191 research outputs found
Stability analysis of the Witten black hole (cigar soliton) under world-sheet RG flow
We analyze the stability of the Euclidean Witten black hole (the cigar
soliton in mathematics literature) under first-order RG (Ricci) flow of the
world-sheet sigma model. This analysis is from the target space point of view.
We find that the Witten black hole has no unstable normalizable perturbative
modes in a linearized mode analysis in which we consider circularly symmetric
perturbations. Finally, we discuss a result from mathematics that implies the
existence of a non-normalizable mode of the Witten black hole under which the
geometry flows to the sausage solution studied by Fateev, Onofri and
Zamolodchikov.Comment: 17 pages, version to appear in Physical Review D, and now has
complete proof of stability for circularly symmetric perturbations, in
response to referee comment
Purification and characterization of a protein-tyrosine kinase encoded by the Abelson murine leukemia virus
Sequences termed v-abl, which encode the protein-tyrosine kinase activity of Abelson murine leukemia virus, have been expressed in Escherichia coli as a fusion product (ptabl50 kinase). This fusion protein contains 80 amino acids of SV40 small t and the 403 amino acid protein kinase domain of v-abl. We report here the purification and characterization of this kinase. The purified material contains two proteins (Mr = 59,800 and 57,200), both of which possess sequences derived from v-abl. Overall purification was 3,750-fold, with a 31% yield, such that 117 micrograms of kinase could be obtained from 40 g of E. coli within 6-7 days. The specific kinase activity is over 170 mumol of phosphate min-1 mumol-1, comparable to the most active protein- serine kinases. Kinase activity is insensitive to K+, Na+, Ca2+, Ca2+- calmodulin, cAMP, or cAMP-dependent protein kinase inhibitor. The Km for ATP is dependent on the concentration of the second substrate. GTP can also be used as a phosphate donor. The enzyme can phosphorylate peptides consisting of as few as two amino acids and, at a very low rate, free tyrosine. Incubation of the kinase with [gamma-32P]ATP results in incorporation of 1.0 mol of phosphate/mol of protein. This reaction, however, cannot be blocked by prior incubation with unlabeled ATP. Incubation of 32P-labeled kinase with either ADP or ATP results in the synthesis of [32P]ATP. This suggests the phosphotyrosine residue on the Abelson kinase contains a high energy phosphate bond
Structural abnormalities in cortical volume, thickness, and surface area in 22q11.2 microdeletion syndrome: Relationship with psychotic symptoms.
Introduction22q11.2 deletion syndrome (22q11DS) represents one of the largest known genetic risk factors for psychosis, yet the neurobiological mechanisms underlying symptom development are not well understood. Here we conducted a cross-sectional study of 22q11DS to decompose cortical volume into its constituent parts, cortical thickness (CT) and surface area (SA), which are believed to have distinct neurodevelopmental origins.MethodsHigh-resolution T1-weighted scans were collected on 65 participants (31 22q11DS, 34 demographically comparable typically developing controls, 10-25 years old). Measures of cortical volume, CT, and SA were extracted from regions of interest using the FreeSurfer image analysis suite. Group differences and age-related trajectories in these structures, as well as their association with psychotic symptomatology, were assessed.ResultsRelative to controls, 22q11DS participants showed bilateral volumetric reductions in the inferior temporal cortex, fusiform gyrus, anterior cingulate, superior parietal cortex, and cuneus, which were driven by decreased SA in these regions. 22q11DS participants also had increased volumes, driven by increased CT, in bilateral insula regions. 22q11DS youth had increased CT in frontal regions, particularly middle frontal and medial orbitofrontal cortices. A pattern of age-associated cortical thinning was observed in typically developing controls in brain regions associated with visual and sensory information-processing (i.e., left pericalcarine cortex and fusiform gyrus, right lingual and postcentral cortices). However, this relationship was disrupted in 22q11DS participants. Finally, correlational analyses revealed that increased CT in right medial orbitofrontal cortex was associated with increased positive symptom severity in 22q11DS.ConclusionDifferential disruptions of CT and SA in distinct cortical regions in 22q11DS may indicate abnormalities in distinct developmental neural processes. Further, neuroanatomic abnormalities in medial frontal brain structures disproportionately affected in idiopathic schizophrenia were associated with psychotic symptom severity in 22q11DS youth, suggesting that disrupted biological processes in these cortical regions may underlie development of psychotic symptoms, both in 22q11DS and in the broader population
Altered white matter microstructure is associated with social cognition and psychotic symptoms in 22q11.2 microdeletion syndrome.
22q11.2 Microdeletion Syndrome (22q11DS) is a highly penetrant genetic mutation associated with a significantly increased risk for psychosis. Aberrant neurodevelopment may lead to inappropriate neural circuit formation and cerebral dysconnectivity in 22q11DS, which may contribute to symptom development. Here we examined: (1) differences between 22q11DS participants and typically developing controls in diffusion tensor imaging (DTI) measures within white matter tracts; (2) whether there is an altered age-related trajectory of white matter pathways in 22q11DS; and (3) relationships between DTI measures, social cognition task performance, and positive symptoms of psychosis in 22q11DS and typically developing controls. Sixty-four direction diffusion weighted imaging data were acquired on 65 participants (36 22q11DS, 29 controls). We examined differences between 22q11DS vs. controls in measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), using both a voxel-based and region of interest approach. Social cognition domains assessed were: Theory of Mind and emotion recognition. Positive symptoms were assessed using the Structured Interview for Prodromal Syndromes. Compared to typically developing controls, 22q11DS participants showed significantly lower AD and RD in multiple white matter tracts, with effects of greatest magnitude for AD in the superior longitudinal fasciculus. Additionally, 22q11DS participants failed to show typical age-associated changes in FA and RD in the left inferior longitudinal fasciculus. Higher AD in the left inferior fronto-occipital fasciculus (IFO) and left uncinate fasciculus was associated with better social cognition in 22q11DS and controls. In contrast, greater severity of positive symptoms was associated with lower AD in bilateral regions of the IFO in 22q11DS. White matter microstructure in tracts relevant to social cognition is disrupted in 22q11DS, and may contribute to psychosis risk
Stabilization and Localization of Xist RNA are Controlled by Separate Mechanisms and are Not Sufficient for X Inactivation
These studies address whether XIST RNA is properly localized to the X chromosome in somatic cells where human XIST expression is reactivated, but fails to result in X inactivation (Tinker, A.V., and C.J. Brown. 1998. Nucl. Acids Res. 26:2935–2940). Despite a nuclear RNA accumulation of normal abundance and stability, XIST RNA does not localize in reactivants or in naturally inactive human X chromosomes in mouse/ human hybrid cells. The XIST transcripts are fully stabilized despite their inability to localize, and hence XIST RNA localization can be uncoupled from stabilization, indicating that these are separate steps controlled by distinct mechanisms. Mouse Xist RNA tightly localized to an active X chromosome, demonstrating for the first time that the active X chromosome in somatic cells is competent to associate with Xist RNA. These results imply that species-specific factors, present even in mature, somatic cells that do not normally express Xist, are necessary for localization. When Xist RNA is properly localized to an active mouse X chromosome, X inactivation does not result. Therefore, there is not a strict correlation between Xist localization and chromatin inactivation. Moreover, expression, stabilization, and localization of Xist RNA are not sufficient for X inactivation. We hypothesize that chromosomal association of XIST RNA may initiate subsequent developmental events required to enact transcriptional silencing
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Artificial Intelligence and Medical Trainees - Valuable Tool or Learning Impediment?
Background
● Artificial intelligence (AI) assisted clinical documentation tools are becoming increasingly available across outpatient clinical settings
● Voice to text recognition programs collect audio from patient-provider interactions and use AI to automatically generate notes documenting the encounter
● These notes can then be made available in the electronic health record within minutes
● Though these tools are available to attending physicians, there has been no research on attitudes regarding when such tools should be made available to medical trainees, such as medical students and residents
● We surveyed US medical students, residents, and attending physicians regarding when such tools should be introduced to learners, if at all, and concerns around such tools
Study Design
● Cross-sectional survey
● Setting: Single institution in the Pacific region
● Study population: Medical students, resident
physicians, fellows, and attending physicians (179
respondents)
● Study timeline: Survey available 5/9/24-6/10/24
● Data collection:
○ Administered 15 question RedCap survey
○ Assessed respondents demographic and
professional characteristics, including gender, highest level of training, percent of time spent in outpatient practice, time spent on patient interactions, and time spent on clinical documentation
● Study outcomes:
○ Relationship between respondents’ demographic and professional characteristics and what level of training they felt that AI-assisted clinical documentation tools should be available to trainees, should enter the medical record, and specific concerns with regard to their use (not meeting documentation milestones, detriment to patient-provider experience, accuracy, bias, violation of patient privacy, detriment to forming differential diagnoses, detriment to forming plans, and concerns about using personal devices)
● Statistical analysis:
○ Chi-squared analysis to determine association between demographic/professional characteristics and outcomes with significance level set at p < 0.05
○ Cramer’s values calculated to determine strength of association
○ Descriptive characterisation of respondents
Results
40% of female attending physicians believed that AI tools should not be available to trainees at all, compared to 25% of attending physicians overall and 17% of respondents in general
Female respondents were far more likely to agree with the statement “I am concerned about AI-assisted clinical documentation violating patient privacy” and far less likely to agree with running the software on a personal device
Summary
● Attending physicians, particularly female attending physicians, felt that AI assisted clinical documentation tools should be introduced to trainees later on and were more likely to believe that trainees should not be able to generate notes using such tools
● Female respondents were far more likely to have concerns about these tools adversely affecting trainees in achieving clinical documentation milestones and were far more likely to have concerns about privacy and use of personal devices surrounding these tools
● Respondents who spent more time with patients (P = 0.01, Cramer’s value = 0.19) and more time writing notes (P = 0.03, Cramer’s value = 0.20) were less likely to believe that that AI-assisted clinical documentation tools should be available to trainees
Limitations
● Single institution survey
● Responses restricted to provided survey options
● Data not collected on experience with ambient clinical
documentation tools within cohort
Discussion
● Previous research has shown that physicians and medical students have positive attitudes and a willingness to learn about AI tools in healthcare
● However, our data suggests that attending physicians and female respondents in general have more concerns about privacy with regard to AI for clinical documentation tools and favor later introduction of such tools to trainees
● While trainees are amenable to learning about AI tools, faculty may recommended delaying the introduction of these tools to residency or later
● More research is needed to better understand why female physicians are more concerned about privacy with regard to AI tools and how these tools should be introduced to medical trainees
● Next steps: conducting interviews with respondents for more nuanced recommendations/understanding of concerns
References
AlZaabi A, AlMaskari S, AalAbdulsalam A. Are physicians and medical students ready for artificial intelligence applications in healthcare? DIGITAL HEALTH. 2023;9. doi:10.1177/20552076231152167
Giavina-Bianchi M, Amaro Jr E, Machado BS, Medical Expectations of Physicians on AI Solutions in Daily Practice: Cross-Sectional Survey Study, JMIRx Med 2024;5:e50803, doi: 10.2196/50803
Waheed MA, Liu L, Perceptions of Family Physicians About Applying AI in Primary Health Care: Case Study From a Premier Health Care Organization, JMIR AI 2024;3:e40781, doi: 10.2196/4078
Myeloid S100 proteins reduce lung inflammation
S100A8 and S100A9 are myeloid cell‐derived proteins that are elevated in several types of inflammatory lung disorders. Pro‐ and anti‐inflammatory properties are reported and these proteins are proposed to activate TLR4. S100A8 and S100A9 can function separately, likely through distinct receptors but a systematic comparison of their effects in vivo are limited. Here we assess inflammation in murine lung following S100A9 and S100A8/A9 inhalation. Unlike S100A8, S100A9 promoted mild neutrophil and lymphocyte influx, possibly mediated in part, by increased mast cell degranulation and selective upregulation of some chemokine genes, particularly CXCL‐10. S100 proteins did not significantly induce proinflammatory mediators including TNF‐α, interleukin‐1β (IL‐1β), IL‐6 or serum amyloid A3 (SAA3). In contrast to S100A8, neither preparation induced S100A8 or IL‐10 mRNA/protein in airway epithelial cells, or in tracheal epithelial cells in vitro. Like S100A8, S100A9 and S100A8/A9 reduced neutrophil influx in acute lung injury provoked by lipopolysaccharide (LPS) challenge but were somewhat less inhibitory, possibly because of differential effects on expression of some chemokines, IL‐1β, SAA3 and IL‐10. Novel common pathways including increased induction of an NAD+‐dependent protein deacetylase sirtuin‐1 that may reduce NF‐κB signalling, and increased STAT3 activation may reduce LPS activation. Results suggest a role for these proteins in normal homeostasis and protective mechanisms in the lung
Pregnancy outcomes in female childhood and adolescent cancer survivors: a linked cancer-birth registry analysis
Objective: To compare birth outcomes among childhood and adolescent female cancer survivors who subsequently bear children, relative to those of women without cancer history.
Design: Retrospective cohort study.
Setting: 4 U.S. regions.
Participants: Cancer registries identified girls <20 years, diagnosed with cancer 1973-2000. Linked birth records identified first live births after diagnosis (n=1898). Comparison subjects were selected from birth records (n=14278). Cervical/genital tract cancer cases were analyzed separately.
Main Exposure: Cancer diagnosis <20 years.
Outcome Measures: Infant low birth weight, preterm delivery, sex ratio, malformations, mortality, delivery method; maternal diabetes, anemia, preeclampsia.
Results: Childhood cancer survivors’ infants were more likely to be preterm (relative risk [RR] 1.54, 95% CI 1.30-1.83) and weigh <2500 g (RR 1.31, 95% CI 1.10-1.57). For cervical/genital cancer patients’ offspring, estimates were 1.33 (95% CI 1.13, 1.56), and 1.29 (95% CI 1.10-1.53), respectively. There were no increased risks of malformations, infant death, or altered sex ratio, suggesting no increased germ cell mutagenicity. In exploratory analysis, bone cancer survivors had an increased risk of diabetes (RR 4.92, 95% CI 1.60-15.13), and anemia was more common among brain tumor survivors (RR 3.05, 95% CI 1.16-7.98) and childhood cancer survivors with initial treatment of chemotherapy only (RR 2.45, 95% CI 1.16-5.17).
Conclusions: Infants of female childhood and adolescent cancer patients were not at increased risk of malformations or death. Increased occurrence of preterm delivery and low birth weight suggest close monitoring is warranted. Increased diabetes and anemia among sub-groups have not been reported, suggesting areas for study
Reproductive outcomes in male childhood cancer survivors: a linked cancer-birth registry analysis
OBJECTIVE: Compare the risk of reproductive and infant outcomes between male childhood cancer survivors and a population-based comparison group.
DESIGN: Retrospective cohort study.
SETTING: 4 U.S. regions.
PARTICIPANTS: Cancer registries identified males <20 years old diagnosed with cancer 1973-2000. Linked birth certificates identified first subsequent live offspring (n=470). Comparison subjects were identified from remaining birth certificates, frequency-matched on year and age at fatherhood, and race/ethnicity (n=4150).
MAIN EXPOSURE: Cancer diagnosis prior to age 20.
OUTCOME MEASURES: Pregnancy and infant outcomes identified from birth certificates.
RESULTS: Compared with infants born to unaffected males, offspring of cancer survivors had a borderline risk of birth weight <2500 g (RR 1.43, 95% CI 0.99-2.05), with risk associated most strongly with younger age of cancer diagnosis and exposure to any chemotherapy (RR 1.96, 95% CI 1.22-3.17) or radiotherapy (RR 1.95, 95% CI 1.14-3.35). However, they were not at risk of being born prematurely, small for gestational age, having malformations or an altered male:female sex ratio. Overall, female partners of male survivors were not more likely to have maternal complications recorded on birth records versus the comparison group. However, preeclampsia was associated with some cancers, especially central nervous system tumors (RR 3.36, 95% CI 1.63-6.90). CONCLUSIONS: Most pregnancies resulting in live births among partners of male childhood cancer survivors were not at significantly greater risk of complications versus comparison subjects. The possibility of a paternal component affected by prior cancer history influencing predisposition towards some adverse perinatal outcomes merits further investigation
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