting the programmed cell death 1(PD-1)pathway with monoclonal antibodies(mAbs),immune checkpoint therapy(ICT)has achieved unprecedented clinical success in the treatment of multiple tumors.1,2 Cancer cells evade the host immune system via both the tolerance of T cells and functional suppression of innate immune cells.3 CD47 provides a“do not eat me”signal by binding to signal regulatory protein alpha(SIRPα)to prevent innate immune cells from attacking host cells.4 Recently,macrophages were found to restore antitumor reactivity by blocking the interaction between upregulated CD47 on tumor cells and SIRPαon innate immune cells.5 However,it remains unknown whether there are blocking“hotspots”on CD47 for mAb-based anti-CD47 therapy or additional blocking hotspot regions within CD47 for therapeutic mAb development.Although it is overexpressed on tumor cells,CD47 is also expressed in many normal cells,including red blood cells and platelets.6 Some validated CD47-blocking mAbs under clinical investigation induce hemagglutination and anemia.7 Thus,designing an engineered CD47-blocking antibody to exert a therapeutic effect with limited hemagglutination is needed.