The coronavirus disease 2019 (COVID-19) pandemic underscores the need to better understand animal-to-human transmission of coronaviruses and adaptive evolution within new hosts. We scanned more than ...182,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes for selective sweep signatures and found a distinct footprint of positive selection located around a non-synonymous change (A1114G; T372A) within the spike protein receptor-binding domain (RBD), predicted to remove glycosylation and increase binding to human ACE2 (hACE2), the cellular receptor. This change is present in all human SARS-CoV-2 sequences but not in closely related viruses from bats and pangolins. As predicted, T372A RBD bound hACE2 with higher affinity in experimental binding assays. We engineered the reversion mutant (A372T) and found that A372 (wild-type WT-SARS-CoV-2) enhanced replication in human lung cells relative to its putative ancestral variant (T372), an effect that was 20 times greater than the well-known D614G mutation. Our findings suggest that this mutation likely contributed to SARS-CoV-2 emergence from animal reservoirs or enabled sustained human-to-human transmission.
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•Over 182,000 SARS-CoV-2 genomes were screened for selective sweep signatures•An adaptive change within the spike protein receptor-binding domain was identified•This change was predicted and experimentally confirmed to increase affinity to hACE2•As a result, viral replication is enhanced relative to the putative ancestral variant
A non-synonymous change (T372A) within the spike protein RBD of human SARS-CoV-2 shows higher binding affinity to hACE2 and enhanced replication in human lung cells compared with its putative ancestral variant (T372), providing evidence of a viral mutation that is likely to have been necessary to enable human-to-human transmission.
In this trial involving 180 persons with food allergies, omalizumab was effective in increasing the reaction threshold for peanut and other common food allergens.
Abstract Pervasive SARS-CoV-2 infections in humans have led to multiple transmission events to animals. While SARS-CoV-2 has a potential broad wildlife host range, most documented infections have ...been in captive animals and a single wildlife species, the white-tailed deer. The full extent of SARS-CoV-2 exposure among wildlife communities and the factors that influence wildlife transmission risk remain unknown. We sampled 23 species of wildlife for SARS-CoV-2 and examined the effects of urbanization and human use on seropositivity. Here, we document positive detections of SARS-CoV-2 RNA in six species, including the deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, and Eastern red bat between May 2022–September 2023 across Virginia and Washington, D.C., USA. In addition, we found that sites with high human activity had three times higher seroprevalence than low human-use areas. We obtained SARS-CoV-2 genomic sequences from nine individuals of six species which were assigned to seven Pango lineages of the Omicron variant. The close match to variants circulating in humans at the time suggests at least seven recent human-to-animal transmission events. Our data support that exposure to SARS-CoV-2 has been widespread in wildlife communities and suggests that areas with high human activity may serve as points of contact for cross-species transmission.
Automated experiments can accelerate research and development. ‘Flexible automation’ enables the cost- and time-effective design, construction and reconfiguration of automated experiments. Flexible ...automation is empowering researchers to deploy new science and technology faster than ever before.
Over 36 million adults over 65 years of age experience accidental falls each year. The underlying neuromechanics (whole-body function) and driving forces behind accidental falls, as well as the ...effects of aging on the ability of the musculoskeletal system to adapt, are poorly understood. We evaluated differences in kinematics (lower extremity joint angles and range of motion), kinetics (ground reaction force), and electromyography (muscle co-contraction), due to changes in surface conditions during gait in 14 older adults with a history of falling and 14 young adults. We investigated the impact of challenging surfaces on musculoskeletal adaptation and compared the mechanisms of adaptation between age-groups. Older adults displayed greater hip and knee flexion and range of motion during gait, reduced initial vertical loading, and 13 % greater knee muscle co-contraction during early stance compared to young adults. Across age groups, the presence of an uneven challenging surface increased lower-limb flexion compared to an even surface. On a slick surface, older adults displayed 30 % greater ankle muscle co-contraction during early stance as compared to young adults. Older adults respond to challenging surfaces differently than their younger counterparts, employing greater flexion during early stance. This study underscores the need for determining lower-limb musculoskeletal adaptation strategies during gait and assessing how these strategies change with age, risk of accidental falls, and environmental surfaces to reduce the risk of accidental falls.
Protein kinases in Toxoplasma gondii Gaji, Rajshekhar Y.; Sharp, Amanda K.; Brown, Anne M.
International journal for parasitology,
05/2021, Letnik:
51, Številka:
6
Journal Article
Recenzirano
Odprti dostop
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•Toxoplasma gondii is an important human pathogen.•Kinase domain architecture with a KEDD signature motif is largely conserved across eukaryotes.•Toxoplasma encodes kinases that ...belong to established eukaryotic kinase families together with apicomplexan-specific groups.•Toxoplasma kinases localise to distinct organelles in the parasite and play critical roles in pathogenesis.•Toxoplasma kinome research is key to establishing parasite specific targets and developing novel therapeutics.
Toxoplasma gondii is an obligatory intracellular pathogen that causes life threatening illness in immunodeficient individuals, miscarriage in pregnant woman, and blindness in newborn children. Similar to any other eukaryotic cell, protein kinases play critical and essential roles in the Toxoplasma life cycle. Accordingly, many studies have focused on identifying and defining the mechanism of function of these signalling proteins with a long-term goal to develop anti-Toxoplasma therapeutics. In this review, we briefly discuss classification and key components of the catalytic domain which are critical for functioning of kinases, with a focus on domains, families, and groups of kinases within Toxoplasma. More importantly, this article provides a comprehensive, current overview of research on kinase groups in Toxoplasma including the established eukaryotic AGC, CAMK, CK1, CMGC, STE, TKL families and the apicomplexan-specific FIKK, ROPK and WNG family of kinases. This work provides an overview and discusses current knowledge on Toxoplasma kinases including their localization, function, signalling network and role in acute and chronic pathogenesis, with a view towards the future in probing kinases as viable drug targets.
Little is known about the epidemiology of Merkel cell carcinoma (MCC) and mucosal melanoma (MM). Using the United States (US) National Cancer Institute's Surveillance, Epidemiology, and End Results ...(SEER) program data, we compared MCC and MM with cutaneous malignant melanoma (CMM) with respect to incidence rates and prognostic factors to better understand disease etiologies. We describe the proportional incidences of the three cancers along with their survival rates based on 20 years of national data. The incidence rates in 2000-2019 were 203.7 per 1,000,000 people for CMM, 5.9 per 1,000,000 people for MCC and 0.1 per 1,000,000 people for MM. The rates of these cancers increased over time, with the rate of MM tripling between 2000-2009 and 2010-2019. The incidences of these cancers increased with age and rates were highest among non-Hispanic Whites. Fewer MCCs and MMS were diagnosed at the local stage compared with CMM. The cases in the 22 SEER registries in California were not proportional to the 2020 population census but instead were higher than expected for CMM and MCC and lower than expected for MM. Conversely, MM rates were higher than expected in Texas and New York. These analyses highlight similarities in the incidence rates of CMM and MCC-and differences between them and MM rates-by state. Understanding more about MCC and MM is important because of their higher potential for late diagnosis and metastasis, which lead to poor survival.
Oral fluids offer a noninvasive sampling method for the detection of Abs. Quantification of IgA and IgG Abs in saliva allows studies of the mucosal and systemic immune response after natural ...infection or vaccination. We developed and validated an enzyme immunoassay (EIA) to detect and quantify salivary IgA and IgG Abs against the prefusion-stabilized form of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein expressed in suspension-adapted HEK-293 cells. Normalization against total Ab isotype was performed to account for specimen differences, such as collection time and sample volume. Saliva samples collected from 187 SARS-CoV-2 confirmed cases enrolled in 2 cohorts and 373 prepandemic saliva samples were tested. The sensitivity of both EIAs was high (IgA, 95.5%; IgG, 89.7%) without compromising specificity (IgA, 99%; IgG, 97%). No cross-reactivity with endemic coronaviruses was observed. The limit of detection for SARS-CoV-2 salivary IgA and IgG assays were 1.98 ng/ml and 0.30 ng/ml, respectively. Salivary IgA and IgG Abs were detected earlier in patients with mild COVID-19 symptoms than in severe cases. However, severe cases showed higher salivary Ab titers than those with a mild infection. Salivary IgA titers quickly decreased after 6 wk in mild cases but remained detectable until at least week 10 in severe cases. Salivary IgG titers remained high for all patients, regardless of disease severity. In conclusion, EIAs for both IgA and IgG had high specificity and sensitivity for the confirmation of current or recent SARS-CoV-2 infections and evaluation of the IgA and IgG immune response.
Glioblastoma multiforme (GBM) is the most aggressive and prevalent form of brain cancer, with an expected survival of 12–15 months following diagnosis. GBM affects the glial cells of the central ...nervous system, which impairs regular brain function including memory, hearing, and vision. GBM has virtually no long-term survival even with treatment, requiring novel strategies to understand disease progression. Here, we identified a somatic mutation in OR2T7, a G-protein-coupled receptor (GPCR), that correlates with reduced progression-free survival for glioblastoma (log rank p-value = 0.05), suggesting a possible role in tumor progression. The mutation, D125V, occurred in 10% of 396 glioblastoma samples in The Cancer Genome Atlas, but not in any of the 2504 DNA sequences in the 1000 Genomes Project, suggesting that the mutation may have a deleterious functional effect. In addition, transcriptome analysis showed that the p38α mitogen-activated protein kinase (MAPK), c-Fos, c-Jun, and JunB proto-oncogenes, and putative tumor suppressors RhoB and caspase-14 were underexpressed in glioblastoma samples with the D125V mutation (false discovery rate < 0.05). Molecular modeling and molecular dynamics simulations have provided preliminary structural insight and indicate a dynamic helical movement network that is influenced by the membrane-embedded, cytofacial-facing residue 125, demonstrating a possible obstruction of G-protein binding on the cytofacial exposed region. We show that the mutation impacts the “open” GPCR conformation, potentially affecting Gα-subunit binding and associated downstream activity. Overall, our findings suggest that the Val125 mutation in OR2T7 could affect glioblastoma progression by downregulating GPCR-p38 MAPK tumor-suppression pathways and impacting the biophysical characteristics of the structure that facilitates Gα-subunit binding. This study provides the theoretical basis for further experimental investigation required to confirm that the D125V mutation in OR2T7 is not a passenger mutation. With validation, the aforementioned mutation could represent an important prognostic marker and a potential therapeutic target for glioblastoma.
Sex differences exist in the regulation of arterial pressure and renal function by the renin-angiotensin system (RAS). This may in part stem from a differential balance in the pressor and depressor ...arms of the RAS. In males, the ACE/AngII/AT
1
R pathways are enhanced, whereas, in females, the balance is shifted towards the ACE2/Ang(1-7)/MasR and AT
2
R pathways. Evidence clearly demonstrates that premenopausal women, as compared to aged-matched men, are protected from renal and cardiovascular disease, and this differential balance of the RAS between the sexes likely contributes. With aging, this cardiovascular protection in women is lost and this may be related to loss of estrogen postmenopause but the possible contribution of other sex hormones needs to be further examined. Restoration of these RAS depressor pathways in older women, or up-regulation of these in males, represents a therapeutic target that is worth pursuing.
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