Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented challenge for health care and the global economy. Repurposing drugs that have shown promise ...in inhibiting other viral infections could allow for more rapid dispensation of urgently needed therapeutics. The Spike protein of SARS-CoV-2 is extensively glycosylated with 22 occupied N glycan sites and is required for viral entry. In other glycosylated viral proteins, glycosylation is required for interaction with calnexin and chaperone-mediated folding in the endoplasmic reticulum, and prevention of this interaction leads to unfolded viral proteins and thus inhibits viral replication. As such, we investigated two iminosugars, celgosivir, a prodrug of castanospermine, and UV-4, or N-(9-methoxynonyl)-1-deoxynojirimycin, a deoxynojirimycin derivative. Iminosugars are known inhibitors of the α-glucosidase I and II enzymes and were effective at inhibiting authentic SARS-CoV-2 viral replication in a cell culture system. Celgosivir prevented SARS-CoV-2-induced cell death and reduced viral replication and Spike protein levels in a dose-dependent manner in culture with Vero E6 cells. Castanospermine, the active form of celgosivir, was also able to inhibit SARS-CoV-2, confirming the canonical castanospermine mechanism of action of celgosivir. The monocyclic UV-4 also prevented SARS-CoV-2-induced death and reduced viral replication after 24 h of treatment, although the reduction in viral copies was lost after 48 h. Our findings suggest that iminosugars should be urgently investigated as potential SARS-CoV-2 inhibitors.
Using a gradient descent algorithm, a study on the linkage between strategic human resource management and organizational effectiveness. A logarithmic function with a base of 10 is used to represent ...the useful value of the fused elements of the association and simplify the expression formula for the usefulness of management. The usefulness of the management approach in achieving organizational effectiveness is measured using the information gain approach. The square of the difference between the predicted and true values is used as the loss function value, and the gradient descent algorithm is combined with the gradient descent algorithm to divide the effective joint data and calculate the solution gradient for all samples. Evaluation indexes such as accuracy and recall test the joint degree effective prediction model. The results show that the usefulness of the joint degree effective prediction model is classified into three degree levels: average 0,0.2), useful 0.2,0.4), and 40% or more as very useful. The team’s organizational commitment results in 50% of employees working hard, and only 5% are unmotivated to work.
•We focuses on seven commonly used hypnotics to analyze the effects of long- and short-term use on adults and older adults.•Main outcomes are total sleep time, sleep efficiency, sleep latency and ...WASO.•ORAs can be widely used in adults and the elderly, and both short-term and long-term use are effective for primary insomnia.•H1-antagonists are more effective in adults than in the elderly.•As a food supplement, melatonin has little effect on adults, but it still has a certain effect on the elderly.
This study focuses on seven commonly used hypnotics to comprehensively analyze the effects of long- and short-term use on sleep outcomes among adults and older adults.
A network meta-analysis was performed. The insomnia medications were classified into seven categories: benzodiazepines, z-drugs, melatonin, H1-antagonists, orexin receptor antagonists (ORAs), antidepressants, and anticonvulsants. We compared their efficacy of total sleep time, sleep latency, sleep efficiency and wake after sleep onset in subgroups short-term, long-term, elderly, and adults.
A total of 111 RCTs involving 25,923 participants were included in this study.
ORAs can be widely used in adults and the elderly, and both short-term and long-term use are effective for primary insomnia. H1-antagonists are more effective in adults than in the elderly. Although benzodiazepines have a more obvious effect on sleep maintenance, it is best to reduce their use due to their side effects, especially for the elderly. As a food supplement, melatonin has little effect on adults, but it still has a certain effect on the elderly.
Zika virus (ZIKV) is an emerging pathogen with no approved therapeutics and only limited diagnostics available. To address this gap, six mouse single-chain antibodies (scFvs) to ZIKV envelope (E) ...protein were isolated rapidly and efficiently from a ribosome-displayed antibody library constructed from the spleens of five immunized mice.
In this report, we have generated a panel of mouse scFvs to ZIKV E protein using ribosome display. The six scFvs demonstrated no cross-reactivity with DENV2 NGC envelope protein, suggesting specificity for ZIKV E protein. These scFvs showed differences in their affinity: two (scFv45-3, scFv63-1) of them were dominant after four rounds of panning, and showed higher affinity (an apparent Kd values from 19 to 27 nM) than the other four (scFv5-1, scFv7-2, scFv38-1, and scFv51-2). All six scFvs showed ZIKV-neutralizing activity in the plaque reduction neutralization test (PRNT) assay and their neutralizing activity was positively correlated with their affinities.
The scFvs (45-3 and 63-1) with highest affinity may have dual utility as diagnostics capable of recognizing ZIKV E subtypes and may be further developed to treat ZIKV infection. Our approach has the added advantage of generating Fc receptor-deficient antibodies, minimizing concern of antibody-dependent enhancement (ADE) of infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hantaviruses are RNA viruses with known epidemic threat and potential for emergence. Several rodent-borne hantaviruses cause zoonoses accompanied by severe illness and death. However, assessments of ...zoonotic risk and the development of countermeasures are challenged by our limited knowledge of the molecular mechanisms of hantavirus infection, including the identities of cell entry receptors and their roles in influencing viral host range and virulence. Despite the long-standing presumption that β3/β1-containing integrins are the major hantavirus entry receptors, rigorous genetic loss-of-function evidence supporting their requirement, and that of decay-accelerating factor (DAF), is lacking. Here, we used CRISPR/Cas9 engineering to knockout candidate hantavirus receptors, singly and in combination, in a human endothelial cell line that recapitulates the properties of primary microvascular endothelial cells, the major targets of viral infection in humans. The loss of β3 integrin, β1 integrin, and/or DAF had little or no effect on entry by a large panel of hantaviruses. By contrast, loss of protocadherin-1, a recently identified entry receptor for some hantaviruses, substantially reduced hantavirus entry and infection. We conclude that major host molecules necessary for endothelial cell entry by PCDH1-independent hantaviruses remain to be discovered.
Objective:
This study was determined to investigate the impact of intranasal dexmedetomidine (DEX) on postoperative sleep quality in older patients (age over 65) with chronic insomnia during their ...hospitalization after surgery.
Design:
A randomized double-blind controlled trial was conducted to compare the effects of intranasal dexmedetomidine spray with a placebo group.
Setting and Participants:
The study was carried out at Xiangya Hospital, Central South University. 110 participants with chronic insomnia were analyzed.
Methods:
This trial enrolled older patients who underwent total hip/knee arthroplasty and randomized them to receive intranasal dexmedetomidine (2.0 μg/kg) or saline daily at around 9 p.m. after surgery until discharge. The primary outcomes were subjective sleep quality assessed with the Leeds Sleep Evaluation Questionnaire (LSEQ). The secondary outcomes included the objective sleep quality measured with the Acti-graph, the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI). The other outcomes included the incidence of delirium, levels of inflammatory factors, visual analog scale (VAS) pain scores, postoperative opioid consumption, and treatment-related adverse events.
Results:
174 patients were screened for eligibility, and 110 were recruited and analyzed. The DEX group had significantly higher scores on both the LSEQ-Getting to sleep and LSEQ-Quality of Sleep at each time point compared to the placebo (
p
< 0.0001), The least squares (LS) mean difference in LSEQ-GTS score at T0 between placebo group and DEX group was 2 (95% CI, −1–6),
p
= 0.4071 and at T5 was −14 (95% CI, −17 to −10),
p
< 0.0001; The LS mean difference in the LSEQ-QOS score at T0 was −1 (95% CI, −4 to 1),
p
= 0.4821 and at T5 was −16 (95% CI, −21 to −10),
p
< 0.0001. The DEX group exhibited significant improvement in Total Sleep Time (TST), Sleep Onset Latency (SOL), and Sleep Efficiency (SE), at each time point after treatment compared to the placebo group (
p
< 0.0001). The PSQI and ISI scores in the DEX group were reduced after treatment (
p
< 0.001). No significant adverse events were reported with the use of dexmedetomidine.
Conclusion and Implications:
This study demonstrates that intranasal administration of dexmedetomidine improves postoperative sleep quality in older patients with chronic insomnia who undergo surgery, without increasing the incidence of adverse effects.
Clinical Trial Registration:
http://www.chictr.org.cn/
, identifier ChiCTR2200057133
The SARS-CoV-2 pandemic has highlighted the need for protective and effective personal protective equipment (PPE). Research has shown that SARS-CoV-2 can survive on personal protective equipment, ...such as commonly used surgical masks. Methods are needed to inactivate virus on contaminated material. We show here that embedding viral-disinfecting compounds during the manufacturing of surgical masks inactivates a high dose (up to 1 × 105 pfu) of live, authentic SARS-CoV-2 within minutes.
Orthohantaviruses cause hantavirus cardiopulmonary syndrome; most cases occur in the southwest region of the United States. We discuss a clinical case of orthohantavirus infection in a 65-year-old ...woman in Michigan and the phylogeographic link of partial viral fragments from the patient and rodents captured near the presumed site of infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: The mechanism underlying delirium, a common acute fluctuating mental state, may be related to the activation of a neuroinflammatory response. In this study, we attempted to investigate ...whether plasma inflammatory response markers, vascular and cerebrovascular injury-related markers, and neurodegeneration-associated markers were associated with emergence delirium (ED). Methods: Patients aged 50 years or above who underwent elective laparoscopic surgery under general anesthesia were included in this study. Delirium was assessed postoperatively with the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scale. Plasma samples were collected from ED patients and non-ED patients to test concentrations of inflammation markers, including interleukin 6 (IL-6), chitinase 3-like 1 (CHI3L1), S100 calciumbinding protein B (S100B), lipoprotein-associated phospholipase-A2 (Lp-PLA2), and macrophage migration inhibitory factor (MIF);vascular and cerebrovascular injury-related markers, including intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM‐1); and neurodegeneration-associated markers, including alpha‐synuclein (α‐Syn) and β‐secretase 1 (BACE1).Binary logistic regression analysis was performed to analyze the relationship between biomarkers and ED, and receiver operating characteristic (ROC) curves were used to analyze the diagnostic value of biomarkers. Results: A total of 104 patients were included in this study, with an average age of 63.69±7.21. IL-6 (OR=2.73, 95% CI: 1.66-6.44, P=0.022), S100B (OR=4.74, 95% CI: 1.88-11.95, P=0.001) and BACE1 (OR=6.54, 95% CI: 2.57-16.65, P<0.000) were independent biological indicators for the occurrence of ED.CHI3L1, Lp-PLA2, MIF, ICAM-1, VCAM-1, and α-Syn were unrelated to ED. Plasma BACE1 level had a possible diagnostic value for ED (area under curve AUC=0.75, 95% CI: 0.66-0.85), whereas plasma IL-6 (AUC=0.62, 95% CI: 0.51-0.73) and S100B (AUC=0.65, 95% CI: 0.54-0.76) levels had little diagnostic value for distinguish ED versus non-ED. Conclusion: Higher levels of systemic inflammation marker IL-6, cerebral inflammation marker S100B, and neurodegeneration-associated marker BACE1 are related to ED. Plasma BACE1 may be a potential diagnostic biomarker for ED.
The gamma-glutamyl transpeptidase-to-platelet ratio (GPR) is a new noninvasive marker for assessing liver fibrosis. We aimed to evaluate the performance of GPR for prediction of 90-day mortality in ...patients with acute-on-chronic liver failure (ACLF).
A total of 355 patients with HBV-associated ACLF were enrolled from two clinical centers and divided into training group (n=210) and validation group (n=145). Potential risk factors for 90-day mortality were analyzed.
Age, MELD score and GPR were independent risk factors associated with ACLF prognosis. A new scoring system (MELD-GPR) was developed. MELD-GPR=9.211−0.029×age−0.290×MELD−0.460×GPR. For ACLF patients with liver cirrhosis, the area under the receiver operating characteristic curve (AUROC) of MELD-GPR was 0.788, which was significantly higher than that of MELD and MELD-Na (0.706 and 0.666, respectively). Patients were stratified into three groups according to MELD-GPR scores (high risk: <−0.19, intermediate risk: −0.19–0.95, and low risk: >0.95), and the high-risk group (MELD-GPR<−0.19) had a poor prognosis (P<0.01). For ACLF patients without liver cirrhosis, MELD-GPR<0.95 predicted a poor prognosis.
Incorporating GPR into MELD may provide more accurate survival prediction in patients with HBV-ACLF.
•Age, TBil, MELD score and GPR were independent risk factors for ACLF prognosis.•A new scoring system (MELD-GPR) was developed and validated.•For LC-ACLF patients, AUROC of MELD-GPR was higher than that of MELD and MELD-Na.•For LC-ACLF patients, the high-risk group (MELD-GPR<−0.13) had a poor prognosis.•For ACLF patients without LC, MELD-GPR<0.39 predicted a poor prognosis.
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