Ultrafast dynamics of fluorene initiated by highly intense laser fields.

We present an investigation of the ultrafast dynamics of the polycyclic aromatic hydrocarbon fluorene initiated by an intense femtosecond near-infrared laser pulse (810 nm) and probed by a weak visible pulse (405 nm). Using a multichannel detection scheme (mass spectra, electron and ion velocity-map imaging), we provide a full disentanglement of the complex dynamics of the vibronically excited parent molecule, its excited ionic states, and fragments. We observed various channels resulting from the strong-field ionization regime. In particular, we observed the formation of the unstable tetracation of fluorene, above-threshold ionization features in the photoelectron spectra, and evidence of ubiquitous secondary fragmentation. We produced a global fit of all observed time-dependent photoelectron and photoion channels. This global fit includes four parent ions extracted from the mass spectra, 15 kinetic-energy-resolved ionic fragments extracted from ion velocity map imaging, and five photoelectron channels obtained from electron velocity map imaging. The fit allowed for the extraction of 60 lifetimes of various metastable photoinduced intermediates.

Generation of entanglement using a short-wavelength seeded free-electron laser.

Quantum entanglement between the degrees of freedom encountered in the classical world is challenging to observe due to the surrounding environment. To elucidate this issue, we investigate the entanglement generated over ultrafast timescales in a bipartite quantum system comprising two massive particles: a free-moving photoelectron, which expands to a mesoscopic length scale, and a light-dressed atomic ion, which represents a hybrid state of light and matter. Although the photoelectron spectra are measured classically, the entanglement allows us to reveal information about the dressed-state dynamics of the ion and the femtosecond extreme ultraviolet pulses delivered by a seeded free-electron laser. The observed generation of entanglement is interpreted using the time-dependent von Neumann entropy. Our results unveil the potential for using short-wavelength coherent light pulses from free-electron lasers to generate entangled photoelectron and ion systems for studying spooky action at a distance.

Wave packet dynamics and control in excited states of molecular nitrogen.

Wave packet interferometry with vacuum ultraviolet light has been used to probe a complex region of the electronic spectrum of molecular nitrogen, N2. Wave packets of Rydberg and valence states were excited by using double pulses of vacuum ultraviolet (VUV), free-electron-laser (FEL) light. These wave packets were composed of contributions from multiple electronic states with a moderate principal quantum number (n ∼ 4-9) and a range of vibrational and rotational quantum numbers. The phase relationship of the two FEL pulses varied in time, but as demonstrated previously, a shot-by-shot analysis allows the spectra to be sorted according to the phase between the two pulses. The wave packets were probed by angle-resolved photoionization using an infrared pulse with a variable delay after the pair of excitation pulses. The photoelectron branching fractions and angular distributions display oscillations that depend on both the time delays and the relative phases of the VUV pulses. The combination of frequency, time delay, and phase selection provides significant control over the ionization process and ultimately improves the ability to analyze and assign complex molecular spectra.

Tissue pharmacokinetics of antisense oligonucleotides.

Pharmacokinetics (PK) of antisense oligonucleotides (ASOs) is characterized by rapid distribution from plasma to tissue and slow terminal plasma elimination driven by re-distribution from tissue. Quantitative understanding of tissue PK and RNA knockdown for various ASO chemistries, conjugations, and administration routes is critical for successful drug discovery. Here, we report concentration-time and RNA knockdown profiles for a gapmer ASO with locked nucleic acid ribose chemistry in mouse liver, kidney, heart, and lung after subcutaneous and intratracheal administration. Additionally, the same ASO with liver targeting conjugation (galactosamine-N-acetyl) is evaluated for subcutaneous administration. Data indicate that exposure and knockdown differ between tissues and strongly depend on administration route and conjugation. In a second study, we show that tissue PK is similar between the three different ribose chemistries locked nucleic acid, constrained ethyl and 2'-O-methoxyethyl, both after subcutaneous and intratracheal administration. Further, we show that the half-life in mouse liver may vary with ASO sequence. Finally, we report less than dose-proportional increase in liver concentration in the dose range of 3-30 µmol/kg. Overall, our studies contribute pivotal data to support design and interpretation of ASO in vivo studies, thereby increasing the probability of delivering novel ASO therapies to patients.

Medical Nature-Based Rehabilitation Program for Individuals with Exhaustion Syndrome: Changes in Quality of Life, Exhaustion Symptoms and Overall Health.

Stress-related health problems have increased sharply over the last two decades and have become a serious issue at all levels of society. In the Jönköping Region in southern Sweden, a nature-based rehabilitation (NBR) program for adults with Exhaustion Syndrome has been developed and then implemented into the Swedish National Healthcare System. The main aim of this study was to investigate the effectiveness of this NBR-program. This was achieved by examining patients' quality of life, exhaustion symptoms and overall health using self-assessment instruments, comparing the results before participation to immediately after, three months after and six months after. With a sample size of 67 participants, the results show a statistically significant improvement for all points. From a public health perspective, and with background knowledge of the nature of the patient group under treatment, the studied program would appear to be effective and economic, having a satisfied patient group as well as a favourable comparison with the outcomes of other research programs. Although the results are promising, as this is a naturalistic field study, there is no control group, and further research is encouraged. We suggest randomised controlled studies, longitudinal studies and investigation of mediators.

Resonant Inner-Shell Photofragmentation of Adamantane (C10H16).

Adamantane, the smallest diamondoid molecule with a symmetrical cage, contains two distinct carbon sites, CH and CH2. The ionization/excitation of the molecule leads to the cage opening and strong structural reorganization. While theoretical predictions suggest that the carbon site CH primarily causes the cage opening, the role of the other CH2 site remains unclear. In this study, we used advanced experimental Auger electron-ion coincidence techniques and theoretical calculations to investigate the fragmentation dynamics of adamantane after resonant inner-shell photoexcitation. Our results demonstrate that some fragmentation channels exhibit site-sensitivity of the initial core-hole location, indicating that different carbon site excitations could lead to unique cage opening mechanisms.

Knowing me, knowing you: a scoping review assessing the current field of social cognition in schizophrenia.

BACKGROUND: Impaired social cognition (SC) occurs frequently in schizophrenia (SCZ), yet compared to autism spectrum disorder (ASD), the research on SC in SCZ is sparse and methodologically heterogeneous. To accurately assess between-group SC differences it is further necessary to establish the relationship between nonsocial cognition (NSC) and SC, particularly as this may not be identical across disorders. PURPOSE: The present study aimed to map, index and assess the quality of research published between 2014-2021 investigating SC in SCZ, and to summarize existing limitations and recommendations for future research. METHOD: Following the PRISMA guidelines for scoping reviews (PRISMA-ScR) fifteen (n = 15) case-control studies were identified and included across three electronic databases. Studies additionally utilizing ASD samples were included because of their clinical utility. RESULTS: Most studies reported significant SC impairments in SCZ relative to healthy controls (HC) with varying effect sizes. Significant differences between SCZ and ASD were not found in most studies including both samples. Weak-to-moderate correlations between SC and NSC were often found, although often only within patient samples. Across studies, SC tests were inconsistently described as measurements of "social cognition", "mentalization" and, most frequently and varyingly, "theory of mind". Most studies lacked methodological transparency. Limitations related to sample sizes and test reliability were most frequently mentioned. CONCLUSIONS: The current research on SC in SCZ is limited by conceptual and methodological uncertainties. Future research should focus on ensuring clear and valid definitions of key terms, evaluating and clarifying SC outcome measures and further untangling the relationship between SC and NSC.

Photodissociation of bromine-substituted nitroimidazole radiosensitizers.

Heavy elements and some nitroimidazoles both exhibit radiosensitizing properties through different mechanisms. In an effort to see how the overall radiosensitivity might be affected when the two radiosensitizers are combined in the same molecule, we studied the gas-phase photodissociation of two brominated nitroimidazoles and a bromine-free reference sample. Synchrotron radiation was employed to initiate the photodynamics and energy-resolved multiparticle coincidence spectroscopy was used to study the ensuing dissociation. We observed the brominated samples releasing high amounts of potentially radiosensitizing fragments upon dissociation. Since bromination also increases the likelihood of the drug molecule being ionised per a given X-ray dose, we conclude that heavy-element substitution of nitroimidazoles appears to be a viable path towards new, potent radiosensitizer drugs.

A comparison between young males and females with anorexia nervosa in a clinical setting.

BACKGROUND: Knowledge of eating disorders in young and adolescent males is sparse. AIM: To investigate clinical presentations in males and females with anorexia nervosa (AN). METHODS: Using a retrospective case-control design, data were collected from case records for 41 males diagnosed with AN. Data for a comparison group of 41 females with AN were collected, matched to the males by age and date at admission. The collected data covered demographic, medical, psychiatric, and treatment information. RESULTS: No differences were found between the sexes in the percentage of expected weight (%EBW) at admission or discharge, or in psychiatric comorbidity. Treatment duration was equal for both sexes, but males received fewer treatment sessions than did females. CONCLUSION: These results indicate that the clinical presentations of young males and females with AN were very similar in terms of clinical characteristics.Impact StatementWhat is already known about this subject? Research on AN in male children and adolescents is sparse. Previous studies comparing male and female patients with EDs have found both differences and similarities between sexes.What does this study add? This study found few differences in terms of clinical presentation of AN between the sexes.

Coincidence study of core-ionized adamantane: site-sensitivity within a carbon cage?

We investigate the fragmentation dynamics of adamantane dications produced after core-ionization at the carbon edge followed by Auger decay. The combination of high-resolution electron spectroscopy, energy-resolved electron-ion multi-coincidence spectroscopy and different theoretical models allows us to give a complete characterization of the processes involved after ionization. We show that energy- and site-sensitivity is observed even for a highly-symmetric molecule that lacks any unique atomic site.

Attosecond dynamics of multi-channel single photon ionization.

Photoionization of atoms and molecules is one of the fastest processes in nature. The understanding of the ultrafast temporal dynamics of this process often requires the characterization of the different angular momentum channels over a broad energy range. Using a two-photon interferometry technique based on extreme ultraviolet and infrared ultrashort pulses, we measure the phase and amplitude of the individual angular momentum channels as a function of kinetic energy in the outer-shell photoionization of neon. This allows us to unravel the influence of channel interference as well as the effect of the short-range, Coulomb and centrifugal potentials, on the dynamics of the photoionization process.

One-year recovery from breast cancer: Importance of tumor and treatment-related factors, resilience, and sociodemographic factors for health-related quality of life.

Aim: This study investigated the changes in health-related quality of life from diagnosis to 1 year after diagnosis in breast cancer (BC) patients and the influence of clinical, psychological, and sociodemographic variables. An additional aim was to explore the mediating and moderating effects of resilience on changes in health-related quality of life. Methods: A longitudinal population-based study was conducted in southern Sweden. Newly diagnosed BC patients filled in measures of health-related quality of life, resilience, and sociodemographic variables at diagnosis (N = 980) and 1 year post-diagnosis (N = 780). Clinical variables were extracted from the Swedish national breast cancer quality registry. Mixed-model analyses were performed. Results: Most health-related quality of life outcomes declined from diagnosis to 1 year post-diagnosis. Role limitations due to emotional problems remained the same, whereas mental health improved. Lower health-related quality of life outcomes were associated with symptomatic detection and axillary dissection. Patients with a higher TNM stage and histologic grade and estrogen receptor (ER)-negative and human epidermal growth factor 2 (HER2)-positive status, who received chemotherapy, antibody therapy, or bisphosphonate therapy, had a steeper decline in outcomes. Changes in resilience were positively associated with all outcomes but did not mediate or moderate changes in any. Resilience at baseline moderated changes in bodily pain, vitality, and mental health, with higher baseline resilience being associated with a steeper decline, possibly due to floor or ceiling effects. Patients with lower socioeconomic status, educational level, and older age had a lower health-related quality of life. Conclusion: Physical health-related quality of life among breast cancer patients declined 1 year post-diagnosis, whereas mental health-related quality of life improved. Low resilient patients may be especially vulnerable at diagnosis. Biopsychosocial assessment at diagnosis can help identify patients who may require additional support. A multidimensional treatment plan should be started early to help overcome the problems in everyday activities.

Observation of Rabi dynamics with a short-wavelength free-electron laser.

Rabi oscillations are periodic modulations of populations in two-level systems interacting with a time-varying field1. They are ubiquitous in physics with applications in different areas such as photonics2, nano-electronics3, electron microscopy4 and quantum information5. While the theory developed by Rabi was intended for fermions in gyrating magnetic fields, Autler and Townes realized that it could also be used to describe coherent light-matter interactions within the rotating-wave approximation6. Although intense nanometre-wavelength light sources have been available for more than a decade7-9, Rabi dynamics at such short wavelengths has not been directly observed. Here we show that femtosecond extreme-ultraviolet pulses from a seeded free-electron laser10 can drive Rabi dynamics between the ground state and an excited state in helium atoms. The measured photoelectron signal reveals an Autler-Townes doublet and an avoided crossing, phenomena that are both fundamental to coherent atom-field interactions11. Using an analytical model derived from perturbation theory on top of the Rabi model, we find that the ultrafast build-up of the doublet structure carries the signature of a quantum interference effect between resonant and non-resonant photoionization pathways. Given the recent availability of intense attosecond12 and few-femtosecond13 extreme-ultraviolet pulses, our results unfold opportunities to carry out ultrafast manipulation of coherent processes at short wavelengths using free-electron lasers.

The kinetic energy of PAH dication and trication dissociation determined by recoil-frame covariance map imaging.

We investigated the dissociation of dications and trications of three polycyclic aromatic hydrocarbons (PAHs), fluorene, phenanthrene, and pyrene. PAHs are a family of molecules ubiquitous in space and involved in much of the chemistry of the interstellar medium. In our experiments, ions are formed by interaction with 30.3 nm extreme ultraviolet (XUV) photons, and their velocity map images are recorded using a PImMS2 multi-mass imaging sensor. Application of recoil-frame covariance analysis allows the total kinetic energy release (TKER) associated with multiple fragmentation channels to be determined to high precision, ranging 1.94-2.60 eV and 2.95-5.29 eV for the dications and trications, respectively. Experimental measurements are supported by Born-Oppenheimer molecular dynamics (BOMD) simulations.

Transcriptional kinetics and molecular functions of long noncoding RNAs.

An increasing number of long noncoding RNAs (lncRNAs) have experimentally confirmed functions, yet little is known about their transcriptional dynamics and it is challenging to determine their regulatory effects. Here, we used allele-sensitive single-cell RNA sequencing to demonstrate that, compared to messenger RNAs, lncRNAs have twice as long duration between two transcriptional bursts. Additionally, we observed increased cell-to-cell variability in lncRNA expression due to lower frequency bursting producing larger numbers of RNA molecules. Exploiting heterogeneity in asynchronously growing cells, we identified and experimentally validated lncRNAs with cell state-specific functions involved in cell cycle progression and apoptosis. Finally, we identified cis-functioning lncRNAs and showed that knockdown of these lncRNAs modulated the nearby protein-coding gene's transcriptional burst frequency or size. In summary, we identified distinct transcriptional regulation of lncRNAs and demonstrated a role for lncRNAs in the regulation of mRNA transcriptional bursting.

Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma.

PURPOSE: More than half of the familial cutaneous melanomas have unknown genetic predisposition. This study aims at characterizing a novel melanoma susceptibility gene. METHODS: We performed exome and targeted sequencing in melanoma-prone families without any known melanoma susceptibility genes. We analyzed the expression of candidate gene DENND5A in melanoma samples in relation to pigmentation and UV signature. Functional studies were carried out using microscopic approaches and zebrafish model. RESULTS: We identified a novel DENND5A truncating variant that segregated with melanoma in a Swedish family and 2 additional rare DENND5A variants, 1 of which segregated with the disease in an American family. We found that DENND5A is significantly enriched in pigmented melanoma tissue. Our functional studies show that loss of DENND5A function leads to decrease in melanin content in vitro and pigmentation defects in vivo. Mechanistically, harboring the truncating variant or being suppressed leads to DENND5A losing its interaction with SNX1 and its ability to transport the SNX1-associated vesicles from melanosomes. Consequently, untethered SNX1-premelanosome protein and redundant tyrosinase are redirected to lysosomal degradation by default, causing decrease in melanin content. CONCLUSION: Our findings provide evidence of a physiological role of DENND5A in the skin context and link its variants to melanoma susceptibility.

Freely Generated Word Responses Analyzed With Artificial Intelligence Predict Self-Reported Symptoms of Depression, Anxiety, and Worry.

BACKGROUND: Question-based computational language assessments (QCLA) of mental health, based on self-reported and freely generated word responses and analyzed with artificial intelligence, is a potential complement to rating scales for identifying mental health issues. This study aimed to examine to what extent this method captures items related to the primary and secondary symptoms associated with Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). We investigated whether the word responses that participants generated contained information of all, or some, of the criteria that define MDD and GAD using symptom-based rating scales that are commonly used in clinical research and practices. METHOD: Participants (N = 411) described their mental health with freely generated words and rating scales relating to depression and worry/anxiety. Word responses were quantified and analyzed using natural language processing and machine learning. RESULTS: The QCLA correlated significantly with the individual items connected to the DSM-5 diagnostic criteria of MDD (PHQ-9; Pearson's r = 0.30-0.60, p < 0.001) and GAD (GAD-7; Pearson's r = 0.41-0.52, p < 0.001; PSWQ-8; Spearman's r = 0.52-0.63, p < 0.001) for respective rating scales. Items measuring primary criteria (cognitive and emotional aspects) yielded higher predictability than secondary criteria (behavioral aspects). CONCLUSION: Together these results suggest that QCLA may be able to complement rating scales in measuring mental health in clinical settings. The approach carries the potential to personalize assessments and contributes to the ongoing discussion regarding the diagnostic heterogeneity of depression.

Pseudogenes: A Novel Source of Trans-Acting Antisense RNAs.

Several recent studies support a functional role for pseudogenes, a copy of a parent gene that has lost protein-coding potential, which was for a long time thought to represent only "junk" DNA. Several hundreds of pseudogenes have now been reported as transcribed RNAs in a large variety of tissues and tumor types. Most studies have focused on pseudogenes expressed in sense direction, relative to their protein-coding gene counterpart, but some reports suggest that pseudogenes can be also transcribed as antisense RNAs (asRNAs). Key regulatory genes, such as PTEN and OCT4, have in fact been reported to be under the regulation of pseudogene-expressed asRNAs. Here, we review what is known about pseudogene-expressed asRNAs, we discuss the functional role that these transcripts may have in gene regulation and we summarize the techniques that are available to study them.

PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma.

BRAF inhibitors (BRAFi) selectively target oncogenic BRAFV600E/K and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of PTEN is negatively regulated by the PTEN pseudogene antisense RNA, PTENP1-AS, and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of PTENP1-AS in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the PTEN promoter, consequently reducing the expression levels of PTEN. Further, we showed that targeting of the PTENP1-AS transcript sensitized resistant cells to BRAFi treatment and that high expression of PTENP1-AS in stage III melanoma correlated with poor survival. Collectively, the data presented here show that PTENP1-AS is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma.

Time-resolved photoelectron imaging of complex resonances in molecular nitrogen.

We have used the FERMI free-electron laser to perform time-resolved photoelectron imaging experiments on a complex group of resonances near 15.38 eV in the absorption spectrum of molecular nitrogen, N2, under jet-cooled conditions. The new data complement and extend the earlier work of Fushitani et al. [Opt. Express 27, 19702-19711 (2019)], who recorded time-resolved photoelectron spectra for this same group of resonances. Time-dependent oscillations are observed in both the photoelectron yields and the photoelectron angular distributions, providing insight into the interactions among the resonant intermediate states. In addition, for most states, we observe an exponential decay of the photoelectron yield that depends on the ionic final state. This observation can be rationalized by the different lifetimes for the intermediate states contributing to a particular ionization channel. Although there are nine resonances within the group, we show that by detecting individual photoelectron final states and their angular dependence, we can identify and differentiate quantum pathways within this complex system.