Circulating NK cells are known to convert to a type 1 innate lymphoid cell (ILC1)-like phenotype in response to TGF-β exposure. However, the precise cellular changes defining this process as well as ...the downstream signaling pathways guiding it remain poorly defined, particularly in humans. We used mass cytometry by time-of-flight (CyTOF) to model this phenotypic shift in vitro and identify a synergistic activity of TGF-β and IL-15 in this cellular conversion. CyTOF profiling identified substantial heterogeneity in the propensity of NK cells to adopt an ILC1-like phenotype in culture, characterized by the step-wise acquisition of various markers, including CD69, CD9, CD103, and CD49a. Activating and inhibitory receptors, including NKG2A, NKG2D, KIR2DL1, KIR3DL1, NKp30, NKp44, and NKp46, were all found to be upregulated exclusively on the cellular subsets that converted most readily in response to TGF-β. An assessment of downstream TGF-β signaling identified TAK1-mediated activation of p38 MAPK as the critical pathway driving conversion. IL-15 enhanced TGF-β-mediated conversion through Ras:RAC1 signaling as well as via the activation of MEK/ERK. Interestingly, the adoption of an ILC1-like phenotype was independent of the effect of IL-15 or TGF-β on mTOR, as the culture of NK cells in the presence of mTOR inhibitors, such as rapamycin or torin1, had minimal impact on the degree of conversion. In conclusion, we have used in vitro human culture systems and CyTOF to define the conversion of circulating NK cells to an ILC1-like phenotype and have clarified the pathways responsible for this process.
Abstract
The beginning of 2020 marked the onset of the COVID-19 pandemic and a new reality. Mainstream learning loss discourse emerged as young people faced new social challenges and rising ...inequities. However, how we define some of these challenges may pose new barriers to equity promotion. Deficit-based narratives often negatively construct youth identities and intertwine with neoliberal forces and systemic inequities. Out-of-school time (OST) spaces offer hope and opportunity for a re-envisioned environment to centralize youth voice and provide critical time for leisure and reconnection. In this article, authors explore the strategies that can exist between youth workers and social workers in cultivating OST spaces for young people to engage with complex social justice development in humane, nurturing, and respectful environments. Authors center the argument for shifting away from extractive neoliberal models that commodify youth, the importance of becoming cognizant of OST’s impact on young people’s development, and raising awareness of the possibilities within OST spaces through youth-focused frameworks.
As the need for school social work (SSW) practitioners increases, more research may be useful to understand how roles and practices are shaped and how this differs from their perceptions of essential ...practice. To understand the roles and functions of SSW, a survey of nine critical components was developed through an evaluation of national association’s standards that offer guidance for SSW practice. Survey respondents (
N
= 318) consisted mostly of SSW practitioners (85%), evaluated nine critical components: advocacy, building capacity, home-school liaison, multi-tier system of support, navigating school settings, professional values, service delivery, social work theory, use of data and evidence, and suggested the addition of new essential components. The results focus on which practices are deemed essential and the frequency of performing these tasks. We conclude with implications of practice essentiality and frequency discussed across the nine critical component domains, offering suggestions for future research, education, training, and professional development of SSW practitioners.
In April 2020, the discourse surrounding the COVID-19 learning loss began. Researchers predicted student learning loss due to school closures, with estimated declines in math and reading during the ...pandemic (Kuhfeld & Tarasawa, 2020). To follow, hundreds of billions of dollars have been allocated to address learning loss (Jordan, 2022). To be clear, the ongoing impact of the COVID-19 pandemic has been extreme and omnipresent. However, the stigma of labeling a generation of students from a deficit-based lens does not offer the support sorely needed in school systems (Zhao, 2021). As social workers, we must be cognizant of the ramifications of yet another stigmatizing label cast on students.Although results varied—not all were negative—learning loss has been inconsistently defined as student learning deficits in math and reading during the pandemic (Kuhfeld, Soland, Tarasawa, Johnson, Ruzek, & Lewis, 2020; Kuhfeld, Soland, Tarasawa, Johnson, Ruzek, & Liu, 2020a, 2020b; Kuhfeld & Tarasawa, 2020; Kuhfeld, Tarasawa, et al., 2020). Education consulting groups led the dissemination of learning loss discourse by providing data, funding reports, and promoting reform through in-house services (i.e., increased testing and tutoring; Dorn et al., 2020a, 2020b; Kuhfeld, Soland, Tarasawa, Johnson, Ruzek, & Lewis, 2020; Kuhfeld, Soland, Tarasawa, Johnson, Ruzek, & Liu, 2020a, 2020b; Kuhfeld & Tarasawa, 2020; Kuhfeld, Tarasawa, et al., 2020). As reform ensues to address learning loss, social workers must help mitigate the harm caused by the deficit-based portrayals of youth.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Purpose
Etomidate and ketamine are hemodynamically stable induction agents often used to sedate critically ill patients during emergency endotracheal intubation. In 2015, quality improvement data ...from our hospital suggested a survival benefit at Day 7 from avoidance of etomidate in critically ill patients during emergency intubation. In this clinical trial, we hypothesized that randomization to ketamine instead of etomidate would be associated with Day 7 survival after emergency endotracheal intubation.
Methods
A prospective, randomized, open-label, parallel assignment, single-center clinical trial performed by an anesthesiology-based Airway Team under emergent circumstances at one high-volume medical center in the United States. 801 critically ill patients requiring emergency intubation were randomly assigned 1:1 by computer-generated, pre-randomized sealed envelopes to receive etomidate (0.2–0.3 mg/kg,
n
= 400) or ketamine (1–2 mg/kg,
n
= 401) for sedation prior to intubation. The pre-specified primary endpoint of the trial was Day 7 survival. Secondary endpoints included Day 28 survival.
Results
Of the 801 enrolled patients, 396 were analyzed in the etomidate arm, and 395 in the ketamine arm. Day 7 survival was significantly lower in the etomidate arm than in the ketamine arm (77.3% versus 85.1%, difference − 7.8, 95% confidence interval − 13, − 2.4,
p
= 0.005). Day 28 survival rates for the two groups were not significantly different (etomidate 64.1%, ketamine 66.8%, difference − 2.7, 95% confidence interval − 9.3, 3.9,
p
= 0.294).
Conclusion
While the primary outcome of Day 7 survival was greater in patients randomized to ketamine, there was no significant difference in survival by Day 28.
This study aims to explore the experiences of family caregivers during the COVID-19 pandemic-imposed visitation restrictions at formal care settings (FCS) such as assisted living centers and ...traditional nursing homes. Participants (N = 512) were recruited from an international caregiving social media site that was developed at the beginning of the COVID-19 pandemic. Descriptive data was collected on the family caregivers, the care recipient and facility. Respondents also provided a single feeling word describing their experience and an open-ended question allowed for further exploration. Caregivers were predominantly daughters (n = 375). The most common reported feeling words were sadness (n = 200), trauma (n = 108), anger (n = 65), frustration (n = 56), helplessness (n = 50), and anxiety (n = 36). Thematic analysis revealed four overarching themes: 1) isolation 2) rapid decline 3) inhumane care and 4) lack of oversight. This study highlights the importance of addressing the mental, emotional and physical needs of both care recipient and family caregiver during this challenging time. Caregiver visitation policy reform that includes the care recipient and family caregiver is also discussed.
CRISPR-Cas9 is the forefront technology for editing the genome. In this system, the Cas9 protein is programmed with guide RNAs to process DNA sequences that match the guide RNA forming an RNA:DNA ...hybrid structure. However, the binding of DNA sequences that do not fully match the guide RNA can limit the applicability of CRISPR-Cas9 for genome editing, resulting in the so-called off-target effects. Here, molecular dynamics is used to probe the effect of DNA base pair mismatches within the RNA:DNA hybrid in CRISPR-Cas9. Molecular simulations revealed that the presence of mismatched pairs in the DNA at distal sites with respect to the Protospacer Adjacent Motif (PAM) recognition sequence induces an extended opening of the RNA:DNA hybrid, leading to novel interactions established by the unwound nucleic acids and the protein counterpart. On the contrary, mismatched pairs upstream of the RNA:DNA hybrid are rapidly incorporated within the heteroduplex, with minor effect on the protein-nucleic acid interactions. As a result, mismatched pairs at PAM distal ends interfere with the activation of the catalytic HNH domain, while mismatches fully embedded in the RNA:DNA do not affect the HNH dynamics and enable its activation to cleave the DNA. These findings provide a mechanistic understanding to the intriguing experimental evidence that PAM distal mismatches hamper a proper function of HNH, explaining also why mismatches within the heteroduplex are much more tolerated. This constitutes a step forward in understanding off-target effects in CRISPR-Cas9, which encourages novel structure-based engineering efforts aimed at preventing the onset of off-target effects.
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