Environmental Press of Urban Greenspace Pre-Post COVID on Older Adults: A Big Data Study in Metropolitan Atlanta (preprint)

The Coronavirus Disease 2019 (COVID-19) impacted the use of urban greenspaces. For older adults who are vulnerable to environmental press, there were more concerns with being outside after COVID-19, especially in metropolitan areas with a high population density. Reframing urban greenspaces to fit the adaptation level of older adults spending time outdoors requires further consideration. Using block group and park POI data from the Atlanta metropolitan area retrieved from SafeGraph, this study assesses the types of urban greens spaces that fit the needs of older adults pre and post COVID-19 and how park features influenced their use of the parks. The results indicate a high decrease in park visitation after COVID-19 for elderly populations. The preferences of older adults visiting urban greenspaces changed from small scale parks pre-pandemic to large scale parks post start of the pandemic. Their daily park visitations were influenced by climate but not event visitations. Paths and trails are the primary park feature attracting older adults pre-post COVID-19. Findings can inform future design and research of urban greenspaces accommodating the competence of older adults.

The Discovery of Novel Ferulic Acid Derivatives Incorporating Substituted Isopropanolamine Moieties as Potential Tobacco Mosaic Virus Helicase Inhibitors.

Target-based drug design, a high-efficiency strategy used to guide the development of novel pesticide candidates, has attracted widespread attention. Herein, various natural-derived ferulic acid derivatives incorporating substituted isopropanolamine moieties were designed to target the tobacco mosaic virus (TMV) helicase. Bioassays demonstrating the optimized A19, A20, A29, and A31 displayed excellent in vivo antiviral curative abilities, affording corresponding EC50 values of 251.1, 336.2, 347.1, and 385.5 µg/mL, which visibly surpassed those of commercial ribavirin (655.0 µg/mL). Moreover, configurational analysis shows that the R-forms of target compounds were more beneficial to aggrandize antiviral profiles. Mechanism studies indicate that R-A19 had a strong affinity (Kd = 5.4 µM) to the TMV helicase and inhibited its ability to hydrolyze ATP (50.61% at 200 µM). Meanwhile, A19 could down-regulate the expression of the TMV helicase gene in the host to attenuate viral replication. These results illustrate the excellent inhibitory activity of A19 towards the TMV helicase. Additionally, docking simulations uncovered that R-A19 formed more hydrogen bonds with the TMV helicase in the binding pocket. Recent studies have unambiguously manifested that these designed derivatives could be considered as promising potential helicase-based inhibitors for plant disease control.

Emergence and antibody evasion of BQ and BA.2.75 SARS-CoV-2 sublineages in the face of maturing antibody breadth at the population level (preprint)

The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and related sub-lineages. Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants at two levels: (i) we tracked over 400,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using antibody pools. (ii) we mapped the antibody response at the individual level using blood from strigently curated vaccine and convalescent cohorts. In pooled antibody samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases we observed increased antibody breadth to variants that were yet to be in circulation. Resolution of viral neutralisation at the cohort level supported equivalent coverage across prior and emerging variants with emerging isolates BQ.1.1, XBB.1 and BR.2.1 the most evasive. Further, these emerging variants were resistant to Evusheld, whilst neutralization resistance to Sotrovimab was restricted to BQ.1.1 and further supported by lack of Spike glycoprotein binding to this variant. An outgrowth advantage through better utilization of TMPRSS2 was observed across BQ lineages and not those derived from BA.2.75. We conclude at this current point in time that variants derived from BQ lineages can evade antibodies at levels equivalent to their most evasive BA.2.75 counterparts but sustain an entry phenotype that would promote an additional outgrowth advantage.

Progress of research on changes of cellular immunity after SARS-CoV-2 infection

The major causes of death of patients with COVID-19 include metabolic acidosis, septic shock, pulmonary edema, multiple organ failure and deep venous thrombosis. These systemic manifestations are associated with severe pathological damages of vital organs like lung and kidney that are caused by inflammatory storms. The occurrence, development and deterioration of disease is closely associated with the immune imbalance mechanisms such as disorder of lymphocyte subsets and emergence of cytokine storm. The cellular immunity plays a vital role. The expression levels of some blood inflammatory factors of the severe COVID-19 patients are remarkably elevated, IL-6 is a typical proinflammatory factor that causes the cytokine storm, which can be used for prediction of prognosis. IL-6 blockade may be an effective method to block the cytokine storm.

Amplification‐Free Detection of SARS‐CoV‐2 and Respiratory Syncytial Virus Using CRISPR Cas13a and Graphene Field‐Effect Transistors

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated (Cas) systems have recently received notable attention for their applications in nucleic acid detection. Despite many attempts, the majority of current CRISPR‐based biosensors in infectious respiratory disease diagnostic applications still require target preamplifications. This study reports a new biosensor for amplification‐free nucleic acid detection via harnessing the trans‐cleavage mechanism of Cas13a and ultrasensitive graphene field‐effect transistors (gFETs). CRISPR Cas13a‐gFET achieves the detection of SARS‐CoV‐2 and respiratory syncytial virus (RSV) genome down to 1 attomolar without target preamplifications. Additionally, we validate the detection performance using clinical SARS‐CoV‐2 samples, including those with low viral loads (Ct value >30). Overall, these findings establish our CRISPR Cas13a‐gFET among the most sensitive amplification‐free nucleic acid diagnostic platforms to date.

Discovery of Epipodophyllotoxin-Derived B2 as Promising XooFtsZ Inhibitor for Controlling Bacterial Cell Division: Structure-Based Virtual Screening, Synthesis, and SAR Study.

The emergence of phytopathogenic bacteria resistant to antibacterial agents has rendered previously manageable plant diseases intractable, highlighting the need for safe and environmentally responsible agrochemicals. Inhibition of bacterial cell division by targeting bacterial cell division protein FtsZ has been proposed as a promising strategy for developing novel antibacterial agents. We previously identified 4'-demethylepipodophyllotoxin (DMEP), a naturally occurring substance isolated from the barberry species Dysosma versipellis, as a novel chemical scaffold for the development of inhibitors of FtsZ from the rice blight pathogen Xanthomonas oryzae pv. oryzae (Xoo). Therefore, constructing structure-activity relationship (SAR) studies of DMEP is indispensable for new agrochemical discovery. In this study, we performed a structure-activity relationship (SAR) study of DMEP derivatives as potential XooFtsZ inhibitors through introducing the structure-based virtual screening (SBVS) approach and various biochemical methods. Notably, prepared compound B2, a 4'-acyloxy DMEP analog, had a 50% inhibitory concentration of 159.4 µM for inhibition of recombinant XooFtsZ GTPase, which was lower than that of the parent DMEP (278.0 µM). Compound B2 potently inhibited Xoo growth in vitro (minimum inhibitory concentration 153 mg L-1) and had 54.9% and 48.4% curative and protective control efficiencies against rice blight in vivo. Moreover, compound B2 also showed low toxicity for non-target organisms, including rice plant and mammalian cell. Given these interesting results, we provide a novel strategy to discover and optimize promising bactericidal compounds for the management of plant bacterial diseases.

Rücktitelbild: Amplification‐Free Detection of SARS‐CoV‐2 and Respiratory Syncytial Virus Using CRISPR Cas13a and Graphene Field‐Effect Transistors

Der Nachweis von Nukleinsäuren spielt eine wichtige Rolle in der medizinischen Diagnostik, der Umweltüberwachung und der Lebensmittelsicherheit. In ihrem Forschungsartikel (e202203826) entwickelten Xue Gao, Yi Zhang und Mitarbeiter einen neuen Biosensor für den amplifikationsfreien Nukleinsäurenachweis, indem sie den trans‐Spaltungsmechanismus von Cas13a und ultrasensitive Graphen‐Feldeffekttransistoren (gFETs) nutzten. Die Abbildung zeigt die Cas13a‐vermittelte RNA‐trans‐Spaltung auf der gFET‐Oberfläche für die Sensorsignalübertragung.

Are private equity and venture capital helping small and medium-sized enterprises during the COVID-19 pandemic? Evidence from China☆

The rapid spread of COVID-19 worldwide since 2020 has, undeniably, negatively influenced the global economy and environment. Small and medium-sized enterprises (SMEs) are among the worst-hit victims of COVID-19, particularly in developing countries. As primary channels financing SMEs, what roles have private equity and venture capital (PE/VC) played in this crisis? Using the 2010–2021 data of 4462 listed companies, we aimed to assess the impact of PE/VC on financial risk among Chinese SMEs. We constructed a capital structure selection model to assess the risk preference of PE/VC and explored the roles of PE/VC in the financial risk management of enterprises during COVID-19. Based on both theory and empirical evidence, PE/VC negatively impacts the financial risk of enterprises, implying that intervention by the management of PE/VC can aggravate the financial risk. However, in reality, PE/VC positively impacted enterprise financial risk during COVID-19. Thus, the government should implement some easing policies to stimulate access and investment policies of PE/VC as well as provide more practical policies to support investment institutions in China and other counties.

Are private equity and venture capital helping small and medium-sized enterprises during the COVID-19 pandemic? Evidence from China.

The rapid spread of COVID-19 worldwide since 2020 has, undeniably, negatively influenced the global economy and environment. Small and medium-sized enterprises (SMEs) are among the worst-hit victims of COVID-19, particularly in developing countries. As primary channels financing SMEs, what roles have private equity and venture capital (PE/VC) played in this crisis? Using the 2010-2021 data of 4462 listed companies, we aimed to assess the impact of PE/VC on financial risk among Chinese SMEs. We constructed a capital structure selection model to assess the risk preference of PE/VC and explored the roles of PE/VC in the financial risk management of enterprises during COVID-19. Based on both theory and empirical evidence, PE/VC negatively impacts the financial risk of enterprises, implying that intervention by the management of PE/VC can aggravate the financial risk. However, in reality, PE/VC positively impacted enterprise financial risk during COVID-19. Thus, the government should implement some easing policies to stimulate access and investment policies of PE/VC as well as provide more practical policies to support investment institutions in China and other counties.

Legionella pneumophila occurrence in reduced-occupancy buildings in 11 cities during the COVID-19 pandemic (preprint)

In spring 2020, reduced water demand was an unintended consequence of COVID-19 pandemic-related building closures. Concerns arose that contaminants associated with water stagnation, such as Legionella pneumophila , could become prevalent. To investigate this potential public health risk, samples from 26 reduced-occupancy buildings across 11 cities in the United States, Canada, and Switzerland were analyzed for L. pneumophila using liquid culture (Legiolert, n=258) and DNA-based methods (qPCR/ddPCR, n=138). L. pneumophila culture-positivity was largely associated with just five buildings, each of which had specific design or operational deficiencies commonly associated with L. pneumophila occurrence. Samples from free chlorine buildings had higher culture-positivity (37%) than chloramine buildings (1%), and 78% of culture-positive samples occurred when the residual was ≤0.1 mg/L Cl 2 . Although overall sample positivities using culture- and DNA-based methods were equivalent (34% vs. 35%), there was disagreement between the methods in 13% of paired samples. Few buildings reported any water management activities, and L. pneumophila concentrations in flushed samples were occasionally greater than in first-draw samples. This study provides insight into how building plumbing characteristics and management practices contribute to L. pneumophila occurrence during low water use periods and can inform targeted prevention and mitigation efforts. Synopsis Statement Legionella pneumophila occurrence was evaluated in reduced-occupancy buildings during the COVID-19 pandemic across multiple cities. Graphic for Table of Contents (TOC)

Sustainable development and health assessment model of higher education in India: A mathematical modeling approach.

The Coronavirus Disease 2019 has resulted in a transition from physical education to online learning, leading to a collapse of the established educational order and a wisdom test for the education governance system. As a country seriously affected by the pandemic, the health of the Indian higher education system urgently requires assessment to achieve sustainable development and maximize educational externalities. This research systematically proposes a health assessment model from four perspectives, including educational volume, efficiency, equality, and sustainability, by employing the Technique for Order Preference by Similarity to an Ideal Solution Model, Principal Component Analysis, DEA-Tobit Model, and Augmented Solow Model. Empirical results demonstrate that India has high efficiency and an absolute health score in the higher education system through multiple comparisons between India and the other selected countries while having certain deficiencies in equality and sustainability. Additionally, single-target and multiple-target path are simultaneously proposed to enhance the Indian current education system. The multiple-target approach of the India-China-Japan-Europe-USA process is more feasible to achieve sustainable development, which would improve the overall health score from .351 to .716. This finding also reveals that the changes are relatively complex and would take 91.5 years considering the relationship between economic growth rates and crucial indicators. Four targeted policies are suggested for each catching-up period, including expanding and increasing the social funding sources, striving for government expenditure support to improve infrastructures, imposing gender equality in education, and accelerating the construction of high-quality teachers.

Crowding perception predicts subway passengers' behavioral decision making during COVID-19 via risk awareness and safety perception

We studied the prediction mechanism of the effects of the crowding perception, risk awareness, and safety perception of subway passengers on their behavioral decision making in the context of COVID-19 as a public health safety crisis. We conducted a survey of 305 subway passengers in Zhejiang Province, China, and used structural equation modeling for data analysis. The results show that the crowding perception of the passengers did not directly predict their behavioral decision making. Rather, risk awareness and safety perception played a chain mediating role between the crowding perception and behavioral decision making of passengers. We further explored the theoretical and practical implications of our findings. [ FROM AUTHOR] Copyright of Social Behavior & Personality: an international journal is the property of Society for Personality Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

A Joint Optimization Model considering the Product User's Risk Preference for Supply System Disruption

Logistics distribution is the terminal link that connects the manufacturer and product user and determines the efficiency of the manufacturer’s service. Therefore, the disruption risk of the joint system is an essential factor affecting the product user experience. In this paper, while considering the product user’s supply disruption risk preference (PUSDRP), a biobjective integer nonlinear programming (INLP) model with subjective cost-utility is proposed to solve the manufacturer’s combined location routing inventory problem (CLRIP). According to the user’s time satisfaction requirement, a routing change selection framework (RCSF) is designed based on the bounded rational behavior of the user. Additionally, the Lagrange Relaxation and Modified Genetic Algorithm (LR-MGA) is proposed. The LR method relaxes the model, and the MGA finds a compromise solution. The experimental results show that the biobjective cost-utility model proposed in this paper is effective and efficient. The RCSF based on user behavior is superior to the traditional expected utility theory model. The compromise solution provides a better solution for the manufacturer order allocation delivery combinatorial optimization problem. The compromise solution not only reduces the manufacturer’s total operating cost but also improves the user's subjective utility. To improve the stability of cooperation between manufacturers and users, the behavior decision-making method urges manufacturers to consider product users’ supply disruption risk preferences (PUSDRPs) in attempting to optimize economic benefits for the long term. This paper uses behavior decision-making methods to expand the ideas of the CLRIP joint system.

Comprehensive genomic, immunological and clinical analysis of COVID-19 vaccine breakthrough infections: a prospective, comparative cohort study (preprint)

Objectives: As the COVID-19 pandemic is still ongoing and SARS-CoV-2 variants are circulating worldwide, an increasing number of breakthrough infections have been detected despite the good efficacy of COVID-19 vaccines. Methods: A prospective, comparative cohort study was conducted in Beijing Ditan Hospital to evaluate the clinical, immunological and genomic characteristics of COVID-19 breakthrough infections. Data on 88 COVID-19 breakthrough cases (vaccinated group) and 41 unvaccinated cases (unvaccinated group) from June 1 to August 20, 2021 were extracted from a cloud database. Among these 129 COVID-19 cases, we successfully sequenced 33 whole genomes, including 16 from the vaccinated group and 17 from the unvaccinated group. Results: Asymptomatic and mild cases predominated in both groups, but 2 patients developed severe disease in the unvaccinated group. Between the two groups, the median time of viral shedding in the vaccinated group were significantly lower than those in the unvaccinated group (p = 0.003). A comparison of dynamic IgG titres of cases in the two groups indicated that IgG titres in the vaccinated group showed a significantly increasing trend (P =0.028). The CD4+T lymphocyte count was lower in the unvaccinated group, and there was a significant difference between the two groups (p=0.018). In the vaccinated group, the number of moderate cases who received Sinopharm BBIBP (42 cases) was significantly higher than those who received Sinovac Coronavac (p=0.020). Whole-genome sequencing revealed 23 cases of delta variants, including 15 patients from the vaccinated group. However, no significant difference was observed in either the RT-qPCR results or viral shedding time. Conclusions: COVID-19 vaccine breakthrough infections were mainly asymptomatic and mild, the IgG titres were significantly higher and increased rapidly, and the viral shedding was short. Delta variants may be more likely to cause breakthrough infections, and vaccination may not reduce the viral loads and shedding time.

Preclinical Immunological Evaluation of an Intradermally Administered Heterologous Vaccine Against SARS-CoV-2 Variants (preprint)

The recent emergence of new variants in the COVID-19 pandemic has led to new requirements for vaccines, with a focus on the capacity of vaccines to elicit high levels of neutralizing antibodies with specific recognition of S antigen variants based on the characterized vaccines licensed for use. A new strategy involving a heterologous vaccine composed of one or two doses of inactivated vaccine and a boost with the S1 protein with mutations (K-S) administered via the intradermal route was designed in this work and was found to improve immune efficacy by increasing neutralizing antibody titers and promoting specific T cell responses against 5 variants of the RBD peptide. A viral challenge test with the B.1.617.2 (Delta) variant confirmed that the both schedules of “1+1” and “2+1” administration ensured a clinical protective effect against this strain. All of these results not only suggested the feasibility of our strategy for protecting against new variants but also provided a technical pathway to enhance the anamnestic immune response in the immunized population.

COVID-19 and liver dysfunction: Epidemiology, association and potential mechanisms.

Currently, there have been more than one hundred million confirmed cases of coronavirus disease 2019 (COVID-19), with two million deaths worldwide. This has caused a huge medical burden. Severe COVID-19 patients can experience multi-organ damage, including cardiac injury, kidney injury, and liver injury. About 2.0%-4.9% of COVID-19 cases involve patients with preexisting liver diseases. Additionally, preexisting liver diseases were reported and associated with severity (odds ratio (OR) or risk ratio (RR) = 1.48-1.70) and mortality (OR or RR = 1.08-2.65) among COVID-19 patients. Furthermore, the prevalence of liver injury was 16%-29% in COVID-19 patients. Higher prevalence of liver injury may worsen prognosis in patients (severity: OR or RR = 1.9-2.6; mortality: OR or RR = 1.1-4.0). The mechanisms of this association between liver injury and severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection are complex, including direct cholangiocyte damage induced by SARS-COV-2, cytokine storm, and drug-induced liver injury. In particular, drug-induced liver injury may be the most important reason. This review discusses the epidemiology of COVID-19 and liver dysfunction as well as potential mechanisms underlying the association between COVID-19 and liver dysfunction or other preexisting liver diseases. However, the association between preexisting liver diseases and COVID-19 prognosis and potential mechanisms underlying these associations require further prospective studies.

Quantitative HPLC-MS/MS determination of Nuc, the active metabolite of remdesivir, and its pharmacokinetics in rat.

Remdesivir is a nucleotide analog prodrug that has received much attention since the outbreak of the COVID-19 pandemic in December 2019. GS-441524 (Nuc) is the active metabolite of remdesivir and plays a pivotal role in the clinical treatment of COVID-19. Here, a robust HPLC-MS/MS method was developed to determine Nuc concentrations in rat plasma samples after a one-step protein precipitation process. Chromatographic separation was accomplished on Waters XBrige C18 column (50 × 2.1 mm, 3.5 µm) under gradient elution conditions. Multiple reaction monitoring transitions in electrospray positive ion mode were m/z 292.2 → 163.2 for Nuc and 237.1 → 194.1 for the internal standard (carbamazepine). The quantitative analysis method was fully validated in line with the United States Food and Drug Administration guidelines. The linearity, accuracy and precision, matrix effect, recovery, and stability results met the requirements of the guidelines. Uncertainty of measurement and incurred sample reanalysis were analyzed to further ensure the robustness and reproducibility of the method. This optimized method was successfully applied in a rat pharmacokinetics study of remdesivir (intravenously administration, 5 mg kg-1). The method can act as a basis for further pharmacokinetic and clinical efficacy investigations in patients with COVID-19. Graphical abstract.

COVID-19 cases from the first local outbreak of SARS-CoV-2 B.1.1.7 variant in China presented more serious clinical features: a prospective, comparative cohort study (preprint)

Background: The SARS-CoV-2 B.1.1.7 variant which was first identified in the United Kingdom (U.K.) has increased sharply in numbers worldwide and was reported to be more contagious. On January 17, 2021, a COVID-19 clustered outbreak caused by B.1.1.7 variant occurred in a community in Daxing District, Beijing, China. Three weeks prior, another non-variant (lineage B.1.470) COVID-19 outbreak occurred in Shunyi District, Beijing. This study aimed to investigate the clinical features of B.1.1.7 variant infection. Methods: A prospective cohort study was conducted on COVID-19 cases admitted to Ditan hospital since January 2020. Data of 74 COVID-19 cases from two independent COVID-19 outbreaks in Beijing were extracted as study subjects from a Cloud Database established in Ditan hospital, which included 41 Shunyi cases (Shunyi B.1.470 group) and 33 Daxing cases (Daxing B.1.1.7 group) that have been hospitalized since December 25, 2020 and January 17, 2021, respectively. We conducted a comparison of the clinical characteristics, RT-qPCR results and genomic features between the two groups. Findings: Cases from Daxing B.1.1.7 group (15 [45.5%] male; median age, 39 years [range, 30.5, 62.5]) and cases from Shunyi B.1.470 group (25 [61.0%] male; median age, 31 years [range, 27.5, 41.0]) had a statistically significant difference in median age (P =0.014). Seven clinical indicators of Daxing B.1.1.7 group were significantly higher than Shunyi B.1.470 group including patients having fever over 38 (14/33 [46.43%] in Daxing B.1.1.7 group vs. 9/41 (21.95%) in Shunyi B.1.470 group [P = 0 .015]), C-reactive protein ([CRP, mg/L], 4.30 [2.45, 12.1] vs. 1.80, [0.85, 4.95], [P = 0.005]), Serum amyloid A ([SAA, mg/L], 21.50 [12.50, 50.70] vs. 12.00 [5.20, 26.95], [P = 0.003]), Creatine Kinase ([CK, U/L]), 110.50 [53.15,152.40] vs. 70.40 [54.35,103.05], [P = 0.040]), D-dimer ([DD, mg/L], 0.31 [0.20, 0.48] vs. 0.24 [0.17,0.31], [P = 0.038]), CD4+ T lymphocyte ([CD4+ T, mg/L], [P = 0.003]) , and Ground-glass opacity (GGO) in lung (15/33 [45.45%] vs. 5/41 [12.20%], [P =0.001]). After adjusting for the age factor, B.1.1.7 variant infection was the risk factor for CRP (P = 0.045, Odds ratio [OR] 2.791, CI [1.025, 0.8610]), SAA (0.011, 5.031, [1.459, 17.354]), CK (0.034, 4.34, [0.05, 0.91]), CD4+ T ( 0.029, 3.31, [1.13, 9.71]), and GGO (0.005, 5.418, [1.656, 17.729]) of patients. The median Ct value of RT-qPCR tests of the N-gene target in the Daxing B.1.1.7 group was significantly lower than the Shunyi B.1.470 group (P=0.036). The phylogenetic analysis showed that only 2 amino acid mutations in spike protein were detected in B.1.470 strains while B.1.1.7 strains had 3 deletions and 7 mutations. Interpretation: Clinical features including a more serious inflammatory response, pneumonia and a possible higher viral load were detected in the cases infected with B.1.1.7 SARS-CoV-2 variant. It could therefore be inferred that the B.1.1.7 variant may have increased pathogenicity.