COVID‐19 lockdown measures impacted citizen science hedgehog observation numbers in Bavaria,Germany

The COVID‐19 pandemic has led to temporary changes in human–animal interactions due to changes in human activities. Here, we report on a surge in hedgehog observations during the first COVID‐19 lockdown in Germany in 2020, on the citizen science Web portal “Igel in Bayern” (Hedgehogs in Bavaria) in Germany. This increase in comparison with previous years was attributed to an increase in the number of people reporting hedgehog observations, rather than an increase in the number of hedgehog observations made by each observer. Additionally, in contrast to other studies on the effects of a COVID‐19 lockdown on observations recorded by citizen science projects, the share of observations made in more urbanized areas during the lockdown time was not higher than the change observed in less urbanized areas. This is possibly a result of the differences in COVID‐19 measures between Germany and other countries where preceding studies were carried out, in particular the lack of measures limiting traveling outdoor activities for citizens.     

An at‐home laboratory in plant biology designed to engage students in the process of science

The COVID‐19 pandemic prompted a transition to remote delivery of courses that lack immersive hands‐on research experiences for undergraduate science students, resulting in a scientific research skills gap. In this report, we present an option for an inclusive and authentic, hands‐on research experience that all students can perform off‐campus. Biology students in a semester‐long (13 weeks) sophomore plant physiology course participated in an at‐home laboratory designed to study the impacts of nitrogen addition on growth rates and root nodulation by wild nitrogen‐fixing Rhizobia in Pisum sativum (Pea) plants. This undergraduate research experience, piloted in the fall semester of 2020 in a class with 90 students, was created to help participants learn and practice scientific research skills during the COVID‐19 pandemic. Specifically, the learning outcomes associated with this at‐home research experience were: (1) generate a testable hypothesis, (2) design an experiment to test the hypothesis, (3) explain the importance of biological replication, (4) perform meaningful statistical analyses using R, and (5) compose a research paper to effectively communicate findings to a general biology audience. Students were provided with an at‐home laboratory kit containing the required materials and reagents, which were chosen to be accessible and affordable in case students were unable to access our laboratory kit. Students were guided through all aspects of research, including hypothesis generation, data collection, and data analysis, with video tutorials and live virtual sessions. This at‐home laboratory provided students an opportunity to practice hands‐on research with the flexibility to collect and analyze their own data in a remote setting during the COVID‐19 pandemic. This, or similar laboratories, could also be used as part of distance learning biology courses.     

Vitamin D and COVID‐19: A review on the role of vitamin D in preventing and reducing the severity of COVID‐19 infection

Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) is a pathogenic coronavirus causing COVID‐19 infection. The interaction between the SARS‐CoV‐2 spike protein and the human receptor angiotensin‐converting enzyme 2, both of which contain several cysteine residues, is impacted by the disulfide‐thiol balance in the host cell. The host cell redox status is affected by oxidative stress due to the imbalance between the reactive oxygen/nitrogen species and antioxidants. Recent studies have shown that Vitamin D supplementation could reduce oxidative stress. It has also been proposed that vitamin D at physiological concentration has preventive effects on many viral infections, including COVID‐19. However, the molecular‐level picture of the interplay of vitamin D deficiency, oxidative stress, and the severity of COVID‐19 has remained unclear. Herein, we present a thorough review focusing on the possible molecular mechanism by which vitamin D could alter host cell redox status and block viral entry, thereby preventing COVID‐19 infection or reducing the severity of the disease.     

TMPRSS2 expression dictates the entry route used by SARS‐CoV‐2 to infect host cells

SARS‐CoV‐2 is a newly emerged coronavirus that caused the global COVID‐19 outbreak in early 2020. COVID‐19 is primarily associated with lung injury, but many other clinical symptoms such as loss of smell and taste demonstrated broad tissue tropism of the virus. Early SARS‐CoV‐2–host cell interactions and entry mechanisms remain poorly understood. Investigating SARS‐CoV‐2 infection in tissue culture, we found that the protease TMPRSS2 determines the entry pathway used by the virus. In the presence of TMPRSS2, the proteolytic process of SARS‐CoV‐2 was completed at the plasma membrane, and the virus rapidly entered the cells within 10 min in a pH‐independent manner. When target cells lacked TMPRSS2 expression, the virus was endocytosed and sorted into endolysosomes, from which SARS‐CoV‐2 entered the cytosol via acid‐activated cathepsin L protease 40–60 min post‐infection. Overexpression of TMPRSS2 in non‐TMPRSS2 expressing cells abolished the dependence of infection on the cathepsin L pathway and restored sensitivity to the TMPRSS2 inhibitors. Together, our results indicate that SARS‐CoV‐2 infects cells through distinct, mutually exclusive entry routes and highlight the importance of TMPRSS2 for SARS‐CoV‐2 sorting into either pathway.     

A virus‐derived microRNA targets immune response genes during SARS‐CoV‐2 infection

SARS‐CoV‐2 infection results in impaired interferon response in patients with severe COVID‐19. However, how SARS‐CoV‐2 interferes with host immune responses is incompletely understood. Here, we sequence small RNAs from SARS‐CoV‐2‐infected human cells and identify a microRNA (miRNA) derived from a recently evolved region of the viral genome. We show that the virus‐derived miRNA produces two miRNA isoforms in infected cells by the enzyme Dicer, which are loaded into Argonaute proteins. Moreover, the predominant miRNA isoform targets the 3′UTR of interferon‐stimulated genes and represses their expression in a miRNA‐like fashion. Finally, the two viral miRNA isoforms were detected in nasopharyngeal swabs from COVID‐19 patients. We propose that SARS‐CoV‐2 can potentially employ a virus‐derived miRNA to hijack the host miRNA machinery, which could help to evade the interferon‐mediated immune response.     

A close‐up view of dynamic biomarkers in the setting of COVID‐19: Striking focus on cardiovascular system

Based on the recent reports, cardiovascular events encompass a large portion of the mortality caused by the COVID‐19 pandemic, which drawn cardiologists into the management of the admitted ill patients. Given that common laboratory values may provide key insights into the illness caused by the life‐threatening SARS‐CoV‐2 virus, it would be more helpful for screening, clinical management and on‐time therapeutic strategies. Commensurate with these issues, this review article aimed to discuss the dynamic changes of the common laboratory parameters during COVID‐19 and their association with cardiovascular diseases. Besides, the values that changed in the early stage of the disease were considered and monitored during the recovery process. The time required for returning biomarkers to basal levels was also discussed. Finally, of particular interest, we tended to abridge the latest updates regarding the cardiovascular biomarkers as prognostic and diagnostic criteria to determine the severity of COVID‐19.     

Effect of ArtemiC in patients with COVID‐19: A Phase II prospective study

Despite intensive efforts, there is no effective remedy for COVID‐19. Moreover, vaccination efficacy declines over time and may be compromised against new SARS‐CoV‐2 lineages. Therefore, there remains an unmet need for simple, accessible, low‐cost and effective pharmacological anti‐SARS‐CoV‐2 agents. ArtemiC is a medical product comprising artemisinin, curcumin, frankincense and vitamin C, all of which possess anti‐inflammatory and anti‐oxidant properties. The present Phase II placebo‐controlled, double‐blinded, multi‐centred, prospective study evaluated the efficacy and safety of ArtemiC in patients with COVID‐19. The study included 50 hospitalized symptomatic COVID‐19 patients randomized (2:1) to receive ArtemiC or placebo oral spray, twice daily on Days 1 and 2, beside standard care. A physical examination was performed, and vital signs and blood tests were monitored daily until hospital discharge (or Day 15). A PCR assessment of SARS‐CoV‐2 carriage was performed at screening and on last visit. ArtemiC improved NEWS2 in 91% of patients and shortened durations of abnormal SpO₂ levels, oxygen supplementation and fever. No treatment‐related adverse events were reported. These findings suggest that ArtemiC curbed deterioration, possibly by limiting cytokine storm of COVID‐19, thus bearing great promise for COVID‐19 patients, particularly those with comorbidities.     

Three tips for creating an online course for nontraditional student populations

In spring 2020, the University of Minnesota Erosion and Stormwater Management Certification Program temporarily ceased in‐person workshops due to the spread of COVID‐19. Twenty workshops were canceled, and the 1,233 attendees (all adult learners) were moved into asynchronous online course sections. These online workshops were the first remote courses that many of the attendees had ever attempted. Here, we provide tips for successfully creating online classes for nontraditional student populations.     

Cyclin D3 restricts SARS‐CoV‐2 envelope incorporation into virions and interferes with viral spread

The COVID‐19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) presents a great threat to human health. The interplay between the virus and host plays a crucial role in successful virus replication and transmission. Understanding host–virus interactions are essential for the development of new COVID‐19 treatment strategies. Here, we show that SARS‐CoV‐2 infection triggers redistribution of cyclin D1 and cyclin D3 from the nucleus to the cytoplasm, followed by proteasomal degradation. No changes to other cyclins or cyclin‐dependent kinases were observed. Further, cyclin D depletion was independent of SARS‐CoV‐2‐mediated cell cycle arrest in the early S phase or S/G2/M phase. Cyclin D3 knockdown by small‐interfering RNA specifically enhanced progeny virus titres in supernatants. Finally, cyclin D3 co‐immunoprecipitated with SARS‐CoV‐2 envelope (E) and membrane (M) proteins. We propose that cyclin D3 impairs the efficient incorporation of envelope protein into virions during assembly and is depleted during SARS‐CoV‐2 infection to restore efficient assembly and release of newly produced virions.     

Genetic prediction of ICU hospitalization and mortality in COVID‐19 patients using artificial neural networks

There is an unmet need of models for early prediction of morbidity and mortality of Coronavirus disease‐19 (COVID‐19). We aimed to a) identify complement‐related genetic variants associated with the clinical outcomes of ICU hospitalization and death, b) develop an artificial neural network (ANN) predicting these outcomes and c) validate whether complement‐related variants are associated with an impaired complement phenotype. We prospectively recruited consecutive adult patients of Caucasian origin, hospitalized due to COVID‐19. Through targeted next‐generation sequencing, we identified variants in complement factor H/CFH, CFB, CFH‐related, CFD, CD55, C3, C5, CFI, CD46, thrombomodulin/THBD, and A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS13). Among 381 variants in 133 patients, we identified 5 critical variants associated with severe COVID‐19: rs2547438 (C3), rs2250656 (C3), rs1042580 (THBD), rs800292 (CFH) and rs414628 (CFHR1). Using age, gender and presence or absence of each variant, we developed an ANN predicting morbidity and mortality in 89.47% of the examined population. Furthermore, THBD and C3a levels were significantly increased in severe COVID‐19 patients and those harbouring relevant variants. Thus, we reveal for the first time an ANN accurately predicting ICU hospitalization and death in COVID‐19 patients, based on genetic variants in complement genes, age and gender. Importantly, we confirm that genetic dysregulation is associated with impaired complement phenotype.     

Cellular and molecular atlas of the placenta from a COVID‐19 pregnant woman infected at midgestation highlights the defective impacts on foetal health

ObjectivesThe impacts of the current COVID‐19 pandemic on maternal and foetal health are enormous and of serious concern. However, the influence of SARS‐CoV‐2 infection at early‐to‐mid gestation on maternal and foetal health remains unclear.Materials and methodsHere, we report the follow‐up study of a pregnant woman of her whole infective course of SARS‐CoV‐2, from asymptomatic infection at gestational week 20 to mild and then severe illness state, and finally cured at Week 24. Following caesarean section due to incomplete uterine rupture at Week 28, histological examinations on the placenta and foetal tissues as well as single‐cell RNA sequencing (scRNA‐seq) for the placenta were performed.ResultsCompared with the gestational age‐matched control placentas, the placenta from this COVID‐19 case exhibited more syncytial knots and lowered expression of syncytiotrophoblast‐related genes. The scRNA‐seq analysis demonstrated impaired trophoblast differentiation, activation of antiviral and inflammatory CD8 T cells, as well as the tight association of increased inflammatory responses in the placenta with complement over‐activation in macrophages. In addition, levels of several inflammatory factors increased in the placenta and foetal blood.ConclusionThese findings illustrate a systematic cellular and molecular signature of placental insufficiency and immune activation at the maternal–foetal interface that may be attributed to SARS‐CoV‐2 infection at the midgestation stage, which highly suggests the extensive care for maternal and foetal outcomes in pregnant women suffering from COVID‐19.     

Machine learning identifies molecular regulators and therapeutics for targeting SARS‐CoV2‐induced cytokine release

Although 15–20% of COVID‐19 patients experience hyper‐inflammation induced by massive cytokine production, cellular triggers of this process and strategies to target them remain poorly understood. Here, we show that the N‐terminal domain (NTD) of the SARS‐CoV‐2 spike protein substantially induces multiple inflammatory molecules in myeloid cells and human PBMCs. Using a combination of phenotypic screening with machine learning‐based modeling, we identified and experimentally validated several protein kinases, including JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, as essential downstream mediators of NTD‐induced cytokine production, implicating the role of multiple signaling pathways in cytokine release. Further, we found several FDA‐approved drugs, including ponatinib, and cobimetinib as potent inhibitors of the NTD‐mediated cytokine release. Treatment with ponatinib outperforms other drugs, including dexamethasone and baricitinib, inhibiting all cytokines in response to the NTD from SARS‐CoV‐2 and emerging variants. Finally, ponatinib treatment inhibits lipopolysaccharide‐mediated cytokine release in myeloid cells in vitro and lung inflammation mouse model. Together, we propose that agents targeting multiple kinases required for SARS‐CoV‐2‐mediated cytokine release, such as ponatinib, may represent an attractive therapeutic option for treating moderate to severe COVID‐19.     

Aging‐related cell type‐specific pathophysiologic immune responses that exacerbate disease severity in aged COVID‐19 patients

Coronavirus disease 2019 (COVID‐19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID‐19 incidence and severity as a function of age. Our analysis leveraged age‐specific COVID‐19 mortality and laboratory testing from a large COVID‐19 registry, along with epidemiological data of ~3.4 million individuals, large‐scale deep immune cell profiling data, and single‐cell RNA‐sequencing data from aged COVID‐19 patients across diverse populations. We found that decreased lymphocyte count and elevated inflammatory markers (C‐reactive protein, D‐dimer, and neutrophil–lymphocyte ratio) are significantly associated with age‐specific COVID‐19 severities. We identified the reduced abundance of naïve CD8 T cells with decreased expression of antiviral defense genes (i.e., IFITM3 and TRIM22) in aged severe COVID‐19 patients. Older individuals with severe COVID‐19 displayed type I and II interferon deficiencies, which is correlated with SARS‐CoV‐2 viral load. Elevated expression of SARS‐CoV‐2 entry factors and reduced expression of antiviral defense genes (LY6E and IFNAR1) in the secretory cells are associated with critical COVID‐19 in aged individuals. Mechanistically, we identified strong TGF‐beta‐mediated immune–epithelial cell interactions (i.e., secretory‐non‐resident macrophages) in aged individuals with critical COVID‐19. Taken together, our findings point to immuno‐inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID‐19 patients.     

Mobile SARS‑CoV‑2 screening facilities for rapid deployment and university‐based diagnostic laboratory

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic has created a public crisis. Many medical and public institutions and businesses went into isolation in response to the pandemic. Because SARS‐CoV‐2 can spread irrespective of a patient''s course of disease, these institutions’ continued operation or reopening based on the assessment and control of virus spread can be supported by targeted population screening. For this purpose, virus testing in the form of polymerase chain reaction (PCR) analysis and antibody detection in blood can be central. Mobile SARS‐CoV‐2 screening facilities with a built‐in biosafety level (BSL)‐2 laboratory were set up to allow the testing offer to be brought close to the subject group''s workplace. University staff members, their expertise, and already available equipment were used to implement and operate the screening facilities and a certified diagnostic laboratory. This operation also included specimen collection, transport, PCR and antibody analysis, and informing subjects as well as public health departments. Screening facilities were established at different locations such as educational institutions, nursing homes, and companies providing critical supply chains for health care. Less than 4 weeks after the first imposed lockdown in Germany, a first mobile testing station was established featuring a build‐in laboratory with two similar stations commencing operation until June 2020. During the 15‐month project period, approximately 33,000 PCR tests and close to 7000 antibody detection tests were collected and analyzed. The presented approach describes the required procedures that enabled the screening facilities and laboratories to collect and process several hundred specimens each day under difficult conditions. This report can assist others in establishing similar setups for pandemic scenarios.     

Antelope space‐use and behavior indicate multilevel responses to varying anthropogenic influences in a highly human‐dominated landscape

A primary means of conserving a species or a habitat in a human‐dominated landscape is through promoting coexistence with humans while minimizing conflict. For this, we should understand how wildlife is impacted by direct and indirect human activities. Such information is rare in areas with high human densities. To investigate how animals respond to altered ecological conditions in human‐dominated landscapes, we focused on a wild herbivore of conservation concern in the Krishnasaar Conservation Area (KrCA) in Nepal. Here, blackbuck Antilope cervicapra, a generalist grazer, lives in refugia located with a growing human population. We studied the impacts of humans on habitat use and behavior of blackbuck. We laid 250 × 250 m grid cells in the entire KrCA and carried out indirect sign surveys with three replications for habitat use assessment. We observed herds of blackbuck for 89 h in different habitat types using scan sampling methods. Our habitat‐use survey showed that habitats under intensive human use were hardly used by blackbuck, even when high‐quality forage was available. Habitat openness was the major predictor of habitat use inside the core area, where levels of human activities were low. We also found a positive correlation between habitat use by blackbuck and livestock. Blackbuck were substantially more vigilant when they were in forest than in grassland, again indicating an influence of risk. Overall, blackbuck appear to be sensitive to the risk associated with both natural and anthropogenic factors. Our findings have direct implications for managing human–wildlife interactions in this landscape, specifically regarding strategies for livestock grazing in habitats highly used by blackbuck and concerning predictions of how changing land use will impact the long‐term persistence of blackbuck. Our work suggests that wild herbivores may be able to persist in landscapes with high human densities so long as there are refuges where human activities are relatively low.     

ADAM10 and ADAM17 promote SARS‐CoV‐2 cell entry and spike protein‐mediated lung cell fusion

The severe‐acute‐respiratory‐syndrome‐coronavirus‐2 (SARS‐CoV‐2) is the causative agent of COVID‐19, but host cell factors contributing to COVID‐19 pathogenesis remain only partly understood. We identify the host metalloprotease ADAM17 as a facilitator of SARS‐CoV‐2 cell entry and the metalloprotease ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVID‐19 pathology. ADAM10 and ADAM17, which are broadly expressed in the human lung, cleave the SARS‐CoV‐2 spike protein (S) in vitro, indicating that ADAM10 and ADAM17 contribute to the priming of S, an essential step for viral entry and cell fusion. ADAM protease‐targeted inhibitors severely impair lung cell infection by the SARS‐CoV‐2 variants of concern alpha, beta, delta, and omicron and also reduce SARS‐CoV‐2 infection of primary human lung cells in a TMPRSS2 protease‐independent manner. Our study establishes ADAM10 and ADAM17 as host cell factors for viral entry and syncytia formation and defines both proteases as potential targets for antiviral drug development.     

Increased risk for COVID‐19 breakthrough infection in fully vaccinated patients with substance use disorders in the United States between December 2020 and August 2021

Individuals with substance use disorders (SUDs) are at increased risk for COVID‐19 infection and for adverse outcomes of the infection. Though vaccines are highly effective against COVID‐19, their effectiveness in individuals with SUDs might be curtailed by compromised immune status and a greater likelihood of exposures, added to the waning vaccine immunity and the new SARS‐CoV‐2 variants. In a population‐based cohort study, we assessed the risk, time trends, outcomes and disparities of COVID‐19 breakthrough infection in fully vaccinated SUD patients starting 14 days after completion of vaccination. The study included 579,372 individuals (30,183 with a diagnosis of SUD and 549,189 without such a diagnosis) who were fully vaccinated between December 2020 and August 2021, and had not contracted COVID‐19 infection prior to vaccination. We used the TriNetX Analytics network platform to access de‐identified electronic health records from 63 health care organizations in the US. Among SUD patients, the risk for breakthrough infection ranged from 6.8% for tobacco use disorder to 7.8% for cannabis use disorder, all significantly higher than the 3.6% in non‐SUD population (p<0.001). Breakthrough infection risk remained significantly higher after controlling for demographics (age, gender, ethnicity) and vaccine types for all SUD subtypes, except for tobacco use disorder, and was highest for cocaine and cannabis use disorders (hazard ratio, HR=2.06, 95% CI: 1.30‐3.25 for cocaine; HR=1.92, 95% CI: 1.39‐2.66 for cannabis). When we matched SUD and non‐SUD individuals for lifetime comorbidities and adverse socioeconomic determinants of health, the risk for breakthrough infection no longer differed between these populations, except for patients with cannabis use disorder, who remained at increased risk (HR=1.55, 95% CI: 1.22‐1.99). The risk for breakthrough infection was higher in SUD patients who received the Pfizer than the Moderna vaccine (HR=1.49, 95% CI: 1.31‐1.69). In the vaccinated SUD population, the risk for hospitalization was 22.5% for the breakthrough cohort and 1.6% for the non‐breakthrough cohort (risk ratio, RR=14.4, 95% CI: 10.19‐20.42), while the risk for death was 1.7% and 0.5% respectively (RR=3.5, 95% CI: 1.74‐7.05). No significant age, gender and ethnic disparities for breakthrough infection were observed in vaccinated SUD patients. These data suggest that fully vaccinated SUD individuals are at higher risk for breakthrough COVID‐19 infection, and this is largely due to their higher prevalence of comorbidities and adverse socioeconomic determinants of health compared with non‐SUD individuals. The high frequency of comorbidities in SUD patients is also likely to contribute to their high rates of hospitalization and death following breakthrough infection.