Miracle-dz/UniFAR-FTUs huggingface dataset:
Arp2/3 inactivation causes intervertebral disc and cartilage degeneration with dysregulated TonEBP-mediated osmoadaptation.

Extracellular matrix and osmolarity influence the development and homeostasis of skeletal tissues through Rho GTPase-mediated alteration of the actin cytoskeleton. This study investigated whether the actin-branching Arp2/3 complex, a downstream effector of the Rho GTPases Cdc42 and Rac1, plays a critical role in maintaining the health of matrix-rich and osmotically loaded intervertebral discs and cartilage. Mice with constitutive intervertebral disc and cartilage-specific deletion of the critical Arp2/3 subunit Arpc2 (Col2-Cre; Arpc2f/f) developed chondrodysplasia and spinal defects. Since these mice did not survive to adulthood, we generated mice with inducible Arpc2 deletion in disc and cartilage (Acan-CreERT2; Arpc2f/f). Inactivation of Arp2/3 at skeletal maturity resulted in growth plate closure, loss of proteoglycan content in articular cartilage, and degenerative changes in the intervertebral disc at 1 year of age. Chondrocytes with Arpc2 deletion showed compromised cell spreading on both collagen and fibronectin. Pharmacological inhibition of Cdc42 and Arp2/3 prevented the osmoadaptive transcription factor TonEBP/NFAT5 from recruiting co-factors in response to a hyperosmolarity challenge. Together, these findings suggest that Arp2/3 plays a critical role in cartilaginous tissues through the regulation of cell-extracellular matrix interactions and modulation of TonEBP-mediated osmoadaptation.
Interactions between amyloid precursor protein-like (APPL) and MAGUK scaffolding proteins contribute to appetitive long-term memory in Drosophila melanogaster

Abstract Amyloid precursor protein (APP), the precursor of amyloid beta peptide, plays a central role in Alzheimer’s disease (AD), a pathology characterized by memory decline and synaptic loss upon aging. Understanding the physiological role of APP is fundamental in deciphering the progression of AD, and several studies suggest a synaptic function via protein-protein interactions. Nevertheless, it remains unclear whether and how these interactions contribute to memory. In Drosophila, we previously showed that APP-like (APPL), the fly APP homolog, is required for aversive associative memory in the olfactory memory center, the mushroom body (MB). In the present study, we show that APPL is required for appetitive long-term memory (LTM), another form of associative memory, in a specific neuronal subpopulation of the MB, the α′/β′ Kenyon cells. Using a biochemical approach, we identify the synaptic MAGUK (membrane-associated guanylate kinase) proteins X11, CASK, Dlgh2 and Dlgh4 as interactants of the APP intracellular domain (AICD). Next, we show that the Drosophila homologs CASK and Dlg are also required for appetitive LTM in the α′/β′ neurons. Finally, using a double RNAi approach, we demonstrate that genetic interactions between APPL and CASK, as well as between APPL and Dlg, are critical for appetitive LTM. In summary, our results suggest that APPL contributes to associative long-term memory through its interactions with the main synaptic scaffolding proteins CASK and Dlg. This function should be conserved across species.
A randomized controlled trial examining the impact of individual trauma-focused therapy for individuals receiving group treatment for depression.

OBJECTIVES Adverse life events are associated with increased likelihood of depression and poorer prognosis. Trauma-focused treatments (TFT) appear to be effective in decreasing comorbid depressive symptoms. Accordingly, the aim of this study was to evaluate the effectiveness of a TFT on the memories of aversive events for individuals with a primary diagnosis of depression. METHODS A randomized controlled trial was conducted with 49 participants recruited from a 10-day outpatient group programme. All participants showed symptoms of depression with a subgroup (80%) meeting the DSM-5 criteria for a major depressive episode. Participants received treatment as usual (TAU); three additional individual trauma-focused sessions; or three additional individual assertiveness training sessions. Participants were assessed with regards to depression diagnosis and related symptoms. RESULTS For participants with a major depressive episode, the addition of trauma-focused sessions significantly increased the likelihood of remission when compared to TAU, or additional assertiveness training. While no significant treatment difference was noted in depressive symptom change post-treatment, six weeks after treatment those who received an adjunct treatment were more likely to maintain treatment gains than those who received TAU. Furthermore, at 12-week follow-up, participants who received a TFT reported significantly fewer depressive symptoms than those who received assertiveness training. CONCLUSIONS While differences in outcomes were minimal immediately post-treatment, differences among treatment groups increased over time. Thus, as few as three additional TFT sessions may impact positively on symptom change for people completing a group programme for the treatment of depression. PRACTITIONER POINTS Depression is the greatest cause of disability worldwide. Adverse experiences are linked with an increased likelihood of depression, more severe symptoms and poor treatment outcomes following evidence-based interventions. As few as three trauma-focused sessions can improve treatment outcomes in terms of depression diagnosis and related symptoms for individuals receiving group cognitive behavioural therapy.
Assessing the impact of aggregating disease stage data in model predictions of human African trypanosomiasis transmission and control activities in Bandundu province (DRC)

Since the turn of the century, the global community has made great progress towards the elimination of gambiense human African trypanosomiasis (HAT). Elimination programs, primarily relying on screening and treatment campaigns, have also created a rich database of HAT epidemiology. Mathematical models calibrated with these data can help to fill remaining gaps in our understanding of HAT transmission dynamics, including key operational research questions such as whether integrating vector control with current intervention strategies is needed to achieve HAT elimination. Here we explore, via an ensemble of models and simulation studies, how including or not disease stage data, or using more updated data sets affect model predictions of future control strategies.
Intergenerational Transmission of Depression.

The study of depression in mothers in relation to transmission of risk for the development of psychopathology in their children relies on solid foundations in the understanding of psychopathology, of development, and of developmental psychopathology per se. This article begins with a description of the scope of the problem, including a summary of knowledge of how mothers' depression is associated with outcomes in children and of moderators of those associations. The sense of scope then informs a theoretical and empirical perspective on knowledge of mechanisms in those associations, with a focus on what has been learned in the past 20 years. Throughout the article, and in conclusions at the end, are suggestions for next steps in research and practice. Expected final online publication date for the Annual Review of Clinical Psychology, Volume 16 is May 7, 2020. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Correction for Chernov-Rogan et al., TRPA1 modulation by piperidine carboxamides suggests an evolutionarily conserved binding site and gating mechanism

PHARMACOLOGY Correction for “TRPA1 modulation by piperidine carboxamides suggests an evolutionarily conserved binding site and gating mechanism,” by Tania Chernov-Rogan, Eleonora Gianti, Chang Liu, Elisia Villemure, Andrew P. Cridland, Xiaoyu Hu, Elisa Ballini, Wienke Lange, Heike Deisemann, Tianbo Li, Stuart I. Ward, David H. Hackos, Steven Magnuson, Brian Safina, Michael L. Klein, Matthew Volgraf, Vincenzo Carnevale, and Jun Chen, which was first published December 3, 2019; 10.1073/pnas.1913929116 (Proc. Natl. Acad. Sci. U.S.A. 116, 26008–26019). The authors note that Figs. 1 and 5 appeared incorrectly. The corrected figures and their legends appear below.
Photoadaptation to ultraviolet B TL01 in psoriatic patients

In the biologic era, narrow‐band ultraviolet B (NB‐UVB) phototherapy still remains a valuable, effective, inexpensive, safe anti‐psoriatic treatment. Patients can lose response to NB‐UVB over time due to photoadaptation. This phenomenon is the tendency of the skin to respond to ultraviolet (UV) exposure by undergoing changes that may result in a decreased future response to an equivalent dose of radiation, thus leading to the need for an increased exposure during phototherapy course.
Drug Metabolite Identification using UHPLC UV Spectroscopy and Parallelized Scans on a Tribrid Orbitrap Mass Spectrometer.

RATIONALE To capture all metabolites in metabolite identification studies, MS/MS information is required in both positive and negative ionisation modes, usually requiring several sample injections to gain all sample information. A high resolution and high mass accuracy quadrupole/linear trap/Orbitrap tribrid instrument was used to gain all this information in a novel single injection "capture all" approach to metabolite identification. METHODS Incubations of diclofenac, a model compound, were conducted in human and rat hepatocytes. These were run using UHPLC/UV coupled to a Thermo Fusion tribrid mass spectrometer. Five parallel scans were employed, positive and negative ion full scan, data dependent MS/MS, both high energy dissociation and collision induced dissociation, and data independent all ion fragmentation were collected in positive and negative ion mode. RESULTS Nine metabolites were identified; a metabolite observed in the UV trace, but not positive ion full scan MS was detected in the same sample injection by negative ion full scan MS. This was identified as a sulfate metabolite and the corresponding negative ion all ion fragmentation allowed for some structural elucidation. The use of a photo diode array detector allowed for spectral assessment in case of changes in absorbance spectra, and subsequent metabolite semi-quantification. CONCLUSION This method provided good quality MS/MS data across the m/z range in both positive and negative ion. The addition of both negative ion full scan MS and negative ion MS/MS allowed for the detection and structural elucidation of metabolites not observed in positive ion. Use of the photo diode array detector allowed metabolite semi-quantification.
CARDUUS CINEREUS (ASTERACEAE) – NEW TO NORTH AMERICA

Abstract Carduus cinereus M.Bieb. populations have been discovered in the Hells Canyon Wilderness of northeastern Oregon and western Idaho. These plants were initially identified as C. pycnocephalus L. They are distinguished from that species by loosely clustered, usually pedunculate, heads and by scarious-margined phyllaries. These plants are genetically distant from other North American Carduus species (<94% similarity) based on DNA sequence comparisons of the internal transcribed spacers between the 18S and 26S nuclear rDNA regions. Carduus cinereus is new to North America. A revised key to the species of Carduus in North America is presented.
Integrating Network Pharmacology and Experimental Models to Investigate the Efficacy of Coptidis and Scutellaria Containing Huanglian Jiedu Decoction on Hepatocellular Carcinoma.

Unlike Western medicines with single-target, the traditional Chinese medicines (TCM) always exhibit diverse curative effects against multiple diseases through its "multi-components" and "multi-targets" manifestations. However, discovery and identification of the major therapeutic diseases and the underlying molecular mechanisms of TCM remain to be challenged. In the current study, we, for the first time, applied an integrated strategy by combining network pharmacology with experimental evaluation, for exploration and demonstration of the therapeutic potentials and the underlying possible mechanisms of a classic TCM formula, Huanglian Jiedu decoction (HLJDD). First, the herb-compound, compound-protein, protein-pathway, and gene-disease networks were constructed to predict the major therapeutic diseases of HLJDD and explore the underlying molecular mechanisms. Network pharmacology analysis showed the top one predicted disease of HLJDD treatment was cancer, especially hepatocellular carcinoma (HCC) and inflammation-related genes played an important role in the treatment of HLJDD on cancer. Next, based on the prediction by network pharmacology analysis, both in vitro HCC cell and in vivo orthotopic HCC implantation mouse models were established to validate the curative role of HLJDD. HLJDD exerted its anti-tumor activity on HCC in vitro, as demonstrated by impaired cell proliferation and colony formation abilities, induced apoptosis and cell cycle arrest, as well as inhibited migratory and invasive properties of HCC cells. The orthotopic HCC implantation mouse model further demonstrated the remarkable antitumour effects of HLJDD on HCC in vivo. In conclusion, our study demonstrated the effectiveness of integrating network pharmacology with experimental study for discovery and identification of the major therapeutic diseases and the underlying molecular mechanisms of TCM.
Will HPV vaccination prevent cervical cancer?

Summary We conducted a critical appraisal of published Phase 2 and 3 efficacy trials in relation to the prevention of cervical cancer in women. Our analysis shows the trials themselves generated significant uncertainties undermining claims of efficacy in these data. There were 12 randomised control trials (RCTs) of Cervarix and Gardasil. The trial populations did not reflect vaccination target groups due to differences in age and restrictive trial inclusion criteria. The use of composite and distant surrogate outcomes makes it impossible to determine effects on clinically significant outcomes. It is still uncertain whether human papillomavirus (HPV) vaccination prevents cervical cancer as trials were not designed to detect this outcome, which takes decades to develop. Although there is evidence that vaccination prevents cervical intraepithelial neoplasia grade 1 (CIN1) this is not a clinically important outcome (no treatment is given). Trials used composite surrogate outcomes which included CIN1. High efficacy against CIN1+ (CIN1, 2, 3 and adenocarcinoma in situ (AIS)) does not necessarily mean high efficacy against CIN3+ (CIN3 and AIS), which occurs much less frequently. There are too few data to clearly conclude that HPV vaccine prevents CIN3+. CIN in general is likely to have been overdiagnosed in the trials because cervical cytology was conducted at intervals of 6–12 months rather than at the normal screening interval of 36 months. This means that the trials may have overestimated the efficacy of the vaccine as some of the lesions would have regressed spontaneously. Many trials diagnosed persistent infection on the basis of frequent testing at short intervals, i.e. less than six months. There is uncertainty as to whether detected infections would clear or persist and lead to cervical changes.
Variability of Lower Limb Artery Systolic–Diastolic Velocities in Futsal Athletes and Non-Athletes: Evaluation by Arterial Doppler Ultrasound

Background: Sports athletes, namely high-intensity practitioners, suffer from vascular remodeling overtime. The purpose of this study was to analyze the systolic and diastolic velocities’ variation between non-athletes and futsal athletes by means of arterial lower limb doppler ultrasound. Additionally, we intended to verify if the velocity variations occur primarily at the systolic or the diastolic level and in which arteries. Methods: Seventy-six young males (mean ± SD: 24.9 ± 2.8 years old) volunteered to participate in this cross-sectional study and were divided into two groups: a futsal athletes group (n = 38; 24 ± 2.78 years) in the central region of Portugal playing on the 2nd national league with the same level of practice (16 ± 2.4 years of practice) and a non-athletes group (n = 38: 26 ± 1.8 years) who did not practice sports regularly and were not federated in any sport. All the subjects agreed to participate in the study with the aim of assessing the arterial lower limb through doppler ultrasound (Philips HD7 echograph with linear transducer 7–12 MHz). Results: Differences between groups (p ≤ 0.05) in the systolic velocity of the left deep femoral artery (p = 0.022; d = 0.546, small) and in the right superficial femoral artery (p = 0.028; d = −0.515, small) were found. We also found differences in the diastolic velocity: in the left common femoral artery (p = 0.002; d = −0.748, moderate), in the right deep femoral artery (p = 0.028; d = −0.521, small), in the right superficial femoral artery (p = 0.026; d = −0.522, small), in the right popliteal artery (p = 0.002; d = −0.763, moderate), and in the left popliteal artery (p = 0.007; d = −0.655, moderate). Moreover, the athletes’ group presented the highest mean values, with the exception of the systolic velocity of the left deep femoral artery. In intragroup analysis of variance referring to systolic and diastolic velocities in arterial levels in the right and left arteries, differences were found in all analyses (p ≤ 0.05). Conclusions: We conclude that futsal athletes of our sample go through a process of changes such as increased blood flow velocity in systolic and diastolic cardiac phase in all studied lower limb arteries, showing that the remodeling occurs regardless of vessel radius. Our results reinforce the existence of vascular remodeling that may vary with the sport and its intensity.
Virtual Reality Relaxation to Decrease Dental Anxiety: Immediate Effect Randomized Clinical Trial

Introduction: Dental anxiety is common and causes symptomatic use of oral health services. Objectives: The aim was to study if a short-term virtual reality intervention reduced preoperative dental anxiety. Methods: A randomized controlled single-center trial was conducted with 2 parallel arms in a public oral health care unit: virtual reality relaxation (VRR) and treatment as usual (TAU). The VRR group received a 1- to 3.5-min 360° immersion video of a peaceful virtual landscape with audio features and sound supporting the experience. TAU groups remained seated for 3 min. Of the powered sample of 280 participants, 255 consented and had complete data. Total and secondary sex-specific mixed effects linear regression models were completed for posttest dental anxiety (Modified Dental Anxiety Scale [MDAS] total score) and its 2 factors (anticipatory and treatment-related dental anxiety) adjusted for baseline (pretest) MDAS total and factor scores and age, taking into account the effect of blocking. Results: Total and anticipatory dental anxiety decreased more in the VRR group than the TAU group (β = −0.75, P < .001, for MDAS total score; β = −0.43, P < .001, for anticipatory anxiety score) in patients of a primary dental care clinic. In women, dental anxiety decreased more in VRR than TAU for total MDAS score (β = −1.08, P < .001) and treatment-related dental anxiety (β = −0.597, P = .011). Anticipatory dental anxiety decreased more in VRR than TAU in both men (β = −0.217, P < .026) and women (β = −0.498, P < .001). Conclusion: Short application of VRR is both feasible and effective to reduce preoperative dental anxiety in public dental care settings (ClinicalTrials.gov NCT03993080). Knowledge Transfer Statement: Dental anxiety, which is a common problem, can be reduced with short application of virtual reality relaxation applied preoperatively in the waiting room. Findings of this study indicate that it is a feasible and effective procedure to help patients with dental anxiety in normal public dental care settings.
The CMS State Innovation Models Initiative and Improved Health Information Technology and Care Management Capabilities of Physician Practices

The Centers for Medicare and Medicaid Services’ (CMS) State Innovation Models (SIMs) initiative funded 17 states to implement health care payment and delivery system reforms to improve health system performance. Whether SIM improved health information technology (HIT) and care management capabilities of physician practices, however, remains unclear. National surveys of physician practices (N = 2,722) from 2012 to 2013 and 2017 to 2018 were linked. Multivariable regression estimated differential adoption of 10 HIT functions and chronic care management processes (CMPs) based on SIM award status (SIM Round 1, SIM Round 2, or non-SIM). HIT and CMP capabilities improved equally for practices in SIM Round 1 (5.3 vs. 6.8 capabilities, p < .001), SIM Round 2 (4.7 vs. 7.0 capabilities, p < .001), and non-SIM (4.2 vs. 6.3 capabilities, p < .001) states. The CMS SIM Initiative did not accelerate the adoption of ten foundational physician practice capabilities beyond national trends.
Triterpenoid glycosides from the rhizomes of Allium ascalonicum and their anoctamin-1 inhibitory activity

Abstract Ten triterpenoid glycosides including two undescribed compounds (1 and 2) were isolated from the methanol extract of Allium ascalonicum rhizomes. These compounds were structurally elucidated to be 3β-O-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl-19α-hydroxyolean-12-ene-28-oic acid 28-O-[α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl] ester (1), 3-O-β-D-glucopyranosyl-(1→3)-[α-L-rhamnopyranosyl-(1→2)]-α-L-arabinopyranosyl-3β,19α-dihydroxyoleanane-12-en-28-oic acid (2), lactifoloside C (3), lactifoloside H (4), randiasaponin IV (5), kudinoside G (6), ilexkudinoside W (7), lactifoloside G (8), kudinoside D (9), and ilexkudinoside T (10) by analyzing their HR-ESI-MS, NMR spectral data and by comparison with those reported in the literature. Compounds 1 – 10 were evaluated for anoctamin-1 (ANO1) inhibitory activity using yellow fluorescent protein reduction assays. At the concentration of 30 µM, compounds 2 and 9 displayed moderate ANO1 inhibitory percentages of 28.9 ± 0.85% and 26.2 ± 0.65%, respectively. Graphical Abstract
Alpha-Lactalbumin Enriched Whey Protein Concentrate to Improve Gut, Immunity and Brain Development in Preterm Pigs

Human milk is rich in nutritional factors, such as alpha-lactalbumin (α-Lac), and important for neonatal development, but nutrient supplementation may be required for optimal growth. Using a pig model, we hypothesized that α-Lac-enriched whey protein concentrate (WPC) supplementation improves neonatal development. Cesarean-delivered preterm pigs were fed either dilute bovine milk (REF) or REF milk supplemented with WPC with normal (STANDARD-ALPHA) or high (HIGH-ALPHA) α-Lac. Clinical, gut, immune and cognitive endpoints (open field, T-maze) were assessed and tissues collected at Day 19. The growth of STANDARD-ALPHA and HIGH-ALPHA were higher than REF (31 vs. 19 g/kg/d). Most organ weights, gut, immunity and brain variables were similar between WPC groups. HIGH-ALPHA had a higher bone mineral content, colon microbial diversity and an abundance of specific bacteria and microbial metabolites, and tended to show a faster food transit time (p = 0.07). Relative to REF, WPC pigs showed higher relative organ weights, blood amino acids, blood neutrophil function, and microbial metabolites, but lower brush-border enzyme activities and plasma cortisol. Cognition outcomes did not differ among the groups. In conclusion, WPC supplementation of milk improved some growth, gut and immunity parameters in preterm pigs. However, increasing the α-Lac content beyond human milk levels had limited effects on the immature gut and developing brain.