Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs

A therapeutic vaccine that induces lasting control of HIV infection could eliminate the need for lifelong adherence to antiretroviral therapy. This study investigated a therapeutic DNA vaccine delivered with a single adjuvant or a novel combination of adjuvants to augment T cell immunity in the blood and gut-associated lymphoid tissue in SIV-infected rhesus macaques. Animals that received DNA vaccines expressing SIV proteins, combined with plasmids expressing adjuvants designed to increase peripheral and mucosal T cell responses, including the catalytic subunit of the E. coli heat-labile enterotoxin, IL-12, IL-33, retinaldehyde dehydrogenase 2, soluble PD-1 and soluble CD80, were compared to mock-vaccinated controls. Following treatment interruption, macaques exhibited variable levels of viral rebound, with four animals from the vaccinated groups and one animal from the control group controlling virus at median levels of 103 RNA copies/ml or lower (controllers) and nine animals, among all groups, exhibiting immediate viral rebound and median viral loads greater than 103 RNA copies/ml (non-controllers). Although there was no significant difference between the vaccinated and control groups in protection from viral rebound, the variable virological outcomes during treatment interruption enabled an examination of immune correlates of viral replication in controllers versus non-controllers regardless of vaccination status. Lower viral burden in controllers correlated with increased polyfunctional SIV-specific CD8+ T cells in mesenteric lymph nodes and blood prior to and during treatment interruption. Notably, higher frequencies of colonic CD4+ T cells and lower Th17/Treg ratios prior to infection in controllers correlated with improved responses to ART and control of viral rebound. These results indicate that mucosal immune responses, present prior to infection, can influence efficacy of antiretroviral therapy and the outcome of immunotherapeutic vaccination, suggesting that therapies capable of modulating host mucosal responses may be needed to achieve HIV cure.
Sex differences in sleep and influence of the menstrual cycle on women’s sleep in junior endurance athletes

Previous research shows that female athletes sleep better according to objective parameters but report worse subjective sleep quality than male athletes. However, existing sleep studies did not investigate variations in sleep and sleep stages over longer periods and have, so far, not elucidated the role of the menstrual cycle in female athletes’ sleep. To address these methodological shortcomings, we investigated sex differences in sleep and sleep stages over 61 continuous days in 37 men and 19 women and examined the role of the menstrual cycle and its phases in 15 women. Sleep was measured by a non-contact radar, and menstrual bleeding was self-reported. Associations were investigated with multilevel modeling. Overall, women tended to report poorer subjective sleep quality (p = .057), but objective measurements showed that women obtained longer sleep duration (p < .001), more light (p = .013) and rapid eye movement sleep (REM; hours (h): p < . 001, %: p = . 007), shorter REM latency (p < .001), and higher sleep efficiency (p = .003) than men. R2 values showed that sleep duration, REM and REM latency were especially affected by sex. Among women, we found longer time in bed (p = .027) and deep sleep (h: p = .036), and shorter light sleep (%: p = .021) during menstrual bleeding vs. non-bleeding days; less light sleep (h: p = .040), deep sleep (%: p = .013) and shorter REM latency (p = .011) during the menstrual than pre-menstrual phase; and lower sleep efficiency (p = .042) and more deep sleep (%: p = .026) during the follicular than luteal phase. These findings indicate that the menstrual cycle may impact the need for physiological recovery, as evidenced by the sleep stage variations. Altogether, the observed sex differences in subjective and objective sleep parameters may be related to the female athletes’ menstrual cycle. The paper provides unique data of sex differences in sleep stages and novel insights into the role of the menstrual cycle in sleep among female athletes.
Multicompartment Particle Assemblies for Bioinspired Encapsulated Reactions

In recent years, interest in mimicking the complex hierarchical architectures and functionalities of biological systems and associated spatially confined reactions has led to the design and synthesis of a range of multicompartment particles. Multicompartmentalization allows the incorporation of a range of structures in a single particle, thus allowing optimization of physicochemical properties of the assembly (e.g., permeability, stability, stimuli-response) and various multiple, spatially separated reactions. In this Perspective, we describe particle-based multicompartment systems, detailing the building blocks and assembly approaches employed to produce each subcompartmentalized system. The properties that contribute to the performance of multicompartment systems in diverse applications are also discussed, with a focus on coupled enzymatic reactions in confined volumes. The challenges associated with these assemblies for encapsulated reactions are identified and further directions and plausible developm.
Molecular basis of mRNA transport by a kinesin-1–atypical tropomyosin complex

Here, Dimitrova-Paternoga et al. present the high-resolution crystal structure of Khc–aTm1 (Drosophila kinesin-1, also called kinesin heavy chain [Khc], in complex with a putative cargo adaptor, the atypical tropomyosin [aTm1]), which mediates transport of oskar mRNA to the posterior pole of the Drosophila oocyte. They show that aTm1 binds to an evolutionarily conserved cargo binding site on Khc, demonstrate that Khc binds RNA directly, and show that aTm1 plays a stabilizing role in the interaction of Khc with RNA, which distinguishes aTm1 from classical motor adaptors.
The Application and Development of Deep Learning in Radiotherapy: A Systematic Review

With the massive use of computers, the growth and explosion of data has greatly promoted the development of artificial intelligence (AI). The rise of deep learning (DL) algorithms, such as convolutional neural networks (CNN), has provided radiation oncologists with many promising tools that can simplify the complex radiotherapy process in the clinical work of radiation oncology, improve the accuracy and objectivity of diagnosis, and reduce the workload, thus enabling clinicians to spend more time on advanced decision-making tasks. As the development of DL gets closer to clinical practice, radiation oncologists will need to be more familiar with its principles to properly evaluate and use this powerful tool. In this paper, we explain the development and basic concepts of AI and discuss its application in radiation oncology based on different task categories of DL algorithms. This work clarifies the possibility of further development of DL in radiation oncology.
Phenolic compounds disrupt spike-mediated receptor-binding and entry of SARS-CoV-2 pseudo-virions

In the pursuit of suitable and effective solutions to SARS-CoV-2 infection, we investigated the efficacy of several phenolic compounds in controlling key cellular mechanisms involved in its infectivity. The way the SARS-CoV-2 virus infects the cell is a complex process and comprises four main stages: attachment to the cognate receptor, cellular entry, replication and cellular egress. Since, this is a multi-part process, it creates many opportunities to develop effective interventions. Targeting binding of the virus to the host receptor in order to prevent its entry has been of particular interest. Here, we provide experimental evidence that, among 56 tested polyphenols, including plant extracts, brazilin, theaflavin-3,3’-digallate, and curcumin displayed the highest binding with the receptor-binding domain of spike protein, inhibiting viral attachment to the human angiotensin-converting enzyme 2 receptor, and thus cellular entry of pseudo-typed SARS-CoV-2 virions. Both, theaflavin-3,3’-digallate at 25 μg/ml and curcumin above 10 μg/ml concentration, showed binding with the angiotensin-converting enzyme 2 receptor reducing at the same time its activity in both cell-free and cell-based assays. Our study also demonstrates that brazilin and theaflavin-3,3’-digallate, and to a still greater extent, curcumin, decrease the activity of transmembrane serine protease 2 both in cell-free and cell-based assays. Similar pattern was observed with cathepsin L, although only theaflavin-3,3’-digallate showed a modest diminution of cathepsin L expression at protein level. Finally, each of these three compounds moderately increased endosomal/lysosomal pH. In conclusion, this study demonstrates pleiotropic anti-SARS-CoV-2 efficacy of specific polyphenols and their prospects for further scientific and clinical investigations.
Sustainable and replicable clinical and financial outcomes in an interprofessional education and collaborative practice nexus

ABSTRACT Our Interprofessional Education and Collaborative Practice (IPECP) Nexus previously reported significant reductions in Emergency Department (ED) visits, hospitalizations, hemoglobin A1c levels, and patient charges. This study examines sustainability of these results over two additional years and replication in two subsequent independent patient cohorts. Participants in the sustainability cohort (N = 276) met ≥1 of the following criteria: (a) ≥3 ED visits in first or second half of the year, (b) hemoglobin A1c level ≥ 9, or (c) Length of Stay, Acuity, Comorbidities, and ER (Emergency Room) Visits (LACE) score ≥ 10. Participants in two replicability cohorts (N = 255) and (N = 160) met the same criteria, but the LACE criterion was changed to ≥3 hospitalizations in baseline years. The Nexus, housed in a family medicine (FM) residency clinic, included professionals and students from multiple disciplines. IPECP skills and interventions included communication, team building, and conflict engagement skills training, daily huddles and pre-visit planning, immediate consultations, small teamlet IPECP interactions, and weekly IPECP case conferences for complex patients. Original health improvements and charge reductions were sustained for two additional years for ED visits, hospitalizations, A1c, and patient charges, and replicated in two additional patient cohorts. The IPECP Nexus interventions were associated with Quadruple Aim outcomes while training the next generation of health care professionals.
Hematologic and systemic metabolic alterations due to Mediterranean class II G6PD deficiency in mice

Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is the single most common enzymopathy, present in approximately 400 million humans (approximately 5%). Its prevalence is hypothesized to be due to conferring resistance to malaria. However, G6PD deficiency also results in hemolytic sequelae from oxidant stress. Moreover, G6PD deficiency is associated with kidney disease, diabetes, pulmonary hypertension, immunological defects, and neurodegenerative diseases. To date, the only available mouse models have decreased levels of WT stable G6PD caused by promoter mutations. However, human G6PD mutations are missense mutations that result in decreased enzymatic stability. As such, this results in very low activity in red blood cells (RBCs) that cannot synthesize new protein. To generate a more accurate model, the human sequence for a severe form of G6PD deficiency, Med(-), was knocked into the murine G6PD locus. As predicted, G6PD levels were extremely low in RBCs, and deficient mice had increased hemolytic sequelae to oxidant stress. Nonerythroid organs had metabolic changes consistent with mild G6PD deficiency, consistent with what has been observed in humans. Juxtaposition of G6PD-deficient and WT mice revealed altered lipid metabolism in multiple organ systems. Together, these findings both establish a mouse model of G6PD deficiency that more accurately reflects human G6PD deficiency and advance our basic understanding of altered metabolism in this setting.
COVID-19 and Adolescent Depression and Suicide Risk Screening Outcomes

BACKGROUND Mental health concerns increased during the coronavirus disease 2019 pandemic, but previous studies have not examined depression screening in pediatric primary care. We aimed to describe changes in screening, depressive symptoms, and suicide risk among adolescents during the coronavirus disease 2019 pandemic. METHODS In a repeat cross-sectional analysis of electronic health record data from a large pediatric primary care network, we compared the percentage of primary care visits where adolescents aged 12 to 21 were screened for depression, screened positive for depressive symptoms, or screened positive for suicide risk between June and December 2019 (prepandemic) and June and December 2020 (pandemic). Changes were examined overall, by month, and by sex, race and ethnicity, insurance type, and income. Modified Poisson regression was used to calculate prevalence ratios (PRs) for the prepandemic to pandemic changes. RESULTS Depression screening at primary care visits declined from 77.6% to 75.8% during the pandemic period (PR: 0.98, 95% confidence interval [CI]: 0.90–1.06). The percentage of adolescents screening positive for depressive symptoms increased from 5.0% to 6.2% (PR: 1.24, 95% CI: 1.15–1.34), with greater increases among female, non-Hispanic Black, and non-Hispanic white adolescents. Positive suicide risk screens increased from 6.1% to 7.1% (PR: 1.16, 95% CI: 1.08–1.26), with a 34% relative increase in reporting recent suicidal thoughts among female adolescents (PR: 1.34, 95% CI: 1.18–1.52). CONCLUSIONS Results suggest that depression and suicide concerns have increased during the pandemic, especially among female adolescents. Results underscore the importance of consistent depression and suicidality screening.
Internet-Administered Cognitive Behavioral Therapy for Common Mental Health Difficulties in Parents of Children Treated for Cancer: Intervention Development and Description Study

Background Following the end of a child’s treatment for cancer, parents may report psychological distress. However, there is a lack of evidence-based interventions that are tailored to the population, and psychological support needs are commonly unmet. An internet-administered low-intensity cognitive behavioral therapy (LICBT)–based intervention (EJDeR [internetbaserad självhjälp för föräldrar till barn som avslutat en behandling mot cancer]) may provide a solution. Objective The first objective is to provide an overview of a multimethod approach that was used to inform the development of the EJDeR intervention. The second objective is to provide a detailed description of the EJDeR intervention in accordance with the Template for Intervention Description and Replication (TIDieR) checklist. Methods EJDeR was developed through a multimethod approach, which included the use of existing evidence, the conceptualization of distress, participatory action research, a cross-sectional survey, and professional and public involvement. Depending on the main presenting difficulty identified during assessment, LICBT behavioral activation or worry management treatment protocols are adopted for the treatment of depression or generalized anxiety disorder when experienced individually or when comorbid. EJDeR is delivered via the Uppsala University Psychosocial Care Programme (U-CARE) portal, a web-based platform that is designed to deliver internet-administered LICBT interventions and includes secure videoconferencing. To guide parents in the use of EJDeR, weekly written messages via the portal are provided by e-therapists comprising final year psychology program students with training in cognitive behavioral therapy. Results An overview of the development process and a description of EJDeR, which was informed by the TIDieR checklist, are presented. Adaptations that were made in response to public involvement are highlighted. Conclusions EJDeR represents a novel, guided, internet-administered LICBT intervention for supporting parents of children treated for cancer. Adopting the TIDieR checklist offers the potential to enhance fidelity to the intervention protocol and facilitate later implementation. The intervention is currently being tested in a feasibility study (the ENGAGE study). International Registered Report Identifier (IRRID) RR2-10.1136/bmjopen-2018-023708
Acute morphine blocks spinal respiratory motor plasticity via long‐latency mechanisms that require toll‐like receptor 4 signalling

While respiratory complications following opioid use are mainly mediated via activation of mu opioid receptors, long‐latency off‐target signalling via innate immune toll‐like receptor 4 (TLR4) may impair other essential elements of breathing control such as respiratory motor plasticity. In adult rats, pre‐treatment with a single dose of morphine blocked long‐term facilitation (LTF) of phrenic motor output via a long‐latency TLR4‐dependent mechanism. In the phrenic motor nucleus, morphine triggered TLR4‐dependent activation of microglial p38 MAPK – a key enzyme that orchestrates inflammatory signalling and is known to undermine phrenic LTF. Morphine‐induced LTF loss may destabilize breathing, potentially contributing to respiratory side effects. Therefore, we suggest minimizing TLR‐4 signalling may improve breathing stability during opioid therapy.
Calorie deprivation impairs the self-control of eating, but not of other behaviors

Abstract Objective Sustained weight loss is difficult to achieve, and weight regain is common due to biological and psychological changes caused by calorie deprivation. These changes are thought to undermine weight loss efforts by making self-control more difficult. However, there is a lack of evidence showing a causal relationship between calorie deprivation and behavioral self-control. Design In this longitudinal field experiment, we tested whether a ten-day period of calorie deprivation leads to the impairment of behavioral self-control. Participants were randomly assigned to either restrict their calorie intake or to continue eating normally for the study period. Main Outcome Measures Participants were given a box of food and non-food ‘treats’ (i.e., chocolates and lottery tickets) that they were asked to resist until the end of the study. On the last day, researchers recorded the number of treats that remained for each participant. Results Nonparametric permutation tests revealed that calorie-deprived participants ate significantly more chocolates than control participants did (p = 0.036), but that participants did not differ in the number of lottery tickets ‘scratched’ by condition (p = 0.332). Conclusion This pattern of findings suggests that calorie deprivation impairs food-related self-control, but that this self-control deficit may not generalize beyond food-related tasks.
Longitudinal Label‐Free Two‐Photon Microscopy of Cellular Healing Processes in Non‐Ablative Fractional Laser Wounds

Wound healing is an important biomedical problem with various associated complications. Although cutaneous wound healing has been studied in vivo extensively using various optical imaging methods, early‐stage cellular healing processes were difficult to study due to scab formation. The objective of this study is to demonstrate that minimal laser wounds and optical microscopy can access the detailed cellular healing processes of cutaneous wounds from the early stage.
QM calculations predict the energetics and infrared spectra of transient glutamine isomers in LOV photoreceptors†

Photosensory receptors containing the flavin-binding light-oxygen-voltage (LOV) domain are modular proteins that fulfil a variety of biological functions ranging from gene expression to phototropism. The LOV photocycle is initiated by blue-light and involves a cascade of intermediate species, including an electronically excited triplet state, that leads to covalent bond formation between the flavin mononucleotide (FMN) chromophore and a nearby cysteine residue. Subsequent conformational changes in the polypeptide chain arise due to the remodelling of the hydrogen bond network in the cofactor binding pocket, whereby a conserved glutamine residue plays a key role in coupling FMN photochemistry with LOV photobiology. Although the dark-to-light transition of LOV photosensors has been previously addressed by spectroscopy and computational approaches, the mechanistic basis of the underlying reactions is still not well understood. Here we present a detailed computational study of three distinct LOV domains: EL222 from Erythrobacter litoralis, AsLOV2 from the second LOV domain of Avena sativa phototropin 1, and RsLOV from Rhodobacter sphaeroides LOV protein. Extended protein-chromophore models containing all known crucial residues involved in the initial steps (femtosecond-to-microsecond) of the photocycle were employed. Energies and rotational barriers were calculated for possible rotamers and tautomers of the critical glutamine side chain, which allowed us to postulate the most energetically favoured glutamine orientation for each LOV domain along the assumed reaction path. In turn, for each evolving species, infrared difference spectra were constructed and compared to experimental EL222 and AsLOV2 transient infrared spectra, the former from original work presented here and the latter from the literature. The good agreement between theory and experiment permitted the assignment of the majority of observed bands, notably the ∼1635 cm−1 transient of the adduct state to the carbonyl of the glutamine side chain after rotation. Moreover, both the energetic and spectroscopic approaches converge in suggesting a facile glutamine flip at the adduct intermediate for EL222 and more so for AsLOV2, while for RsLOV the glutamine keeps its initial configuration. Additionally, the computed infrared shifts of the glutamine and interacting residues could guide experimental research addressing early events of signal transduction in LOV proteins.
Potential role of vector-mediated natural selection in dengue virus genotype/lineage replacements in two epidemiologically contrasted settings

ABSTRACT Dengue virus (DENV) evolutionary dynamics are characterized by frequent DENV genotype/lineage replacements, potentially associated with changes in disease severity and human immunity. New Caledonia (NC) and Cambodia, two contrasted epidemiological settings, respectively experienced a DENV-1 genotype IV to I replacement in 2012 and a DENV-1 genotype I lineage 3–4 replacement in 2005–2007, both followed by a massive dengue outbreak. However, their underlying evolutionary drivers have not been elucidated. Here, we tested the hypothesis that these genotype/lineage switches reflected a higher transmission fitness of the replacing DENV genotype/lineage in the mosquito vector using in vivo competition experiments. For this purpose, field-derived Aedes aegypti from NC and Cambodia were orally challenged with epidemiologically relevant pairs of four DENV-1 genotype I and IV strains from NC or four DENV-1 genotype I lineage 3 and 4 strains from Cambodia, respectively. The relative transmission fitness of each DENV-1 genotype/lineage was measured by quantitative RT–PCR for infection, dissemination, and transmission rates. Results showed a clear transmission fitness advantage of the replacing DENV-1 genotype I from NC within the vector. A similar but more subtle pattern was observed for the DENV-1 lineage 4 replacement in Cambodia. Our results support the hypothesis that vector-driven selection contributed to the DENV-1 genotype/lineage replacements in these two contrasted epidemiological settings, and reinforce the idea that natural selection taking place within the mosquito vector plays an important role in DENV short-term evolutionary dynamics.