Miracle-dz/UniFAR-FTUs huggingface dataset:
The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition

Systematic examination of patient-derived RNF43 mutations identifies rules to guide patient selection, including that truncation or point mutations in well-defined functional domains sensitize cancers to PORCN inhibitors. A subset of Wnt-addicted cancers are sensitive to targeted therapies that block Wnt secretion or receptor engagement. RNF43 loss-of-function (LOF) mutations that increase cell surface Wnt receptor abundance cause sensitivity to Wnt inhibitors. However, it is not clear which of the clinically identified RNF43 mutations affect its function in vivo. We assayed 119 missense and 45 truncating RNF43 mutations found in human cancers using a combination of cell-based reporter assays, genome editing, flow cytometry, and immunofluorescence microscopy. Five common germline variants of RNF43 exhibited wild-type activity. Cancer-associated missense mutations in the RING ubiquitin ligase domain and a subset of mutations in the extracellular domain hyperactivate Wnt/β-catenin signaling through formation of inactive dimers with endogenous RNF43 or ZNRF3. RNF43 C-terminal truncation mutants, including the common G659fs mutant are LOF specifically when endogenous mutations are examined, unlike their behavior in transient transfection assays. Patient-derived xenografts and cell lines with C-terminal truncations showed increased cell surface Frizzled and Wnt/β-catenin signaling and were responsive to porcupine (PORCN) inhibition in vivo, providing clear evidence of RNF43 impairment. Our study provides potential guidelines for patient assignment, as virtually all RNF43 nonsense and frameshift mutations, including those in the C-terminal domain and a large number of patient-associated missense mutations in the RING domain and N-terminal region compromise its activity, and therefore predict response to upstream Wnt inhibitors in cancers without microsatellite instability. This study expands the landscape of actionable RNF43 mutations, extending the benefit of these therapies to additional patients. Significance: Systematic examination of patient-derived RNF43 mutations identifies rules to guide patient selection, including that truncation or point mutations in well-defined functional domains sensitize cancers to PORCN inhibitors.
The role of Toll/interleukin-1 receptor adaptor protein in the pathogenesis of myelodysplastic syndromes

ii PREFACE . iv TABLE OF CONTENTS . v LIST OF TABLES . viii LIST OF FIGURES . ix LIST OF ABBREVIATIONS . xi ACKNOWLEDGEMENTS . xvii DEDICATION . xix
Wearing Compression Garment Enhances Central Hemodynamics? A Systematic Review and Meta-Analysis

Abstract Lee, DCW, Ali, A, Sheridan, S, Chan, DKC, and Wong, SHS. Wearing compression garment enhances central hemodynamics? a systematic review and meta-analysis. J Strength Cond Res 36(8): 2349–2359, 2022—Compression garments (CG) are believed to enhance exercise performance and recovery by improving central hemodynamic responses. However, evidence is inconclusive. We performed a systematic review and meta-analysis to determine the effect of wearing CG at rest or after a physiological challenge on central hemodynamic responses, including cardiac output, stroke volume (SV), heart rate (HR), systolic blood pressure, diastolic blood pressure (DBP), and systemic vascular resistance in healthy individuals. The English language searches of the electronic databases SPORTDiscus, MEDLINE, and Web of Science were conducted from November 2018–February 2019. The studies involved were limited to the following: (a) original articles; (b) randomized controlled trials; (c) monitoring of central hemodynamic responses (either at rest or after a physiological challenge: maximal exercise or orthostatic challenge); and (d) healthy individuals. Of the 786 studies identified, 12 were included in the systematic review and meta-analysis. Meta-analysis was performed by the restricted maximum likelihood method. The results indicated that the effect size (ES) of wearing CG on improving central hemodynamic responses was large overall (Hedges' g = 0.55) and was large in SV (Hedges' g = 1.09) and HR (Hedges' g = 0.65). Subgroup analysis showed that the ESs in “post-physiological challenge” was large in overall (Hedges' g = 0.98), SV (Hedges' g = 1.78), HR (Hedges' g = 1.10), and DBP (Hedges' g = 0.75). Their ESs in “at rest” were not significant in all central hemodynamic responses, apart from a significant medium ES observed in SV (Hedges' g = 0.44). Healthy individuals who wear CG have marked improvement in central hemodynamic responses, particularly after a physiological challenge. More pronounced effects of CG are observed in increasing SV and reducing HR.
Features of Structure and Properties of pHEMA-gr-PVP Block Copolymers, Obtained in the Presence of Fe2+

This paper presents the research results of the copolymer structure and properties of 2-hydroxyethylmethacrylate (HEMA) with polyvinylpyrrolidone (PVP) and their hydrogels, obtained by block polymerization in the presence of iron sulfate (II). By the methods of chemical analysis, IR spectroscopy, Thermogravimetric (TG) and Differential Thermal Analysis (DTA), the course of grafted copolymerization of HEMA on PVP with the formation of a cross-linked copolymer was confirmed. The results received by scanning electron microscopy showed that due to the copolymerization of HEMA with PVP, macroporous hydrogels with a pore size of 10–30 μm were obtained. The peculiarities of the structure formation of the obtained copolymers depending on the initial composition formulation were established and their structural parameters were investigated: PVP grafting efficiency, PVP content in copolymer, molecular weight of internodal fragment of polymer network, crosslinking degree, and crosslinking density. The interrelation of sorption–diffusion, physical–mechanical and thermophysical properties along with the structure of the obtained materials was proved. It was shown that with the increasing PVP content in the original composition, the efficiency of its grafting and crosslinking density of the polymer network decreased, but the surface hardness, heat resistance, sorption capacity of copolymers in the dry state, as well as ion permeability and elasticity in the swollen state increased, while their tensile strength deteriorated. It is proved that by changing the original composition formulation it is possible to change the structure and hence the properties of the copolymers in the desired direction.
Compression Socks Reduce Running-Induced Intestinal Damage

Abstract Zadow, EK, Edwards, KH, Kitic, CM, Fell, JW, Adams, MJ, Singh, I, Kundur, A, Johnstone, ANB, Crilly, J, Bulmer, AC, Halson, SL, and, and Wu, SSX. Compression socks reduce running-induced intestinal damage. J Strength Cond Res 36(9): 2461–2464, 2022—Exercise is associated with a reduction in splanchnic blood flow that leads to the disruption of intestinal epithelium integrity, contributing to exercise-induced gastrointestinal syndrome. Strategies that promote intestinal blood flow during exercise may reduce intestinal damage, which may be advantageous for subsequent recovery and performance. This study aimed to explore if exercise-associated intestinal damage was influenced by wearing compression garments, which may improve central blood flow. Subjects were randomly allocated to wear compression socks (n = 23) or no compression socks (control, n = 23) during a marathon race. Blood samples were collected 24 hours before and immediately after marathon and analyzed for intestinal fatty acid–binding protein (I-FABP) concentration as a marker of intestinal damage. The magnitude of increase in postmarathon plasma I-FABP concentration was significantly greater in control group (107%; 95% confidence interval [CI], 72–428%) when compared with runners wearing compression socks (38%; 95% CI, 20–120%; p = 0.046; d = 0.59). Wearing compression socks during a marathon run reduced exercise-associated intestinal damage. Compression socks may prove an effective strategy to minimize the intestinal damage component of exercise-induced gastrointestinal syndrome.
Identification of Inflammatory and Disease-Associated Plasma Proteins that Associate with Intake of Added Sugar and Sugar-Sweetened Beverages and Their Role in Type 2 Diabetes Risk

It has been suggested that high intake of added sugar and sugar-sweetened beverages (SSBs) increase the level of circulating inflammatory proteins and that chronic inflammation plays a role in type 2 diabetes (T2D) development. We aim to examine how added sugar and SSB intake associate with 136 measured plasma proteins and C-reactive protein (CRP) in the Malmö Diet and Cancer–Cardiovascular Cohort (n = 4382), and examine if the identified added sugar- and SSB-associated proteins associate with T2D incidence. A two-step iterative resampling approach was used to internally replicate proteins that associated with added sugar and SSB intake. Nine proteins were identified to associate with added sugar intake, of which only two associated with T2D incidence (p < 0.00045). Seven proteins were identified to associate with SSB intake, of which six associated strongly with T2D incidence (p < 6.9 × 10−8). No significant associations were observed between added sugar and SSB intake and CRP concentrations. In summary, our elucidation of the relationship between plasma proteome and added sugar and SSB intake, in relation to future T2D risk, demonstrated that SSB intake, rather than the total intake of added sugar, was related to a T2D-pathological proteomic signature. However, external replication is needed to verify the findings.
Understanding How Nutrition Literacy Links to Dietary Adherence in Patients Undergoing Maintenance Hemodialysis: A Theoretical Exploration using Partial Least Squares Structural Equation Modeling

Dietary non-adherence is pervasive in the hemodialysis (HD) population. Health literacy is a plausible predictor of dietary adherence in HD patients, but its putative mechanism is scarcely studied. Thus, this study aimed to establish the causal model linking nutrition literacy to dietary adherence in the HD population. This was a multi-centre, cross-sectional study, involving 218 randomly selected multi-ethnic HD patients from nine dialysis centres in Klang Valley, Malaysia. Dietary adherence and self-management skills were assessed using validated End-Stage Renal Disease Adherence Questionnaire and Perceived Kidney/Dialysis Self-Management Scale, respectively. Validated self-developed scales were used to gauge nutrition literacy, dietary knowledge and Health Belief Model constructs. Relationships between variables were examined by multiple linear regressions and partial least squares structural equation modeling. Limited nutrition literacy was evident in 46.3% of the HD patients, associated with older age, lower education level, and shorter dialysis vintage. Dietary adherence rate was at 34.9%. Nutrition literacy (β = 0.390, p < 0.001) was an independent predictor of dietary adherence, mediated by self-efficacy (SIE = 0.186, BC 95% CI 0.110–0.280) and self-management skills (SIE = 0.192, BC 95% CI 0.103–0.304). Thus, nutrition literacy-enhancing strategies targeting self-efficacy and self-management skills should be considered to enhance dietary adherence in the HD population.
Involvement of the C‐terminal domain in cell surface localization and G‐protein coupling of mGluR6

Metabotropic glutamate receptor 6, mGluR6, interacts with scaffold proteins and Gβγ subunits via its intracellular C‐terminal domain (CTD). The mGluR6 pathway is critically involved in the retinal processing of visual signals. We herein investigated whether the CTD (residues 840–871) was necessary for mGluR6 cell surface localization and G‐protein coupling using mGluR6‐CTD mutants with immunocytochemistry, surface biotinylation assays, and electrophysiological approaches. We used 293T cells and primary hippocampal neurons as model systems. We examined C‐terminally truncated mGluR6 and showed that the removal of up to residue 858 did not affect surface localization or glutamate‐induced G‐protein‐mediated responses, whereas a 15‐amino acid deletion (Δ857‐871) impaired these functions. However, a 21‐amino acid deletion (Δ851‐871) restored surface localization and glutamate‐dependent responses, which were again attenuated when the entire CTD was removed. The sequence alignment of group III mGluRs showed conserved amino acids resembling an ER retention motif in the CTD. These results suggest that the intracellular CTD is required for the cell surface transportation and receptor function of mGluR6, whereas it may contain regulatory elements for intracellular trafficking and signaling.
LED Lights Affecting Morphogenesis and Isosteroidal Alkaloid Contents in Fritillaria cirrhosa D. Don—An Important Chinese Medicinal Herb

Investigations were carried out to study the effects of light-emitting diode (LED) lights on growth and development of isosteroidal alkaloids in embryogenic calli of Fritillaria cirrhosa D. Don, an important traditional Chinese medicine herb. Calli were cultured in glass bottles, each containing 100 mL of Murashige and Skoog’s basal medium supplemented with 2% sucrose and 0.4% gellan gum powder, a gelling agent. These bottles were incubated in a specially designed plant growth chamber equipped with eight different LED lights consisting of single or combinations of four different light spectra emitting blue (450 nm), green (525 nm), red (660 nm), and far-red (730 nm) light. After three months of incubation, morphological changes in embryogenic calli were recorded, and LC-MS/MS analysis of cultures was carried out for peimisine, sipeimine, peiminine, and peimine. The highest number of somatic embryos and the maximum fresh weight was recorded in calli incubated under red (9R), infrared (9IR), and a combination of red+blue+infrared (3R3B3IR), respectively, in decreasing order. The highest contents of peimisine, peiminine, and peimine were recorded under red (9R) and infrared (9IR) lights, respectively. Eight LED lights had significant effects on the morphogenesis of embryogenic calli of F. cirrhosa D. Don and contents of isosteroidal alkaloids.
Swiss University Students’ Risk Perception and General Anxiety during the COVID-19 Pandemic

University students were confronted with abrupt changes to their daily lives by the COVID-19 lock-down. We investigated Generalized Anxiety Disorder Scale-7 (GAD-7) and anxiety levels, and the association between perceived impact on well-being, studies, and daily lives and anxiety levels, adjusted for gender, age, social class and affiliation. Early in the lock-down all students of the Zurich University of Applied Sciences (N = 12,429) were invited to a voluntary longitudinal health survey. Participation rate was 20% (n = 2437): 70% females, median age 25 yrs. (IQR 23–28). A total of 10% reported a deterioration of well-being compared to pre-Corona. LCA yielded three classes varying in perceived COVID-19 impact: 1 (low, n = 675), 2 (moderate, n = 1098), and 3 (strong, n = 656). Adjusted proportion of moderate to severe anxiety by class were 45% (95% CI: 28.0–62.0), 15.5% (95% CI: 13.1–17.9), and 5.1% (95% CI: 4.7–5.6), respectively. Multivariate regression analyses yielded an OR for moderate to severe anxiety of 3.88 (95% CI: 2.5–6.0, class 2) and 22.43 (95% CI: 14.5–34.6, class 3) compared to class-1. The investigated association implies that containment measures have a selective effect on anxiety in students. The diversity of students’ perception and associated anxiety should be monitored and considered in future response to pandemics.
Investigation of Age-Related Changes in the Skin Microbiota of Korean Women

The microbiota of human skin is influenced by host and environmental factors. To determine if chronological age influences the composition of the skin microbiota on the forehead and hands, 73 Korean women were sorted into one of three age groups: (1) 10–29 years (n = 24), (2) 30–49 years (n = 21), and (3) 50–79 years (n = 28). From the 73 women, 146 skin samples (two skin sites per person) were collected. 16S rRNA gene amplicon sequencing was then conducted to analyze the skin microbiota. The overall microbial distribution varied on the forehead but was similar on the hands across the three age groups. In addition, the composition of the skin microbiota differed between the forehead and hands. Commensal microbiota, such as Streptococcus, Staphylococcus, Cutibacterium, and Corynebacterium, which contribute to maintaining skin health via dominant occupation, were affected by increasing age on forehead and hand skin. Alpha diversity indices increased significantly with age on forehead skin. This study indicates that older people may be more susceptible to pathogenic invasions due to an imbalanced skin microbiota resulting from age-related changes. The results of our study may help develop new strategies to rebalance skin microbiota shifted during aging.
Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions

Background Natural killer (NK) cells play a crucial role in tumor immunosurveillance through their cytotoxic effector functions and their capacity to interact with other immune cells to build a coordinated antitumor immune response. Emerging data reveal NK cell dysfunction within the tumor microenvironment (TME) through checkpoint inhibitory molecules associated with a regulatory phenotype. Objective We aimed at analyzing the gene expression profile of intratumoral NK cells compared with non-tumorous NK cells, and to characterize their inhibitory function in the TME. Methods NK cells were sorted from human lung tumor tissue and compared with non- tumoral distant lungs. Results In the current study, we identify a unique gene signature of NK cell dysfunction in human non-small cell lung carcinoma (NSCLC). First, transcriptomic analysis reveals significant changes related to migratory pattern with a downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) and CX3C chemokine receptor 1 (CX3CR1) and overexpression of C-X-C chemokine receptor type 5 (CXCR5) and C-X-C chemokine receptor type 6 (CXCR6). Second, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and killer cell lectin like receptor (KLRC1) inhibitory molecules were increased in intratumoral NK cells, and CTLA-4 blockade could partially restore MHC class II level on dendritic cell (DC) that was impaired during the DCs/NK cell cross talk. Finally, NK cell density impacts the positive prognostic value of CD8+ T cells in NSCLC. Conclusions These findings demonstrate novel molecular cues associated with NK cell inhibitory functions in NSCLC.
Effectiveness of Non-Pharmacological Interventions for Overweight or Obese Infertile Women: A Systematic Review and Meta-Analysis

Obesity is a well-known risk factor for infertility, and nonpharmacological treatments are recommended as effective and safe, but evidence is still lacking on whether nonpharmacological interventions improve fertility in overweight or obese women. The aim of this study was to systematically assess the current evidence in the literature and to evaluate the impact of nonpharmacological interventions on improving pregnancy-related outcomes in overweight or obese infertile women. Seven databases were searched for randomized controlled trials (RCTs) of nonpharmacological interventions for infertile women with overweight or obesity through August 16, 2019 with no language restriction. A meta-analysis was conducted of the primary outcomes. A total of 21 RCTs were selected and systematically reviewed. Compared to the control group, nonpharmacological interventions significantly increased the pregnancy rate (relative risk (RR), 1.37; 95% CI, 1.04–1.81; p = 0.03; I2 = 58%; nine RCTs) and the natural conception rate (RR, 2.17, 95% CI, 1.41–3.34; p = 0.0004; I2 = 19%, five RCTs). However, they had no significant effect on the live birth rate (RR, 1.36, 95% CI, 0.94–1.95; p=0.10, I2 = 65%, eight RCTs) and increased the risk of miscarriage (RR: 1.57, 95% CI, 1.05–2.36; p = 0.03; I2 = 0%). Therefore, nonpharmacological interventions could have a positive effect on the pregnancy and natural conception rates, whereas it is unclear whether they improve the live birth rate. Further research is needed to demonstrate the integrated effects of nonpharmacological interventions involving psychological outcomes, as well as pregnancy-related outcomes.
NESTS OF NORTHERN SPOTTED OWLS ON THE OLYMPIC PENINSULA, WASHINGTON

We located 155 nests in 82 territories occupied by Northern Spotted Owls (Strix occidentalis caurina) on the Olympic Peninsula, Washington. All nests were in trees. Of 1 16 nests that were measured, 105 were in cavities and I I were in external platforms on tree limbs. Cavity nests were typically in large holes in the side of the trunk or in the broken top of the trunk. Aspect of cavity entrances was non-random, with the majority of cavities facing east-north-east. Location of nest trees did not differ from expected values for slope aspect or position on slope. Proportions of nest sites in different percent slope categories differed from availability, with more nests than expected in the higher percent slope categories. Nests usually were in stands with high overall canopy closure (2 70%), but canopy closure in the immediate vicinity of the nest varied from 35-90%. Most nests (87%) were in multilayered stands dominated by large trees. Nests in younger stands were typically in stands where remnant old trees were present. Owls changed nests between successive nesting events in 80% of all cases. Changes in pair members on a territory did not influence the frequency with which pairs switched to a new nest tree in the next nesting year. Based on observed rates of attrition, the expected life span of nests was 120 years. Received 23 Jan. 1996, accepted 23 Aug. 1996.
Subspecific differentiation in male reproductive traits

Many species display local variations in pre-mating signals and in mating preferences. This may lead to discriminationagainstpotentialforeignmatesthatmayultimatelyleadtoreproductiveisolation.However,theextent to which population differentiation in mating cues affects the species recognition has received little empirical support. Here, we investigate the consequence of geographic differentiation in male reproductive traits on female preferences to these traits in Bombus terrestris. We characterise (1) the geographic differentiation in male cephalic labial gland secretions (CLGS), a key trait for mate attraction, and (2) the preference of virgin females to the CLGS of different subspecies. Our results show geographic CLGS differences parallel with divergences in female preferences for these secretions. This geographic CLGS differentiation in males, along with female preference for sympatric males, could lead to or reflect a pre-mating isolation among subspecies.