Inflammatory myofibroblastic tumor of the cecum presenting as acute abdomen, a rare pathology with a rarer presentation.

Inflammatory myofibroblastic tumor is an extremely rare neoplastic lesion with a predilection for aggressive local and recurrent behavior. The tumor tends to occur in the lungs of children and young adults, and although it can develop in older patients and other organs, this is extremely rare. Symptoms are nonspecific and depend on the location and size of the tumor. The gastrointestinal tract is rarely this mass's primary site of origin, and the cecum is an even rarer location. We present the case of an otherwise healthy 55-year-old female who presented with an acute abdomen and a mass in her abdomen; after successful surgery, she fully recovered. Inflammatory myofibroblastic tumor causing acute abdomen was the final diagnosis.

Quantum Mechanical Versus Polarizable Embedding Schemes: A Study of the Xray Absorption Spectra of Aqueous Ammonia and Ammonium.

The X-ray absorption spectra of aqueous ammonia and ammonium are computed using a combination of coupled cluster singles and doubles (CCSD) with different quantum mechanical and molecular mechanical embedding schemes. Specifically, we compare frozen Hartree-Fock (HF) density embedding, polarizable embedding (PE), and polarizable density embedding (PDE). Integrating CCSD with frozen HF density embedding is possible within the CC-in-HF framework, which circumvents the conventional system-size limitations of standard coupled cluster methods. We reveal similarities between PDE and frozen HF density descriptions, while PE spectra differ significantly. By including approximate triple excitations, we also investigate the effect of improving the electronic structure theory. The spectra computed using this approach show an improved intensity ratio compared to CCSD-in-HF. Charge transfer analysis of the excitations shows the local character of the pre-edge and main-edge, while the post-edge is formed by excitations delocalized over the first solvation shell and beyond.

Understanding X-ray absorption in liquid water using triple excitations in multilevel coupled cluster theory.

X-ray absorption (XA) spectroscopy is an essential experimental tool to investigate the local structure of liquid water. Interpretation of the experiment poses a significant challenge and requires a quantitative theoretical description. High-quality theoretical XA spectra require reliable molecular dynamics simulations and accurate electronic structure calculations. Here, we present the first successful application of coupled cluster theory to model the XA spectrum of liquid water. We overcome the computational limitations on system size by employing a multilevel coupled cluster framework for large molecular systems. Excellent agreement with the experimental spectrum is achieved by including triple excitations in the wave function and using molecular structures from state-of-the-art path-integral molecular dynamics. We demonstrate that an accurate description of the electronic structure within the first solvation shell is sufficient to successfully model the XA spectrum of liquid water within the multilevel framework. Furthermore, we present a rigorous charge transfer analysis of the XA spectrum, which is reliable due to the accuracy and robustness of the electronic structure methodology. This analysis aligns with previous studies regarding the character of the prominent features of the XA spectrum of liquid water.

Core-ionization spectrum of liquid water.

We present state-of-the-art calculations of the core-ionization spectrum of water. Despite significant progress in procedures developed to mitigate various experimental complications and uncertainties, the experimental determination of ionization energies of solvated species involves several non-trivial steps such as assessing the effect of the surface potential, electrolytes, and finite escape depths of photoelectrons. This provides a motivation to obtain robust theoretical values of the intrinsic bulk ionization energy and the corresponding solvent-induced shift. Here we develop theoretical protocols based on coupled-cluster theory and electrostatic embedding. Our value of the intrinsic solvent-induced shift of the 1sO ionization energy of water is -1.79 eV. The computed absolute position and the width of the 1sO peak in photoelectron spectrum of water are 538.47 eV and 1.44 eV, respectively, agreeing well with the best experimental values.

Multifactorial analysis of terminator performance on heterologous gene expression in Physcomitrella.

KEY MESSAGE: Characterization of Physcomitrella 3'UTRs across different promoters yields endogenous single and double terminators for usage in molecular pharming. The production of recombinant proteins for health applications accounts for a large share of the biopharmaceutical market. While many drugs are produced in microbial and mammalian systems, plants gain more attention as expression hosts to produce eukaryotic proteins. In particular, the good manufacturing practice (GMP)-compliant moss Physcomitrella (Physcomitrium patens) has outstanding features, such as excellent genetic amenability, reproducible bioreactor cultivation, and humanized protein glycosylation patterns. In this study, we selected and characterized novel terminators for their effects on heterologous gene expression. The Physcomitrella genome contains 53,346 unique 3'UTRs (untranslated regions) of which 7964 transcripts contain at least one intron. Over 91% of 3'UTRs exhibit more than one polyadenylation site, indicating the prevalence of alternative polyadenylation in Physcomitrella. Out of all 3'UTRs, 14 terminator candidates were selected and characterized via transient Dual-Luciferase assays, yielding a collection of endogenous terminators performing equally high as established heterologous terminators CaMV35S, AtHSP90, and NOS. High performing candidates were selected for testing as double terminators which impact reporter levels, dependent on terminator identity and positioning. Testing of 3'UTRs among the different promoters NOS, CaMV35S, and PpActin5 showed an increase of more than 1000-fold between promoters PpActin5 and NOS, whereas terminators increased reporter levels by less than tenfold, demonstrating the stronger effect promoters play as compared to terminators. Among selected terminator attributes, the number of polyadenylation sites as well as polyadenylation signals were found to influence terminator performance the most. Our results improve the biotechnology platform Physcomitrella and further our understanding of how terminators influence gene expression in plants in general.

Electronic Characterization of Glycolaldehyde: Experimental and Theoretical Insights from the Core- and Valence-Level Spectroscopy.

The core-level electron excitation and ionization spectra of glycolaldehyde have been investigated by photoabsorption and photoemission spectroscopy at both carbon and oxygen K-edges; the valence ionization spectra were also recorded by photoelectron spectroscopy in the UV-vis region. The spectra are interpreted by means of ab initio calculations based on the equation-of-motion coupled cluster singles and doubles (EOM-CCSD) and coupled cluster singles, doubles, and perturbative are in good agreement with the experimental results, and many of the observed features are assigned. The photoabsorption spectra are not only dominated by transitions from core-level orbitals to unoccupied π and σ orbitals but also show structures due to Rydberg transitions.

Reversible Cross-linked Thermoresponsive Polycaprolactone Micelles for Enhanced Stability and Controlled Release.

Thermoresponsive amphiphilic poly(ε-caprolactone)s (PCL)s are excellent candidates for drug delivery due to their biodegradability, biocompatibility, and controlled release. However, the thermoresponsivity of modified PCL can often lead to premature drug release because their lower critical solution temperature (LCST) is close to physiological temperature conditions. To address this issue, we developed a novel approach that involves functionalizing redox-responsive lipoic acid to the hydrophobic block of PCL. Lipoic acid has disulfide bonds that undergo reversible cross-linking after encapsulating the drug. Herein, we synthesized an ether-linked propargyl-substituted PCL as the hydrophobic block of an amphiphilic copolymer along with unsubstituted PCL. The propargyl group was used to attach lipoic acid through a postpolymerization modification reaction. The hydrophilic block is composed of an ether-linked, thermoresponsive tri(ethylene glycol)-substituted PCL. Anticancer drug doxorubicin (DOX) was encapsulated within the core of the micelles and induced cross-linking in the presence of a reducing agent, dithiothreitol. The developed micelles are thermodynamically stable and demonstrated thermoresponsivity with an LCST value of 37.5 °C but shifted to 40.5 °C after cross-linking. The stability and release of both uncross-linked (LA-PCL) and cross-linked (CLA-PCL) micelles were studied at physiological temperatures. The results indicated that CLA-PCL was stable, and only 35% release was observed after 46 h at 37 °C while LA-PCL released more than 70% drug at the same condition. Furthermore, CLA-PCL was able to release a higher amount of DOX in the presence of glutathione and above the LCST condition (42 °C). Cytotoxicity experiments revealed that CLA-PCL micelles are more toxic toward MDA-MB-231 breast cancer cells at 42 °C than at 37 °C, which supported the thermoresponsive release of the drug. These results indicate that the use of reversible cross-linking is a great approach toward synthesizing stable thermoresponsive micelles with reduced premature drug leakage.

Cross-sectional evaluation of an asynchronous multiple mini-interview (MMI) in selection to health professions training programmes with 10 principles for fairness built-in.

OBJECTIVES: We aimed to explore the psychometric properties of the first known online asynchronous multiple mini-interview (MMI) designed for fairness with subgroup analyses by key characteristics, usability and acceptability. DESIGN: Cross-discipline multimethod evaluation. SETTING: One UK University. PARTICIPANTS: Applicants to nursing, midwifery and paramedic science undergraduate programmes during 2021-2022. PRIMARY, SECONDARY OUTCOME MEASURES: Psychometric properties (internal consistency, construct validity, dimensionality) were assessed using Cronbach's alpha (α), parallel analysis (PA), Schmid-Leiman transformation and ordinal confirmatory factor analysis (CFA). Usability and acceptability were evaluated using descriptive statistics and conventional content analysis. METHODS: The system was configured in a seven question 4 min MMI. Applicants' videorecorded their answers which were later assessed by interviewers and scores summed. Applicants and interviewers completed online evaluation questionnaires. RESULTS: Performance data from 712 applicants determined good-excellent reliability for the asynchronous MMI (mean α 0.72) with similar results across subgroups (gender, age, disability/support needs, UK/non-UK). PA and factor analysis results suggested there were seven factors relating to the MMI questions with an underlying general factor that explained the variance in observed candidate responses. A CFA testing a seven-factor hierarchical model showed an excellent fit to the data (Confirmatory Fit Index=0.99), Tucker Lewis Index=0.99, root mean square error (RMSE) =0.034). Applicants (n=210) viewed the flexibility, relaxed environment and cost savings advantageous. Interviewers (n=65) reported the system to be intuitive, flexible with >70% time saved compared with face-to-face interviews. Reduced personal communication was cited as the principal disadvantage. CONCLUSIONS: We found that the asynchronous MMI was reliable, time-efficient, fair and acceptable and building fairness in was lost-cost. These novel, insights are applicable across health professions selection internationally informing the future configuration of online interviews to ensure workforces represent the societies they serve.

Effects of familiar music exposure on deliberate retrieval of remote episodic and semantic memories in healthy aging adults.

Familiar music facilitates memory retrieval in adults with dementia. However, mechanisms behind this effect, and its generality, are unclear because of a lack of parallel work in healthy aging. Exposure to familiar music enhances spontaneous recall of memories directly cued by the music, but it is unknown whether such effects extend to deliberate recall more generally - e.g., to memories not directly linked to the music being played. It is also unclear whether familiar music boosts recall of specific episodes versus more generalised semantic memories, or whether effects are driven by domain-general mechanisms (e.g., improved mood). In a registered report study, we examined effects of familiar music on deliberate recall in healthy adults ages 65-80 years (N = 75) by presenting familiar music from earlier in life, unfamiliar music, and non-musical audio clips across three sessions. After each clip, we assessed free recall of remote memories for pre-selected events. Contrary to our hypotheses, we found no effects of music exposure on recall of prompted events, though familiar music evoked spontaneous memories most often. These results suggest that effects of familiar music on recall may be limited to memories specifically evoked in response to the music (Preprint and registered report protocol at https://osf.io/kjnwd/).

Whole-Genome and Long-Read Sequencing Identify a Novel Mechanism in RFC1 Resulting in CANVAS Syndrome.

Objectives: Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) results from biallelic intronic pentanucleotide repeats in RFC1. We describe an adult male proband with progressive imbalance, cerebellar atrophy, somatosensory neuronopathy, and absence of peripheral vestibular function for whom clinical testing demonstrated a heterozygous RFC1 expansion consistent with an unaffected carrier. Methods: We performed whole-genome sequencing (WGS) on peripheral blood DNA samples from the proband and his unaffected mother. We performed DNA long-read sequencing and synthesized complementary DNA from RNA using peripheral blood from the proband. Results: WGS confirmed the maternally inherited RFC1 expansion and identified a rare, nonsense RFC1 variant: c.C1147T; p.R383X in the proband but not the maternal DNA sample. RFC1 variants were confirmed in trans with long-read sequencing. Functional studies demonstrated the absence of complementary DNA (cDNA) transcript from the c.C1147T; p.R383X variant supporting nonsense-mediated decay of this transcript. Discussion: We report an adult with CANVAS due to compound heterozygous pathogenic RFC1 variants: the pathogenic intronic pentanucleotide expansion confirmed in trans with a nonsense variant. This report represents a novel molecular mechanism for CANVAS. Sequencing for RFC1 should be considered for adults meeting clinical criteria for the CANVAS phenotype if only a heterozygous pathogenic RFC1 expansion is identified.

Alpha Suppression Is Associated with the Tip-of-the-Tongue (TOT) State Whereas Alpha Expression Is Associated with Knowing That One Does Not Know.

The tip-of-the-tongue (TOT) state is a spontaneously occurring metacognitive state that indicates that the answer to a query is almost, but not quite, at hand, i.e., that resolution is imminent. Since the time of William James, a distinctive feeling of nagging frustration has been observed to be associated with TOT states. On a more positive note, TOT states are also associated with intense goal-directed curiosity and with a strong desire to know that translates into successful mental action. The present study showed that prior to the presentation of resolving feedback to verbal queries-if the individual was in a TOT state-alpha suppression was in evidence in the EEG. This alpha suppression appears to be a marker of a spontaneously occurring, conscious, and highly motivating goal-directed internal metacognitive state. At the same time, alpha expression in the same time period was associated with the feeling of not knowing, indicating a more discursive state. Both alpha and alpha suppression were observed broadly across centro-parietal scalp electrodes and disappeared immediately upon presentation of the resolving feedback. Analyses indicated that the occurrence of alpha suppression was associated with participants' verbal affirmations of being in a TOT state, which is also related to subsequent expression of a late positivity when feedback is provided, and to enhanced memory.

Oscillator Strengths in the Framework of Equation of Motion Multilevel CC3.

We present an efficient implementation of the equation of motion oscillator strengths for the closed-shell multilevel coupled cluster singles and doubles with perturbative triples method (MLCC3) in the electronic structure program eT. The orbital space is split into an active part treated with CC3 and an inactive part computed at the coupled cluster singles and doubles (CCSD) level of theory. Asymptotically, the CC3 contribution scales as O(nVnv3no3) floating-point operations, where nV is the total number of virtual orbitals while nv and no are the number of active virtual and occupied orbitals, respectively. The CC3 contribution, thus, only scales linearly with the full system size and can become negligible compared to the cost of CCSD. We demonstrate the capabilities of our implementation by calculating the ultraviolet-visible spectrum of azobenzene and a core excited state of betaine 30 with more than 1000 molecular orbitals.

The impact of the COVID-19 pandemic on the research activity and working experience of clinical academics, with a focus on gender and ethnicity: a qualitative study in the UK.

OBJECTIVE: To investigate the impact of the COVID-19 pandemic on the research activity and working experience of clinical academics, with a focus on gender and ethnicity. DESIGN: Qualitative study based on interviews and audio/written diary data. SETTING: UK study within clinical academia. PARTICIPANTS: Purposive sample of 82 clinical academics working in medicine and dentistry across all career stages ranging from academic clinical fellows and doctoral candidates to professors. METHODS: Qualitative semistructured interviews (n=68) and audio diary data (n=30; including 16 participants who were also interviewed) collected over an 8-month period (January-September 2020), thematically analysed. RESULTS: 20 of 30 (66.6%) audio diary contributors and 40 of 68 (58.8%) interview participants were female. Of the participants who disclosed ethnicity, 5 of 29 (17.2%) audio diary contributors and 19/66 (28.8%) interview participants identified as Black, Asian or another minority (BAME). Four major themes were identified in relation to the initial impact of COVID-19 on clinical academics: opportunities, barriers, personal characteristics and social identity, and fears and uncertainty. COVID-19 presented opportunities for new avenues of research. Barriers included access to resources to conduct research and the increasing teaching demands. One of the most prominent subthemes within 'personal characteristics' was that of the perceived negative impact of the pandemic on the work of female clinical academics. This was attributed to inequalities experienced in relation to childcare provision and research capacity. Participants described differential experiences based upon their gender and ethnicity, noting intersectional identities. CONCLUSIONS: While there have been some positives afforded to clinical academics, particularly for new avenues of research, COVID-19 has negatively impacted workload, future career intentions and mental health. BAME academics were particularly fearful due to the differential impact on health. Our study elucidates the direct and systemic discrimination that creates barriers to women's career trajectories in clinical academia. A flexible, strategic response that supports clinical academics in resuming their training and research is required. Interventions are needed to mitigate the potential lasting impact on capacity from the pandemic, and the potential for the loss of women from this valuable workforce.

Transplacental Zika virus transmission in ex vivo perfused human placentas.

A Zika virus (ZIKV) infection during pregnancy can result in severe birth defects such as microcephaly. To date, it is incompletely understood how ZIKV can cross the human placenta. Furthermore, results from studies in pregnant mice and non-human primates are conflicting regarding the role of cross-reactive dengue virus (DENV) antibodies on transplacental ZIKV transmission. Elucidating how ZIKV can cross the placenta and which risk factors contribute to this is important for risk assessment and for potential intervention strategies for transplacental ZIKV transmission. In this study we use an ex vivo human placental perfusion model to study transplacental ZIKV transmission and the effect that cross-reactive DENV antibodies have on this transmission. By using this model, we demonstrate that DENV antibodies significantly increase ZIKV uptake in perfused human placentas and that this increased uptake is neonatal Fc-receptor-dependent. Furthermore, we show that cross-reactive DENV antibodies enhance ZIKV infection in term human placental explants and in primary fetal macrophages but not in primary trophoblasts. Our data supports the hypothesis that presence of cross-reactive DENV antibodies could be an important risk factor for transplacental ZIKV transmission. Furthermore, we demonstrate that the ex vivo placental perfusion model is a relevant and animal friendly model to study transplacental pathogen transmission.

Age-related change in task-evoked amygdala-prefrontal circuitry: A multiverse approach with an accelerated longitudinal cohort aged 4-22 years.

The amygdala and its connections with medial prefrontal cortex (mPFC) play central roles in the development of emotional processes. While several studies have suggested that this circuitry exhibits functional changes across the first two decades of life, findings have been mixed - perhaps resulting from differences in analytic choices across studies. Here we used multiverse analyses to examine the robustness of task-based amygdala-mPFC function findings to analytic choices within the context of an accelerated longitudinal design (4-22 years-old; N = 98; 183 scans; 1-3 scans/participant). Participants recruited from the greater Los Angeles area completed an event-related emotional face (fear, neutral) task. Parallel analyses varying in preprocessing and modeling choices found that age-related change estimates for amygdala reactivity were more robust than task-evoked amygdala-mPFC functional connectivity to varied analytical choices. Specification curves indicated evidence for age-related decreases in amygdala reactivity to faces, though within-participant changes in amygdala reactivity could not be differentiated from between-participant differences. In contrast, amygdala-mPFC functional connectivity results varied across methods much more, and evidence for age-related change in amygdala-mPFC connectivity was not consistent. Generalized psychophysiological interaction (gPPI) measurements of connectivity were especially sensitive to whether a deconvolution step was applied. Our findings demonstrate the importance of assessing the robustness of findings to analysis choices, although the age-related changes in our current work cannot be overinterpreted given low test-retest reliability. Together, these findings highlight both the challenges in estimating developmental change in longitudinal cohorts and the value of multiverse approaches in developmental neuroimaging for assessing robustness of results.

Multi-electron excitation contributions towards primary and satellite states in the photoelectron spectrum.

The computation of Dyson orbitals and corresponding ionization energies has been implemented within the equation of motion coupled cluster singles, doubles and perturbative triples (EOM-CC3) method. Coupled to an accurate description of the electronic continuum via a time-dependent density functional approach using a multicentric B-spline basis, this yields highly accurate photoionization dynamical parameters (cross-sections, branching ratios, asymmetry parameters and dichroic coefficients) for primary (1h) states as well as satellite states of (2h1p) character. Illustrative results are presented for the molecular systems H2O, H2S, CS, CS2 and (S)-propylene oxide (a.k.a. methyloxirane).

Excited state absorption of DNA bases in the gas phase and in chloroform solution: a comparative quantum mechanical study.

We study the excited state absorption (ESA) properties of the four DNA bases (thymine, cytosine, adenine, and guanine) by different single reference quantum mechanical methods, namely, equation of motion coupled cluster singles and doubles (EOM-CCSD), singles, doubles and perturbative triples (EOM-CC3), and time-dependent density functional theory (TD-DFT), with the long-range corrected CAM-B3LYP functional. Preliminary results at the Tamm-Dancoff (TDA) CAM-B3LYP level using the maximum overlap method (MOM) are reported for thymine. In the gas phase, the three methods predict similar One Photon Absorption (OPA) spectra, which are consistent with the experimental results and with the most accurate computational studies available in the literature. The ESA spectra are then computed for the ππ* states (one for pyrimidine, two for purines) associated with the lowest-energy absorption band, and for the close-lying nπ* state. The EOM-CC3, EOM-CCSD and CAM-B3LYP methods provide similar ESA spectral patterns, which are also in qualitative agreement with literature RASPT2 results. Once validated in the gas phase, TD-CAM-B3LYP has been used to compute the ESA in chloroform, including solvent effects by the polarizable continuum model (PCM). The predicted OPA and ESA spectra in chloroform are very similar to those in the gas phase, most of the bands shifting by less than 0.1 eV, with a small increase of the intensities and a moderate destabilization of the nπ* state. Finally, ESA spectra have been computed from the minima of the lowest energy ππ* state, and found in line with the available experimental transient absorption spectra of the nucleosides in solution, providing further validation of our computational approach.

Predictions of Pre-edge Features in Time-Resolved Near-Edge X-ray Absorption Fine Structure Spectroscopy from Hole-Hole Tamm-Dancoff-Approximated Density Functional Theory.

Time-resolved near-edge X-ray absorption fine structure (TR-NEXAFS) spectroscopy is a powerful technique for studying photochemical reaction dynamics with femtosecond time resolution. In order to avoid ambiguity in TR-NEXAFS spectra from nonadiabatic dynamics simulations, core- and valence-excited states must be evaluated on equal footing and those valence states must also define the potential energy surfaces used in the nonadiabatic dynamics simulation. In this work, we demonstrate that hole-hole Tamm-Dancoff-approximated density functional theory (hh-TDA) is capable of directly simulating TR-NEXAFS spectroscopies. We apply hh-TDA to the excited-state dynamics of acrolein. We identify two pre-edge features in the oxygen K-edge TR-NEXAFS spectrum associated with the S2 (ππ*) and S1 (nπ*) excited states. We show that these features can be used to follow the internal conversion dynamics between the lowest three electronic states of acrolein. Due to the low, O(N2) apparent computational complexity of hh-TDA and our GPU-accelerated implementation, this method is promising for the simulation of pre-edge features in TR-NEXAFS spectra of large molecules and molecules in the condensed phase.