Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (COVID-19). There is a dire need for novel effective antivirals to treat COVID-19, as ...the only approved direct-acting antiviral to date is remdesivir, targeting the viral polymerase complex. A potential alternate target in the viral life cycle is the main SARS-CoV-2 protease 3CLpro (Mpro). The drug candidate PF-00835231 is the active compound of the first anti-3CLpro regimen in clinical trials. Here, we perform a comparative analysis of PF-00835231, the preclinical 3CLpro inhibitor GC-376, and the polymerase inhibitor remdesivir, in alveolar basal epithelial cells modified to express ACE2 (A549+ACE2 cells). We find PF-00835231 with at least similar or higher potency than remdesivir or GC-376. A time-of-drug-addition approach delineates the timing of early SARS-CoV-2 life cycle steps in A549+ACE2 cells and validates PF-00835231’s early time of action. In a model of the human polarized airway epithelium, both PF-00835231 and remdesivir potently inhibit SARS-CoV-2 at low micromolar concentrations. Finally, we show that the efflux transporter P-glycoprotein, which was previously suggested to diminish PF-00835231’s efficacy based on experiments in monkey kidney Vero E6 cells, does not negatively impact PF-00835231 efficacy in either A549+ACE2 cells or human polarized airway epithelial cultures. Thus, our study provides in vitro evidence for the potential of PF-00835231 as an effective SARS-CoV-2 antiviral and addresses concerns that emerged based on prior studies in nonhuman in vitro models. IMPORTANCE The arsenal of SARS-CoV-2 specific antiviral drugs is extremely limited. Only one direct-acting antiviral drug is currently approved, the viral polymerase inhibitor remdesivir, and it has limited efficacy. Thus, there is a substantial need to develop additional antiviral compounds with minimal side effects and alternate viral targets. One such alternate target is its main protease, 3CLpro (Mpro), an essential component of the SARS-CoV-2 life cycle processing the viral polyprotein into the components of the viral polymerase complex. In this study, we characterize a novel antiviral drug, PF-00835231, which is the active component of the first-in-class 3CLpro-targeting regimen in clinical trials. Using 3D in vitro models of the human airway epithelium, we demonstrate the antiviral potential of PF-00835231 for inhibition of SARS-CoV-2.
The aim of this work is to analytically study the thermo-mechanical response of two-dimensional skin tissues when subjected to instantaneous heating. A complete understanding of the heat transfer ...process and the associated thermal and mechanical effects on the patient's skin tissues is critical to ensuring the effective applications of thermal therapy techniques and procedures. The surface boundary of the half-space undergoes a heat flux characterized by an exponentially decaying pulse, while maintaining a condition of zero traction. The utilization of Laplace and Fourier transformations is employed, and the resulting formulations are then applied to human tissues undergoing regional hyperthermia treatment for cancer therapy. To perform the inversion process for Laplace and Fourier transforms, a numerical programming method based on Stehfest numerical inverse method is employed. The findings demonstrate that blood perfusion rate and thermal relaxation time significantly influence all the analyzed distributions. Numerical findings suggest that thermo-mechanical waves propagate through skin tissue over finite distances, which helps mitigate the unrealistic predictions made by the Pennes' model.
•Bio-thermoelastic interaction in 2D living tissue is established.•The bioheat model with one thermal relaxation time is established.•The analytical solutions are obtained by Fourier and Laplace transforms.•The analytical solution is studied by the eigenvalue approach techniques.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a public health threat for which preventive and therapeutic agents are urgently needed. Neutralizing antibodies are a key class of ...therapeutics that may bridge widespread vaccination campaigns and offer a treatment solution in populations less responsive to vaccination. Here, we report that high-throughput microfluidic screening of antigen-specific B cells led to the identification of LY-CoV555 (also known as bamlanivimab), a potent anti-spike neutralizing antibody from a hospitalized, convalescent patient with coronavirus disease 2019 (COVID-19). Biochemical, structural, and functional characterization of LY-CoV555 revealed high-affinity binding to the receptor-binding domain, angiotensin-converting enzyme 2 binding inhibition, and potent neutralizing activity. A pharmacokinetic study of LY-CoV555 conducted in cynomolgus monkeys demonstrated a mean half-life of 13 days and a clearance of 0.22 ml hour
kg
, consistent with a typical human therapeutic antibody. In a rhesus macaque challenge model, prophylactic doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract in samples collected through study day 6 after viral inoculation. This antibody has entered clinical testing and is being evaluated across a spectrum of COVID-19 indications, including prevention and treatment.
Reovirus serotype 3 Dearing (T3D) replicates preferentially in transformed cells and is in clinical trials as a cancer therapy. Laboratory strains of T3D, however, exhibit differences in plaque size ...on cancer cells and differences in oncolytic activity
This study aimed to determine why the most oncolytic T3D reovirus lab strain, the Patrick Lee laboratory strain (T3D
), replicates more efficiently in cancer cells than other commonly used laboratory strains, the Kevin Coombs laboratory strain (T3D
) and Terence Dermody laboratory (T3D
) strain. In single-step growth curves, T3D
titers increased at higher rates and produced ∼9-fold higher burst size. Furthermore, the number of reovirus antigen-positive cells increased more rapidly for T3D
than for T3D
In conclusion, the most oncolytic T3D
possesses replication advantages in a single round of infection. Two specific mechanisms for enhanced infection by T3D
were identified. First, T3D
exhibited higher cell attachment, which was attributed to a higher proportion of virus particles with insufficient (≤3) σ1 cell attachment proteins. Second, T3D
transcribed RNA at rates superior to those of the less oncolytic T3D strains, which is attributed to polymorphisms in M1-encoding μ2 protein, as confirmed in an
transcription assay, and which thus demonstrates that T3D
has an inherent transcription advantage that is cell type independent. Accordingly, T3D
established rapid onset of viral RNA and protein synthesis, leading to more rapid kinetics of progeny virus production, larger virus burst size, and higher levels of cell death. Together, these results emphasize the importance of paying close attention to genomic divergence between virus laboratory strains and, mechanistically, reveal the importance of the rapid onset of infection for reovirus oncolysis.
Reovirus serotype 3 Dearing (T3D) is in clinical trials for cancer therapy. Recently, it was discovered that highly related laboratory strains of T3D exhibit large differences in their abilities to replicate in cancer cells
, which correlates with oncolytic activity in a murine model of melanoma. The current study reveals two mechanisms for the enhanced efficiency of T3D
in cancer cells. Due to polymorphisms in two viral genes, within the first round of reovirus infection, T3D
binds to cells more efficiency and more rapidly produces viral RNAs; this increased rate of infection relative to that of the less oncolytic strains gives T3D
a strong inherent advantage that culminates in higher virus production, more cell death, and higher virus spread.
The call by some groups to incorporate the Rukun Negara as the preamble to the Federal Constitution is timely. The Rukun Negara was first introduced as the national philosophy by the fourth Yang ...di-Pertuan Agong, the late Sultan of Terengganu, during Merdeka Day in 1970. Among the primary goals of the Rukun Negara are to realise Malaysias ambitions towards enhancing unity among the people; safeguarding the spirit of democracy; establishing a just society; maintaining a liberal approach in addressing diversity; and creating a progressive and technologically advanced society. In fulfilling the above ideals, the Rukun Negara underlines five core principles: Belief in God; Loyalty to the King and Country; Supremacy of the Constitution; Rule of Law; and Good Behaviour and Morality.
Thyroid abnormalities are documented consequences of quetiapine treatment. This may have clinical implications as changes in thyroid hormones may deteriorate a person's affective state. Yet less is ...known about the clinical factors and underlying mechanisms associated with thyroid hormones on quetiapine therapy. We therefore systematically reviewed the published literature of evidence of quetiapine‐induced thyroid abnormalities. We searched MEDLINE, PsycINFO, Google Scholar, and EMBASE for articles in which individuals developed biochemically confirmed thyroid abnormalities (with or without clinical symptoms) while on quetiapine treatment. We included case reports, case series, observational, and experimental studies. We included 32 studies, 20 of which were observational and experimental studies. There were 10 case reports and 1 case series. All the research designs suggested an association between quetiapine and hypothyroidism. However, these findings were limited by the quality of the included studies and the general lack of either a clear temporal relationship or dose response. Quetiapine has been associated with thyroid abnormalities, mainly with hypothyroidism. Drug imputability in these abnormalities is not always clear, and the underlying pathophysiology may include immunological and nonimmunological mechanisms. Large prospective studies are required to clarify this association and to further inform the management of patients treated with quetiapine where hypothyroidism occurs.
Today, automatic emotion recognition in speech is one of the most important areas of research in signal processing. Identifying emotional content in Arabic speech is regarded as a very challenging ...and intricate task due to several obstacles, such as the wide range of cultures and dialects, the influence of cultural factors on emotional expression, and the scarcity of available datasets. This study used a variety of artificial intelligence models, including Xgboost, Adaboost, KNN, DT, and SOM, and a deep-learning model named SERDNN. ANAD was employed as a training dataset, which contains three emotions, "angry", "happy", and "surprised", with 844 features. This study aimed to present a more efficient and accurate technique for recognizing emotions in Arabic speech. Precision, accuracy, recall, and F1-score metrics were utilized to evaluate the effectiveness of the proposed techniques. The results showed that the Xgboost, SOM, and KNN classifiers achieved superior performance in recognizing emotions in Arabic speech. The SERDNN deep learning model outperformed the other techniques, achieving the highest accuracy of 97.40% with a loss rate of 0.1457. Therefore, it can be relied upon and deployed to recognize emotions in Arabic speech.
The issue of unilateral conversion of minors has once again generated widespread uproar in Malaysia when the Federal Court unanimously decided, in the case of Indira Ghandi on 29 January 2018, that ...both the parents consent was required in determining the faith of minors. In Malaysia, Article 12 (4) of the Federal Constitution provides that "For the purposes of Clause (3) the religion of a person under the age of eighteen years shall be decided by his parent or guardian." The Federal Court held, in this case, that the word 'parent' must be understood in the plural form, denoting both 'parents, based on Schedule Eleven of the Federal Constitution and sections 5 and 11 of the Guardianship Act 1961. This decision marked a departure from the previous Federal Court judgement in Subashini (2007) in which parent was defined as one of the parents. The Federal Court in the Indira Ghandi case also rejected the argument put forth by some parties that the decision in the case of Susie Teoh (1990), who voluntarily converted to Islam at the age of 16, had a bearing on the interpretation of the word parent as singular or plural.
The performance of rainfed-based Megathyrsus maximus (syn. Urochloa maxima and Panicum maximum) was investigated in the semi-arid pastures of Sudan. Split-plot complete design experiments with three ...replications were applied for two consecutive seasons (2020-2021). The treatments were two in situ rainwater harvesting systems i.e. ridges plus terraces (RD) and terraces (TR), three seeding rates (i.e. 1.5, 2.5 and 3.5 kg ha
−1
) and two urea fertilisation rates 0 kg ha
−1
(Z) and 95 kg ha
−1
(F). These treatments were compared to a control (a flat, unfertilised and zero-tillage plot). Hydrological, biological and chemical indicators were used in the assessment. The results showed that the adopted RWH improved semi-arid pastures, with the RD treatment providing the best results for sustaining biomass production, water use efficiency, nutritional quality and soil quality. The highest plant density (112 000 plants ha
−1
) was associated with the RD3.5 treatment. The FSR1.5-RD treatment resulted in the greatest plant length (63.5 cm) and number of leaves per plant (34.59), whilst the FSR3.5-RD resulted in both the highest fresh biomass (25.9 t ha
−1
) and dry biomass (6.3 t ha
−1
). The chemical compositions of M. maximus (i.e. crude protein, organic matter and nitrogen contents) were also substantially improved by fertilisation. The water use efficiency of M. maximus was plant-, management- and climate-dependent.
Background
In 2020, the World Health Organization (WHO) declared COVID-19 a global health pandemic. The rapid spread and high fatalities associated with COVID-19 have increased interest in assessing ...Knowledge, Attitude, and Practice (KAP) toward this illness among the general population in comparison to specific subgroups. Most publications to date have explored KAP among the general public, healthcare providers, and people with chronic conditions, but not amongst those with mental illness. Yet, research has shown patients with mental illness are at higher risk of poor outcomes related to infectious diseases such as COVID-19. The objective of this study is to compare KAP toward COVID-19 between people with mental illness and the general public.
Materials and methods
This is a cross-sectional study, done over 3
°
months in 2020, to compare KAP during the COVID-19 pandemic in three groups: outpatients from outpatient Psychiatry clinics (
N
= 165), inpatients admitted to a Psychiatry ward (
N
= 100), and the general public (
N
= 345). KAP parameters were assessed through online surveys.
Results
The proportion of subjects in the public group (84.8%) giving the correct responses to most Knowledge questions was significantly higher than those in the inpatient and outpatient groups. Compared to the public and inpatient groups, subjects in the outpatient group (92.7%) were significantly more optimistic and confident that COVID-19 would be brought under control. A higher proportion of subjects from the general public (82.9%) indicated that they attended crowded places and were more compliant in wearing masks. Multiple linear regression analyses showed that poorer COVID-19 knowledge was associated with being single and having a young age (18–29), with both inpatients and outpatients and with primary-or secondary-level education.
Conclusion
Patient populations, both inpatients and outpatients, had inadequate Knowledge, more positive attitudes and confidence regarding the outcome of COVID-19, and less safe practices than the public. This highlights the need for targeted approaches around COVID-19 and pandemics in general in this vulnerable population.
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