Abstract
In this work, we investigate how the complex structure found in solar wind proton velocity distribution functions (VDFs), rather than the commonly assumed two-component bi-Maxwellian ...structure, affects the onset and evolution of parallel-propagating microinstabilities. We use the
Arbitrary Linear Plasma Solver
, a numerical dispersion solver, to find the real frequencies and growth/damping rates of the Alfvén modes calculated for proton VDFs extracted from Wind spacecraft observations of the solar wind. We compare this wave behavior to that obtained by applying the same procedure to core-and-beam bi-Maxwellian fits of the Wind proton VDFs. We find several significant differences in the plasma waves obtained for the extracted data and bi-Maxwellian fits, including a strong dependence of the growth/damping rate on the shape of the VDF. By applying the quasilinear diffusion operator to these VDFs, we pinpoint resonantly interacting regions in velocity space where differences in VDF structure significantly affect the wave growth and damping rates. This demonstration of the sensitive dependence of Alfvén mode behavior on VDF structure may explain why the Alfvén ion-cyclotron instability thresholds predicted by linear theory for bi-Maxwellian models of solar wind proton background VDFs do not entirely constrain spacecraft observations of solar wind proton VDFs, such as those made by the Wind spacecraft.
In this work, we investigate how the complex structure found in solar wind
proton velocity distribution functions (VDFs), rather than the commonly assumed
two-component bi-Maxwellian structure, ...affects the onset and evolution of
parallel-propagating microinstabilities. We use the Arbitrary Linear Plasma
Solver (ALPS), a numerical dispersion solver, to find the real frequencies and
growth/damping rates of the Alfv\'en modes calculated for proton VDFs extracted
from Wind spacecraft observations of the solar wind. We compare this wave
behavior to that obtained by applying the same procedure to core-and-beam
bi-Maxwellian fits of the Wind proton VDFs. We find several significant
differences in the plasma waves obtained for the extracted data and
bi-Maxwellian fits, including a strong dependence of the growth/damping rate on
the shape of the VDF. By application of the quasilinear diffusion operator to
these VDFs, we pinpoint resonantly interacting regions in velocity space where
differences in VDF structure significantly affect the wave growth and damping
rates. This demonstration of the sensitive dependence of Alfv\'en mode behavior
on VDF structure may explain why the Alfv\'en ion-cyclotron instability
thresholds predicted by linear theory for bi-Maxwellian models of solar wind
proton background VDFs do not entirely constrain spacecraft observations of
solar wind proton VDFs, such as those made by the Wind spacecraft.
In this work, we investigate how the complex structure found in solar wind proton velocity distribution functions (VDFs), rather than the commonly assumed two-component bi-Maxwellian structure, ...affects the onset and evolution of parallel-propagating microinstabilities. We use the Arbitrary Linear Plasma Solver (ALPS), a numerical dispersion solver, to find the real frequencies and growth/damping rates of the Alfvén modes calculated for proton VDFs extracted from Wind spacecraft observations of the solar wind. We compare this wave behavior to that obtained by applying the same procedure to core-and-beam bi-Maxwellian fits of the Wind proton VDFs. We find several significant differences in the plasma waves obtained for the extracted data and bi-Maxwellian fits, including a strong dependence of the growth/damping rate on the shape of the VDF. By application of the quasilinear diffusion operator to these VDFs, we pinpoint resonantly interacting regions in velocity space where differences in VDF structure significantly affect the wave growth and damping rates. This demonstration of the sensitive dependence of Alfvén mode behavior on VDF structure may explain why the Alfvén ion-cyclotron instability thresholds predicted by linear theory for bi-Maxwellian models of solar wind proton background VDFs do not entirely constrain spacecraft observations of solar wind proton VDFs, such as those made by the Wind spacecraft.
In this study, we identified and characterized an N-ethyl-N-nitrosourea (ENU) induced mutation in Usp14 (nmf375) that leads to adult-onset neurological disease. The nmf375 mutation causes aberrant ...splicing of Usp14 mRNA, resulting in a 95% reduction in USP14. We previously showed that loss of USP14 in ataxia (ax (J)) mice results in reduced ubiquitin levels, motor endplate disease, Purkinje cell axonal dystrophy and decreased hippocampal paired pulse facilitation (PPF) during the first 4-6 weeks of life, and early postnatal lethality by two months of age. Although the loss of USP14 is comparable between the nmf375 and ax (J) mice, the nmf375 mice did not exhibit these ax (J) developmental abnormalities. However, by 12 weeks of age the nmf375 mutants present with ubiquitin depletion and motor endplate disease, indicating a continual role for USP14-mediated regulation of ubiquitin pools and neuromuscular junction (NMJ) structure in adult mice. The observation that motor endplate disease was only seen after ubiquitin depletion suggests that the preservation of NMJ structure requires the stable maintenance of synaptic ubiquitin pools. Differences in genetic background were shown to affect ubiquitin expression and dramatically alter the phenotypes caused by USP14 deficiency.
Key points
Mice carrying the ataxia (axJ) mutation have a 95% reduction in the deubiquitinating enzyme USP14, which results in a reduction in hippocampal paired pulse facilitation, a form of ...short‐term synaptic plasticity.
Hippocampal synapses in axJ mice have a 50% reduction in synaptic vesicles but no change in the initial release probability, which is a novel mechanism for regulating paired pulse facilitation.
USP14 modulates hippocampal short‐term plasticity and structure independent of its deubiquitinating activity, as overexpression of a catalytically inactive form of USP14 restores hippocampal paired pulse facilitation and vesicle number to the ataxia mice.
Pharmacological inhibition of the proteasome also rescues the deficits in hippocampal short‐term plasticity in ataxia mice, implying that the loss of USP14 causes increased protein degradation.
These results suggest that USP14 plays a modulatory role in regulating protein turnover by the proteasome that is independent of its canonical role in the disassembly of polyubiquitin conjugates.
The ubiquitin proteasome system is required for the rapid and precise control of protein abundance that is essential for synaptic function. USP14 is a proteasome‐bound deubiquitinating enzyme that recycles ubiquitin and regulates synaptic short‐term synaptic plasticity. We previously reported that loss of USP14 in axJ mice causes a deficit in paired pulse facilitation (PPF) at hippocampal synapses. Here we report that USP14 regulates synaptic function through a novel, deubiquitination‐independent mechanism. Although PPF is usually inversely related to release probability, USP14 deficiency impairs PPF without altering basal release probability. Instead, the loss of USP14 causes a large reduction in the number of synaptic vesicles. Over‐expression of a catalytically inactive form of USP14 rescues the PPF deficit and restores synaptic vesicle number, indicating that USP14 regulates presynaptic structure and function independently of its role in deubiquitination. Finally, the PPF deficit caused by loss of USP14 can be rescued by pharmacological inhibition of proteasome activity, suggesting that inappropriate protein degradation underlies the PPF impairment. Overall, we demonstrate a novel, deubiquitination‐independent function for USP14 in influencing synaptic architecture and plasticity.
Historical discourses about the Caribbean often chronicle West African and European influence to the general neglect of indigenous people's contributions to the contemporary region. Consequently, ...demographic histories of Caribbean people prior to and after European contact are not well understood. Although archeological evidence suggests that the Lesser Antilles were populated in a series of northward and eastern migratory waves, many questions remain regarding the relationship of the Caribbean migrants to other indigenous people of South and Central America and changes to the demography of indigenous communities post-European contact. To explore these issues, we analyzed mitochondrial DNA and Y-chromosome diversity in 12 unrelated individuals from the First Peoples Community in Arima, Trinidad, and 43 unrelated Garifuna individuals residing in St. Vincent. In this community-sanctioned research, we detected maternal indigenous ancestry in 42% of the participants, with the remainder having haplotypes indicative of African and South Asian maternal ancestry. Analysis of Y-chromosome variation revealed paternal indigenous American ancestry indicated by the presence of haplogroup Q-M3 in 28% of the male participants from both communities, with the remainder possessing either African or European haplogroups. This finding is the first report of indigenous American paternal ancestry among indigenous populations in this region of the Caribbean. Overall, this study illustrates the role of the region's first peoples in shaping the genetic diversity seen in contemporary Caribbean populations.
Objectives
From a genetic perspective, relatively little is known about how mass emigrations of African, European, and Asian peoples beginning in the 16th century affected Indigenous Caribbean ...populations. Therefore, we explored the impact of serial colonization on the genetic variation of the first Caribbean islanders.
Materials and methods
Sixty‐four members of St. Vincent's Garifuna Community and 36 members of Trinidad's Santa Rosa First People's Community (FPC) of Arima were characterized for mitochondrial DNA and Y‐chromosome diversity via direct sequencing and targeted SNP and STR genotyping. A subset of 32 Garifuna and 18 FPC participants were genotyped using the GenoChip 2.0 microarray. The resulting data were used to examine genetic diversity, admixture, and sex biased gene flow in the study communities.
Results
The Garifuna were most genetically comparable to African descendant populations, whereas the FPC were more similar to admixed American groups. Both communities also exhibited moderate frequencies of Indigenous American matrilines and patrilines. Autosomal SNP analysis indicated modest Indigenous American ancestry in these populations, while both showed varying degrees of African, European, South Asian, and East Asian ancestry, with patterns of sex‐biased gene flow differing between the island communities.
Discussion
These patterns of genetic variation are consistent with historical records of migration, forced, or voluntary, and suggest that different migration events shaped the genetic make‐up of each island community. This genomic study is the highest resolution analysis yet conducted with these communities, and provides a fuller understanding of the complex bio‐histories of Indigenous Caribbean peoples in the Lesser Antilles.
Hypotension is common during tracheal intubation of critically ill adults and increases the risk of cardiac arrest and death. Whether administering an intravenous fluid bolus to critically ill adults ...undergoing tracheal intubation prevents severe hypotension, cardiac arrest, or death remains uncertain.
To determine the effect of fluid bolus administration on the incidence of severe hypotension, cardiac arrest, and death.
This randomized clinical trial enrolled 1067 critically ill adults undergoing tracheal intubation with sedation and positive pressure ventilation at 11 intensive care units in the US between February 1, 2019, and May 24, 2021. The date of final follow-up was June 21, 2021.
Patients were randomly assigned to receive either a 500-mL intravenous fluid bolus (n = 538) or no fluid bolus (n = 527).
The primary outcome was cardiovascular collapse (defined as new or increased receipt of vasopressors or a systolic blood pressure <65 mm Hg between induction of anesthesia and 2 minutes after tracheal intubation, or cardiac arrest or death between induction of anesthesia and 1 hour after tracheal intubation). The secondary outcome was the incidence of death prior to day 28, which was censored at hospital discharge.
Among 1067 patients randomized, 1065 (99.8%) completed the trial and were included in the primary analysis (median age, 62 years IQR, 51-70 years; 42.1% were women). Cardiovascular collapse occurred in 113 patients (21.0%) in the fluid bolus group and in 96 patients (18.2%) in the no fluid bolus group (absolute difference, 2.8% 95% CI, -2.2% to 7.7%; P = .25). New or increased receipt of vasopressors occurred in 20.6% of patients in the fluid bolus group compared with 17.6% of patients in the no fluid bolus group, a systolic blood pressure of less than 65 mm Hg occurred in 3.9% vs 4.2%, respectively, cardiac arrest occurred in 1.7% vs 1.5%, and death occurred in 0.7% vs 0.6%. Death prior to day 28 (censored at hospital discharge) occurred in 218 patients (40.5%) in the fluid bolus group compared with 223 patients (42.3%) in the no fluid bolus group (absolute difference, -1.8% 95% CI, -7.9% to 4.3%; P = .55).
Among critically ill adults undergoing tracheal intubation, administration of an intravenous fluid bolus compared with no fluid bolus did not significantly decrease the incidence of cardiovascular collapse.
ClinicalTrials.gov Identifier: NCT03787732.
IntroductionIntubation-related complications are less frequent when intubation is successful on the first attempt. The rate of first attempt success in the emergency department (ED) and intensive ...care unit (ICU) is typically less than 90%. The bougie, a semirigid introducer that can be placed into the trachea to facilitate a Seldinger-like technique of tracheal intubation and is typically reserved for difficult or failed intubations, might improve first attempt success. Evidence supporting its use, however, is from a single academic ED with frequent bougie use. Validation of these findings is needed before widespread implementation.Methods and analysisThe BOugie or stylet in patients Undergoing Intubation Emergently trial is a prospective, multicentre, non-blinded randomised trial being conducted in six EDs and six ICUs in the USA. The trial plans to enrol 1106 critically ill adults undergoing orotracheal intubation. Eligible patients are randomised 1:1 for the use of a bougie or use of an endotracheal tube with stylet for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcome is severe hypoxaemia, defined as an oxygen saturation less than 80% between induction until 2 min after completion of intubation. Enrolment began on 29 April 2019 and is expected to be completed in 2021.Ethics and disseminationThe trial protocol was approved with waiver of informed consent by the Central Institutional Review Board at Vanderbilt University Medical Center or the local institutional review board at an enrolling site. The results will be submitted for publication in a peer-reviewed journal and presented at scientific conferences.Trial registration numberClinicalTrials.gov Registry (NCT03928925).
IBM Watson for Oncology trained by Memorial Sloan Kettering (WFO) is a clinical decision support tool designed to assist physicians in choosing therapies for patients with cancer. Although ...substantial technical and clinical expertise has guided the development of WFO, patients' perspectives of this technology have not been examined. To facilitate the optimal delivery and implementation of this tool, we solicited patients' perceptions and preferences about WFO.
We conducted nine focus groups with 46 patients with breast, lung, or colorectal cancer with various treatment experiences: neoadjuvant/adjuvant chemotherapy, chemotherapy for metastatic disease, or systemic therapy through a clinical trial. In-depth qualitative and quantitative data were collected and analyzed to describe patients' attitudes and perspectives concerning WFO and how it may be used in clinical care.
Analysis of the qualitative data identified three main themes: patient acceptance of WFO, physician competence and the physician-patient relationship, and practical and logistic aspects of WFO. Overall, participant feedback suggested high levels of patient interest, perceived value, and acceptance of WFO, as long as it was used as a supplementary tool to inform their physicians' decision making. Participants also described important concerns, including the need for strict processes to guarantee the integrity and completeness of the data presented and the possibility of physician overreliance on WFO.
Participants generally reacted favorably to the prospect of WFO being integrated into the cancer treatment decision-making process, but with caveats regarding the comprehensiveness and accuracy of the data powering the system and the potential for giving WFO excessive emphasis in the decision-making process. Addressing patients' perspectives will be critical to ensuring the smooth integration of WFO into cancer care.
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