Some persons who have recovered from Covid-19 have antibodies to the spike protein of SARS-CoV-2. In 43 such persons who had received a first mRNA vaccine dose, high levels of neutralizing antispike ...antibodies were produced — in many cases even higher than after a second dose in 67 persons without baseline antibodies to the virus. Systemic reactions were more common in those seropositive before vaccination.
Due to differences in human and murine angiotensin converting enzyme 2 (ACE-2) receptor, initially available SARS-CoV-2 isolates could not infect mice. Here we show that serial passaging of ...USA-WA1/2020 strain in mouse lungs results in "mouse-adapted" SARS-CoV-2 (MA-SARS-CoV-2) with mutations in S, M, and N genes, and a twelve-nucleotide insertion in the S gene. MA-SARS-CoV-2 infection causes mild disease, with more pronounced morbidity depending on genetic background and in aged and obese mice. Two mutations in the S gene associated with mouse adaptation (N501Y, H655Y) are present in SARS-CoV-2 variants of concern (VoCs). N501Y in the receptor binding domain of viruses of the B.1.1.7, B.1.351, P.1 and B.1.1.529 lineages (Alpha, Beta, Gamma and Omicron variants) is associated with high transmissibility and allows VoCs to infect wild type mice. We further show that S protein mutations of MA-SARS-CoV-2 do not affect neutralization efficiency by human convalescent and post vaccination sera.
Dysregulation of the Ras oncogene in development causes developmental disorders, "Rasopathies," whereas mutational activation or amplification of Ras in differentiated tissues causes cancer. Rabex-5 ...(also called RabGEF1) inhibits Ras by promoting Ras mono- and di-ubiquitination. We report here that Rabex-5-mediated Ras ubiquitination requires Ras Tyrosine 4 (Y4), a site of known phosphorylation. Ras substitution mutants insensitive to Y4 phosphorylation did not undergo Rabex-5-mediated ubiquitination in cells and exhibited Ras gain-of-function phenotypes in vivo. Ras Y4 phosphomimic substitution increased Rabex-5-mediated ubiquitination in cells. Y4 phosphomimic substitution in oncogenic Ras blocked the morphological phenotypes associated with oncogenic Ras in vivo dependent on the presence of Rabex-5. We developed polyclonal antibodies raised against an N-terminal Ras peptide phosphorylated at Y4. These anti-phospho-Y4 antibodies showed dramatic recognition of recombinant wild-type Ras and RasG12V proteins when incubated with JAK2 or SRC kinases but not of RasY4F or RasY4F,G12V recombinant proteins suggesting that JAK2 and SRC could promote phosphorylation of Ras proteins at Y4 in vitro. Anti-phospho-Y4 antibodies also showed recognition of RasG12V protein, but not wild-type Ras, when incubated with EGFR. A role for JAK2, SRC, and EGFR (kinases with well-known roles to activate signaling through Ras), to promote Ras Y4 phosphorylation could represent a feedback mechanism to limit Ras activation and thus establish Ras homeostasis. Notably, rare variants of Ras at Y4 have been found in cerebellar glioblastomas. Therefore, our work identifies a physiologically relevant Ras ubiquitination signal and highlights a requirement for Y4 for Ras inhibition by Rabex-5 to maintain Ras pathway homeostasis and to prevent tissue transformation.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The USA has failed to codify the protection of children from gun violence (GV) as a human right. This study employs a youth participatory action research methodology, within the framework of the ...United Nations Convention on the Rights of the Child (UNCRC), to investigate the relationships between GV exposure, self-identified gender and perceptions of children's rights and safety.
An anonymous survey based on UNICEF USA's Child Friendly Cities Initiative interactive survey tool targeting adolescents was modified by East Harlem, New York high school student co-researchers in collaboration with near-peer graduate students. The 61-question survey was administered at an East Harlem high school. Analysis consisted of univariate, bivariate and logistic regression using SPSS®.
A total of 153 students completed the survey: 48.4% self-identified as male and 45.8% as female. Thirty-five percent reported witnessing GV. Most (79.1%) were aware of child rights regardless of gender or GV exposure but there were differences in perceptions of safety. Fifteen percent of females reported never feeling safe at school compared to 3% of males (p = 0.01). Females were 2.2 times as likely as males to report transportation waiting areas as never safe (p = 0.008). Almost a third of females reported never feeling safe from sexual harassment in public, compared to 10% of males (p = 0.004). In multivariable logistic regression adjusted for gender, race/ethnicity and grade level, students who witnessed GV were 4.6 times more likely to report never feeling safe from violence (95% CI 1.7-12.4). Thirty percent of students who witnessed GV reported not attending school because of safety concerns. Students who witnessed GV had 2.2 times the odds of carrying a weapon to school (95% CI 1.1-4.5). These patterns continued for other perceptions of safety.
The students in this study affirmed their rights to participate and express their views on matters that may affect them, as articulated in the UNCRC. The study revealed differences in perceptions of safety by self-identified gender and identified gun violence as a major contributor of youth's perception of lack of safety. The study evinces the efficacy of employing YPAR methodology to identify and answer youth concerns of community safety and prioritize honoring child rights.
Category: Ankle Introduction/Purpose: One of the emerging trends in contemporary healthcare is the shift in surgical resources to the outpatient setting coupled with institutional focus of reducing ...inpatient length of stay to facilitate cost containment. Through a multi-center retrospective review of operatively treated ankle fractures, we sought to calculate the actual financial cost of each procedure as well as to compare the economics of performing outpatient versus inpatient surgery. Additionally, we sought to determine whether the surgery location (inpatient and outpatient) was associated with specific patient demographics, medical co- morbidities, or surgeon practice patterns. Methods: A multi-center retrospective comparative study of 240 surgically treated ankle fractures over a two-year period was performed. Two tertiary care hospitals and their affiliated ambulatory surgery centers were included in the study. Patient selection was based on Current Procedural Terminology codes while exclusion criteria included pediatric patient, open trauma, distal tibia pilon fracture, or history of prior ankle fracture. The total direct cost of each surgery was calculated including categorized charges for room and board, pharmacy, rehabilitation, radiology, surgical implant materials, and surgeon professional fees. Patient age, medical co-morbidities, presence of poly-trauma, ordering of ankle CT-scan, and fellowship training of the orthopaedic surgeon were also evaluated in the study. The chi-square test or Fisher’s exact test was used to compare inpatients and outpatients for each variable. Results: 142 inpatient and 98 outpatient ankle fracture surgeries were performed. Median length of stay was 5 days for inpatients and the mean total direct cost was $11,466 for each inpatient case with room and board charges averaging $2,694. The mean total direct cost for each outpatient procedure was $3,111. Regarding patient demographics, statistically significant higher percentages were recorded among inpatients in the following groups: age 65 years or older (p < 0.0003), hypertension (p < 0.0230), presence of poly-trauma (p < 0.0149) and ordering of ankle CT-scan (p < 0.0001). 84% of ankle fracture surgeries performed by foot and ankle surgeons were outpatient procedures while 71% of ankle fracture surgeries performed by orthopaedic trauma surgeons were inpatient procedures. Conclusion: Our data shows that with 5 day median length of stay for the hospitalized patient group, the average total cost for inpatient ankle fracture surgery was nearly four times higher and $8,000 more than the total cost for outpatient ankle fracture surgery. Increased patient age and other specific medical co-morbidities were statistically linked with inpatient admission. In this multi-center study, foot and ankle surgeons were more likely than trauma surgeons to perform outpatient ankle fracture surgery. Healthcare institutions may realize substantial practice management cost savings by shifting ankle fracture surgery to the outpatient setting.
In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast-derived mAbs from individuals who received SARS-CoV-2 spike mRNA vaccine. Polyclonal antibody responses in ...vaccinees were robust and comparable to or exceeded those seen after natural infection. However, the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD and RBD of SARS-CoV-2 spike and an original antigenic-sin like backboost to spikes of seasonal human coronaviruses OC43 and HKU1. Neutralizing activity of NTD mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD was abolished, suggesting that a proportion of vaccine-induced RBD binding antibodies may provide substantial protection against viral variants carrying single E484K RBD mutations.
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•Antibody responses after SARS-CoV-2 mRNA vaccination target RBD, NTD, and S2•SARS-CoV-2 mRNA vaccination induces a high rate of non-neutralizing antibodies•Crossreactive antibodies to seasonal β-coronaviruses are induced by vaccination•Variant mutation N501Y enhances affinity to human ACE2 while E484K reduces it
An analysis of mRNA vaccine-induced polyclonal antibodies and plasmablast-derived monoclonal antibodies from individuals vaccinated against SARS-CoV-2 identifies a high proportion of non-neutralizing antibodies and the induction of cross-reactive antibodies to seasonal coronaviruses and also maps the regions in the spike protein that are targeted, even among viral variants.
It is thought that mRNA-based vaccine-induced immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wanes quickly, based mostly on short-term studies. Here, we analyzed the ...kinetics and durability of the humoral responses to SARS-CoV-2 infection and vaccination using >8,000 longitudinal samples collected over a 3-year period in New York City. Upon primary immunization, participants with pre-existing immunity mounted higher antibody responses faster and achieved higher steady-state antibody titers than naive individuals. Antibody kinetics were characterized by two phases: an initial rapid decay, followed by a stabilization phase with very slow decay. Booster vaccination equalized the differences in antibody concentration between participants with and without hybrid immunity, but the peak antibody titers decreased with each successive antigen exposure. Breakthrough infections increased antibodies to similar titers as an additional vaccine dose in naive individuals. Our study provides strong evidence that SARS-CoV-2 antibody responses are long lasting, with initial waning followed by stabilization.
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•COVID-19-vaccine-induced immunity wanes but stabilizes at an individual setpoint•Pre-existing immunity results in rapid antibody responses upon vaccination•Boosters equalize antibody titers between individuals with and without hybrid immunity•Antibody kinetics show two phases: an initial rapid decay followed by a steady state
SARS-CoV-2 mRNA-based vaccine-induced immunity is thought to wane quickly based on short-term studies. Using longitudinal data, Srivastava et al. find that participants with hybrid immunity show faster, higher antibody responses after initial vaccination, but boosters evened out differences. Modeling of antibody kinetics revealed an initial rapid decay followed by a stabilization phase, challenging the idea that vaccine immunity fades quickly.
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