Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations.

Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.

Final analysis of 379 pregnancy outcomes after exposure to dimethyl fumarate in a prospective international registry.

BACKGROUND: Dimethyl fumarate (DMF) has a favorable benefit-risk profile treating people with multiple sclerosis and should be used in pregnant women only if the potential benefits outweigh potential risks to the fetus. OBJECTIVE: Assess pregnancy outcomes in a completed international registry (TecGistry) of women with MS exposed to DMF. METHODS: TecGistry included pregnant women with MS exposed to DMF, with data collected at enrollment, 6-7 months gestation, 4 weeks after estimated due date, and at postpartum weeks 4, 12, and 52. Outcomes included live births, gestational size, pregnancy loss, ectopic/molar pregnancies, birth defects, and infant/maternal death. RESULTS: Of 397 enrolled, median (range) age was 32 years (19-43). Median (range) gestational week at enrollment was 10 (0-39) and at first DMF exposure was 1 (0-13). Median (range) duration of gestational DMF exposure was 5 weeks (0-40). Fifteen (3.8%) spontaneous abortions occurred. Of 360 (89.1%) live births, 323 were full term and 37 were premature. One neonatal death and no maternal deaths occurred. Adjudicator-confirmed EUROCAT birth defects were found in 2.2%. CONCLUSION: DMF exposure during pregnancy did not adversely affect pregnancy outcomes; birth defects, preterm birth, and spontaneous abortion were in line with rates from the general population.

Ecological characteristics of sugar beet plant and rhizosphere soil in response to high boron stress: A study of the remediation potential.

High boron (B) stress degrades the soil environment and reduces plant productivity. Sugar beet has a high B demand and potential for remediation of B-toxic soils. However, the mechanism regarding the response of sugar beet plants and rhizosphere soil microbiome to high B stress is not clear. In the potted soil experiment, we set different soil effective B environments (0.5, 5, 10, 30, 50, and 100 mg kg-1) to study the growth status of sugar beets under different B concentrations, as well as the characteristics of soil enzyme activity and microbial community changes. The results showed that sugar beet growth was optimal at 5 mg kg-1 of B. Exceeding this concentration the tolerance index decreased. The injury threshold EC20 was reached at an available B concentration of 35.8 mg kg-1. Under the treatment of 100 mg kg-1, the B accumulation of sugar beet reached 0.22 mg plant-1, and the tolerance index was still higher than 60%, which had not yet reached the lethal concentration of sugar beet. The abundance of Acidobacteriota, Chloroflexi and Patescibacteria increased, which was beneficial to the resistance of sugar beet to high B stress. In summary, under high B stress sugar beet had strong tolerance, enhanced capacity for B uptake and enrichment, and changes in soil microbial community structure. This study provides a theoretical basis for clarifying the mechanism of sugar beet resistance to high B stress and soil remediation.

Research on phytotoxicity assessment and photosynthetic characteristics of nicosulfuron residues on Beta vulgaris L.

Nicosulfuron is a common herbicide used to control weeds in maize fields. In northeast China, sugar beet is often grown as a subsequent crop after maize, and its frequently suffers from soil nicosulfuron residue damage, but the related toxicity evaluation and photosynthetic physiological mechanisms are not clear. Therefore, we experimented to evaluate the impacts of nicosulfuron residues on beet growth, photochemical properties, and antioxidant defense system. The results showed that when the nicosulfuron residue content reached 0.3 µg kg-1, it inhibited the growth of sugar beet. When it reached 36 µg kg-1 (GR50), the growth stagnated. Compared to the control group, a nicosulfuron residue of 36 µg kg-1 significantly decreased beet plant height (70.93 %), leaf area (91.85 %), dry weights of shoot (70.34 %) and root (32.70 %). It also notably reduced the potential photochemical activity (Fv/Fo) by 12.41 %, the light energy absorption performance index (PIabs) by 46.09 %, and light energy absorption (ABS/CSm) by 6.56 %. It decreased the capture (TRo/CSm) by 9.30 % and transferred energy (ETo/CSm) by 16.13 % per unit leaf cross-section while increasing the energy flux of heat dissipation (DIo/CSm) by 22.85 %. This ultimately impaired the photochemical capabilities of PSI and PSII, leading to a reduction in photosynthetic performance. Furthermore, nicosulfuron increased malondialdehyde (MDA) content while decreasing superoxide dismutase (SOD) and catalase (CAT) activities. In conclusion, this research clarified the toxicity risk level, lethal dose, and harm mechanism of the herbicide nicosulfuron residue. It provides a theoretical foundation for the rational use of herbicides in agricultural production and sugar beet planting management.

Initial indicators for the prognosis of Acinetobacter Baumannii bacteremia in children.

BACKGROUND: Risk factors related to mortality due to Acinetobacter baumannii (AB) bacteremia have been unveiled previously, but early clinical manifestations of AB bacteremia based on prognosis remain uncovered. METHODS: The demographic characteristics, clinical features, antibiotic susceptibility, and outcomes of 37 hospitalized children with laboratory-confirmed AB bacteremia from Suzhou, China, were collected and analyzed retrospectively. RESULTS: Of the 37 children with AB bacteremia included in this study, 23 were males and 14 were females, with a median age of 4.83 (0.60 to 10.15) years. Among the children, 18 died (48.65%, 18/37) and 19 survived (51.35%, 19/37). The dead group had a significantly higher incidence of respiratory failure (p = 0.008), shock (P = 0.000), MODS (p = 0.000), neutropenia (< 1.5 × 109/L) (p = 0.000) and serious neutropenia (< 0.5 × 109/L) (p = 0.000) than those in the survival group. The death group had significantly more invasive procedures (2 or more) than that in the survival group at 2 weeks before onset (p = 0.005). The proportion of MDR-AB in the death group was significantly higher than that in the survival group (p = 0.000), while the PICS score was significantly lower in the survival group than that in the death group (p = 0.000). There was no significant difference in effective antibiotic use within 24 h between these two groups (p = 0.295). Among the 37 children with bloodstream infection of AB, 56.76% (21/37) of the underlying diseases were hematological diseases and oncology. Among them, 17 (81.00%) were died in the hospital. The proportion of white blood cells (p = 0.000), neutrophils (p = 0.042), eosinophils (p = 0.029), the ANC (p = 0.000) and lymphocyte (p = 0.000), the NLR(p = 0.011), hemoglobin (p = 0.001), platelets (p = 0.000), prealbumin (P = 0.000), LDH (p = 0.017), blood gas pH (p = 0.000), and serum potassium (p = 0.002) in the death group were significantly lower than those in the survival group. However, CRP (p = 0.000) and blood glucose(p = 0.036) were significantly higher in the death group than those in the survival group. By further multivariate analysis, CRP [OR (95% CI): 1.022(1.003, 1.041), p = 0.021] and neutropenia [OR (95% CI): 21.634 (2.05, 228.313, p = 0.011] within 24 h of infection were independent risk factors for death in children with AB bacteremia. When CRP was higher than 59.02 mg/L, the sensitivity of predicting mortality was 88.9%, and the specificity was 78.9%. And the sensitivity and specificity of neutropenia for predicting mortality were 83.3% and 84.2%. CONCLUSIONS: AB bacteremia has a high mortality in children, especially in patients with hematological diseases and oncology. Many early indicators were associated with poor prognosis, while elevated CRP and neutropenia were the independent predictors for the 30-day mortality of children with laboratory-confirmed AB bacteremia.

Rate of neuropathic progression in hereditary transthyretin amyloidosis with polyneuropathy and other peripheral neuropathies: a systematic review and meta-analysis.

BACKGROUND: We aimed to compare neuropathic progression rate between hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and other peripheral neuropathies, including diabetic peripheral neuropathy (DPN) and Charcot-Marie-Tooth disease (CMT). METHODS: Literature searches identified studies reporting neuropathic progression, measured by Neuropathy Impairment Score (NIS) or NIS-Lower Limbs (NIS-LL). Our study also included unpublished data from a clinical registry of patients who were diagnosed with different peripheral neuropathies and seen at the Oregon Health & Science University (OHSU) during 2016-2020. Meta-analysis and meta-regression models examined and compared annual progression rates, calculated from extracted data, between studies of ATTRv-PN and other peripheral neuropathies. RESULTS: Data were synthesized from 15 studies in which NIS and/or NIS-LL total scores were assessed at least twice, with ≥12 weeks between assessments, among untreated patients with ATTRv-PN or other peripheral neuropathies. Meta-analysis models yielded that the annual progression rate in NIS total scores was significantly different from zero for studies in ATTRv-PN and CMT (11.77 and 1.41; both P < 0.001), but not DPN (- 1.96; P = 0.147). Meta-regression models showed significantly faster annual progression in studies in ATTRv-PN, which statistically exceeded that in other peripheral neuropathies by 12.45 points/year for NIS, and 6.96 for NIS-LL (both P < 0.001). CONCLUSIONS: Peripheral nervous function deteriorates more rapidly in patients with ATTRv-PN than for other peripheral neuropathies. These findings may improve understanding of the natural history of neuropathy in ATTRv-PN, facilitate early diagnosis, and guide the development of assessment tools and therapies specifically targeting neuropathic progression in this debilitating disease.

Exome Array Analysis of Early-Onset Ischemic Stroke.

BACKGROUND AND PURPOSE: The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease. METHODS: Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases. RESULTS: Gene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79×10-6). Pathway analysis of the top 517 genes (P<0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (P<2.05×10-7), several were near, including an intronic variant in LEXM (rs7549251; P=4.08×10-7) and an exonic variant in TRAPPC11 (rs67383011; P=5.19×10-6). CONCLUSIONS: Exome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.

The relationship between frequency and severity of vaso-occlusive crises and health-related quality of life and work productivity in adults with sickle cell disease.

PURPOSE: Patients with sickle cell disease (SCD) may experience sickle cell-related pain crises, also referred to as vaso-occlusive crises (VOCs), which are a substantial cause of morbidity and mortality. The study explored how VOC frequency and severity impacts health-related quality of life (HRQoL) and work productivity. METHODS: Three hundred and three adults with SCD who completed an online survey were included in the analysis. Patients answered questions regarding their experience with SCD and VOCs, and completed the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) and the Workplace Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP). Differences in ASCQ-Me and WPAI:SHP domains were assessed according to VOC frequency and severity. RESULTS: Nearly half of the patient sample (47.2%) experienced ≥ 4 VOCs in the past 12 months. The most commonly reported barriers to receiving care for SCD included discrimination by or trouble trusting healthcare professionals (39.6%, 33.3%, respectively), limited access to treatment centers (38.9%), and difficulty affording services (29.4%). Patients with more frequent VOCs reported greater impacts on emotion, social functioning, stiffness, sleep and pain, and greater absenteeism, overall productivity loss, and activity impairment than patients with less frequent VOCs (P < 0.05). Significant impacts on HRQoL and work productivity were also observed when stratifying by VOC severity (P < 0.05 for all ASCQ-Me and WPAI domains, except for presenteeism). CONCLUSIONS: Results from the survey indicated that patients with SCD who had more frequent or severe VOCs experienced deficits in multiple domains of HRQoL and work productivity. Future research should examine the longitudinal relationship between these outcomes.

Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development.

The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprinα1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95. Whereas Cdk5 phosphorylates liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 phosphorylation by a small interfering peptide, siLIP, promotes the synaptic localization of PSD-95 and enhances synaptic strength in vivo. Our findings collectively demonstrate that the Cdk5-dependent phosphorylation of liprinα1 is important for the postsynaptic organization during activity-dependent synapse development.

Immune and cytokine/chemokine responses of PBMCs in rotavirus-infected rhesus infants and their significance in viral pathogenesis.

The rotavirus (RV) is the most important causative agent of severe gastroenteritis in infants and children aged less than 5 years worldwide. However, the response and the roles of peripheral blood mononuclear cell (PBMC) in RV clearance have yet to be fully elucidated. In this study, we established the neonatal rhesus monkey model of RV infection with histopathological changes in the small intestine. Then, we investigated gene expression changes in PBMCs from the monkey model of RV infection. Similar pathways regulated in rhesus monkeys that received intragastric administration of the RV monkey SA11 strain (G3P[2]) and the human wild-type strain ZTR-68 (G1P[8]). Gene profiling showed differences in functional genes mainly associated with chemokine signaling pathways and cytokine-cytokine receptor interactions post RV infection. Transferrin and C-C motif chemokine ligand 23 (CCL23) gene expression were upregulated in PBMCs of monkeys when stimulated by simian and human RV strains. Monkeys infected with RV had an enhanced and prolonged inflammatory response that was associated with increased levels of CCL20, CCL23, and C-X-C motif chemokine ligand 1; while inhibition of major histocompatibility complex class I expression may be important for immune evasion by RV. The RV infection was also characterized by pathological changes in the small intestine with a cytokine and chemokine storm. This study identified the chemokine signaling pathway and immune response genes involved in RV infection in infant rhesus monkeys. The SA11 RV strain is more suitable for establishing a monkey diarrhea model than the ZTR-68 RV strain.

Aerial Cooperative Jamming for Cellular-Enabled UAV Secure Communication Network: Joint Trajectory and Power Control Design.

To improve the secrecy performance of cellular-enabled unmanned aerial vehicle (UAV) communication networks, this paper proposes an aerial cooperative jamming scheme and studies its optimal design to achieve the maximum average secrecy rate. Specifically, a base station (BS) transmits confidential messages to a UAV and meanwhile another UAV performs the role of an aerial jammer by cooperatively sending jamming signals to oppose multiple suspicious eavesdroppers on the ground. As the UAVs have the advantage of the controllable mobility, the objective is to maximize the worst-case average secrecy rate by the joint optimization of the two UAVs' trajectories and the BS's/UAV jammer's transmit/jamming power over a given mission period. The objective function of the formulated problem is highly non-linear regarding the optimization variables and the problem has non-convex constraints, which is, in general, difficult to achieve a globally optimal solution. Thus, we divide the original problem into four subproblems and then solve them by applying the successive convex approximation (SCA) and block coordinate descent (BCD) methods. Numerical results demonstrate that the significantly better secrecy performance can be obtained by using the proposed algorithm in comparison with benchmark schemes.

Characterization of a novel EB1 acetylation site important for the regulation of microtubule dynamics and cargo recruitment.

Microtubule plus ends undergo highly dynamic modifications to regulate different aspects of cellular activities. Most microtubule plus-end tracking proteins (+TIPs) are recruited to the microtubule ends by the master loading factor, end-binding protein 1 (EB1). These proteins coordinately regulate microtubule dynamics and cellular plasticity. Acetylation is known to modulate EB1 function; however, the molecular details of EB1 acetylation remain largely unclear. We mapped the acetylation pattern of EB1 and identified several previously uncharacterized sites of EB1 acetylation. We examined the effects of lysine-212 (K212) acetylation and found that acetylation of this site accelerates autophagy-mediated EB1 degradation. By time-lapse microscopy, we found that the acetylation-deficient K212R mutant increased the percentage of fast-growing and long-lived microtubules. Although K212 acetylation did not affect microtubule stability in vitro and the association of EB1 with microtubules, the K212R mutant significantly promoted microtubule regrowth in cells. Coimmunoprecipitation assays further revealed that the K212 site was critical for the recruitment of different +TIP cargoes. These data thus uncover a critical role for a novel EB1 acetylation site in regulating the dynamic structure of microtubules.

Rotavirus-encoded virus-like small RNA triggers autophagy by targeting IGF1R via the PI3K/Akt/mTOR pathway.

Rotaviruses are double-stranded RNA viruses that are a major cause of viral diarrhea in infants. Examining virus-host cell interaction is important for elucidating mechanisms of virus proliferation in host cells. Viruses can create an environment that promotes their survival and self-proliferation by encoding miRNAs or miRNA-like molecules that target various host cell. However, it remains unclear whether RNA viruses encode viral miRNAs, and their regulation mechanisms are largely unknown. We previously performed deep sequencing analysis to investigate rotavirus-encoded miRNAs, and identified the small RNA molecule Chr17_1755, which we named RV-vsRNA1755. In our present study, we determined that RV-vsRNA1755 is encoded by the rotavirus NSP4 gene and that it targets the host cell IGF1R, which is part of the PI3K/Akt pathway. We further explored the biological characteristics and functions of RV-vsRNA1755.Our results suggest that rotavirus adapts to manipulate PI3K/Akt signaling at early phases of infection. RV-vsRNA1755 targets IGF1R, blockading the PI3K/Akt pathway and triggering autophagy, but it ultimately inhibits autophagy maturation. A mechanism through which rotavirus encodes a virus-like small RNA (RV-vsRNA1755) that triggers autophagy by targeting the host cell IGF1R gene was revealed. These data provide a theoretical basis for therapeutic drug screening targeting RV-vsRNA1755.

The butyrophilin 3A1 intracellular domain undergoes a conformational change involving the juxtamembrane region.

Small isoprenoid diphosphates, such as (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), are ligands of the internal domain of BTN3A1. Ligand binding in target cells promotes activation of Vγ9Vδ2 T cells. We demonstrate by small-angle X-ray scattering (SAXS) that HMBPP binding to the internal domain of BTN3A1 induces a conformational change in the position of the B30.2 domain relative to the juxtamembrane (JM) region. To better understand the molecular details of this conformational rearrangement, NMR spectroscopy was used to discover that the JM region interacts with HMBPP, specifically at the diphosphate. The spectral location of the affected amide peaks, partial NMR assignments, and JM mutants (ST296AA or T304A) investigated, confirm that the backbone amide of at least one Thr (Thr304), adjacent to conserved Ser, comes close to the HMBPP diphosphate, whereas double mutation of nonconserved residues (Ser/Thr296/297) may perturb the local fold. Cellular mutation of either of the identified Thr residues reduces the activation of Vγ9Vδ2 T cells by HMBPP, zoledronate, and POM2-C-HMBP, but not by a partial agonist BTN3 antibody. Taken together, our results show that ligand binding to BTN3A1 induces a conformational change within the intracellular domain that involves the JM region and is required for full activation.-Nguyen, K., Li, J., Puthenveetil, R., Lin, X., Poe, M. M., Hsiao, C.-H. C., Vinogradova, O., Wiemer, A. J. The butyrophilin 3A1 intracellular domain undergoes a conformational change involving the juxtamembrane region.

The Epstein-Barr Virus BART miRNA Cluster of the M81 Strain Modulates Multiple Functions in Primary B Cells.

The Epstein-Barr virus (EBV) is a B lymphotropic virus that infects the majority of the human population. All EBV strains transform B lymphocytes, but some strains, such as M81, also induce spontaneous virus replication. EBV encodes 22 microRNAs (miRNAs) that form a cluster within the BART region of the virus and have been previously been found to stimulate tumor cell growth. Here we describe their functions in B cells infected by M81. We found that the BART miRNAs are downregulated in replicating cells, and that exposure of B cells in vitro or in vivo in humanized mice to a BART miRNA knockout virus resulted in an increased proportion of spontaneously replicating cells, relative to wild type virus. The BART miRNAs subcluster 1, and to a lesser extent subcluster 2, prevented expression of BZLF1, the key protein for initiation of lytic replication. Thus, multiple BART miRNAs cooperate to repress lytic replication. The BART miRNAs also downregulated pro- and anti-apoptotic mediators such as caspase 3 and LMP1, and their deletion did not sensitize B-cells to apoptosis. To the contrary, the majority of humanized mice infected with the BART miRNA knockout mutant developed tumors more rapidly, probably due to enhanced LMP1 expression, although deletion of the BART miRNAs did not modify the virus transforming abilities in vitro. This ability to slow cell growth could be confirmed in non-humanized immunocompromized mice. Injection of resting B cells exposed to a virus that lacks the BART miRNAs resulted in accelerated tumor growth, relative to wild type controls. Therefore, we found that the M81 BART miRNAs do not enhance B-cell tumorigenesis but rather repress it. The repressive effects of the BART miRNAs on potentially pathogenic viral functions in infected B cells are likely to facilitate long-term persistence of the virus in the infected host.

The Genetics of Physical Activity.

PURPOSE OF REVIEW: Physical activity (PA) is a well-established modifiable lifestyle determinant for multiple cardio-metabolic outcomes. While many psychosocial and environmental correlates of PA have been identified, current understanding of the genetic architecture that contributes to PA is still very limited, especially when compared to other phenotypes such as obesity and diabetes. RECENT FINDINGS: This review systematically and comprehensively assesses available evidence from animal experiments, family studies, population-based candidate gene analyses, and genome-wide association studies (GWAS) studying the genetics of physical activity patterns. It discusses the scientific evolution in the field of PA genetics, including the recognition of increased sample sizes, the shift from early family-based approaches to association-based design, and the rapidly advancement of enabling genotyping and sequencing technologies. In addition, this review points to the gaps in the current knowledge base, including the general lack of GWAS and whole-genome sequence analyses particularly understudied populations, and the need for large-scale collaborative effort in both observational and experimental settings. In this review, we also call for research utilizing systems biology strategies for PA genetic research and accounting for complex gene-environment interactions that may vary by race/ethnicity. The epidemic of physical inactivity has been a public health nemesis, encompassing a large burden of diseases and high societal costs. A better understanding of the genetic basis of PA can inform public health policies for the prevention, control, and treatment of many chronic diseases related to physical inactivity.

FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

Cocoa Flavanol Intake and Biomarkers for Cardiometabolic Health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Cocoa flavanols may improve cardiometabolic health. Evidence from small short-term randomized clinical trials (RCTs) remains inconsistent, and large long-term RCTs testing the efficacy of cocoa flavanols are still lacking. OBJECTIVE: We performed a systematic review and meta-analysis of RCTs to quantify the effect of cocoa flavanol intake on cardiometabolic biomarkers. METHODS: We searched PubMed, Web of Science, and the Cochrane Library for RCTs that evaluated the effects of cocoa flavanols on biomarkers relevant to vascular disease pathways among adults. Data were extracted following a standardized protocol. We used DerSimonian and Laird random-effect models to compute the weighted mean differences (WMDs) and 95% CIs. We also examined potential modification by intervention duration, design, age, sex, comorbidities, and the form and amount of cocoa flavanol intake. RESULTS: We included 19 RCTs that comprised 1131 participants, and the number of studies for a specific biomarker varied. The amount of cocoa flavanols ranged from 166 to 2110 mg/d, and intervention duration ranged from 2 to 52 wk. Cocoa flavanol intake significantly improved insulin sensitivity and lipid profile. The WMDs between treatment and placebo were -0.10 mmol/L (95% CI: -0.16, -0.04 mmol/L) for total triglycerides, 0.06 mmol/L (95% CI: 0.02, 0.09 mmol/L) for HDL cholesterol, -2.33 µIU/mL (95% CI: -3.47, -1.19 µIU/mL) for fasting insulin, -0.93 (95% CI: -1.31, -0.55) for the homeostatic model assessment of insulin resistance, 0.03 (95% CI: 0.01, 0.05) for the quantitative insulin sensitivity check index, 2.54 (95% CI: 0.63, 4.44) for the insulin sensitivity index, -0.83 mg/dL (95% CI: -0.88, -0.77 mg/dL) for C-reactive protein, and 85.6 ng/mL (95% CI: 16.0, 155 ng/mL) for vascular cell adhesion molecule 1. No significant associations were found for other biomarkers. None of the modifiers seemed to qualitatively modify the effects of cocoa flavanol intake. CONCLUSIONS: Our study suggests that cocoa flavanol intake has favorable effects on select cardiometabolic biomarkers among adults. These findings support the need for large long-term RCTs to assess whether cocoa flavanol intake reduces the risk of diabetes and cardiovascular events.

Skelemin association with αIIbß3 integrin: a structural model.

Over the last two decades, our knowledge concerning intracellular events that regulate integrin's affinity to their soluble ligands has significantly improved. However, the mechanism of adhesion-induced integrin clustering and development of focal complexes, which could further mature to form focal adhesions, still remains under-investigated. Here we present a structural model of tandem IgC2 domains of skelemin in complex with the cytoplasmic tails of integrin αIIbß3. The model of tertiary assembly is generated based upon NMR data and illuminates a potential link between the essential cell adhesion receptors and myosin filaments. This connection may serve as a basis for generating the mechanical forces necessary for cell migration and remodeling.

Meaningful score changes for SF-36v2, FACIT-fatigue, and RASIQ in rheumatoid arthritis.

BACKGROUND: Interpretation thresholds for patient-reported outcome (PRO) scores are of crucial importance, particularly when interpreting treatment benefit. This study was designed to determine the within-patient meaningful improvement (WPMI) thresholds for the Short-Form 36 Health Survey version 2 (SF-36v2), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and the novel Rheumatoid Arthritis Symptoms and Impact Questionnaire (RASIQ) among patients with rheumatoid arthritis (RA). METHODS: In this post-hoc analysis, anchor-based and supportive distribution-based methods were used to derive WPMI based on blinded data from all treatment arms in two Phase 2 RA trials with otilimab. Patient's Global Assessment of Disease Activity (PtGA) was the general anchor for all SF-36v2 scales. SF-36 Patient's Global Impression of Status (PGIS), PtGA, and VT03 (an SF-36v2 item) were used as anchors for FACIT-Fatigue. SF-36 PGIS, PtGA, and Patient's Assessment of Arthritis Pain (PAIN) were anchors for RASIQ. Mean change was calculated for the anchor category associated with minimal meaningful improvement from baseline to Week 24 for SF-36v2 and FACIT-Fatigue, and to Week 12 for RASIQ. Sensitivity and specificity were used to evaluate the accuracy of estimated WPMI values. RESULTS: For the SF-36v2 physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health domains, anchor-based estimates of WPMI based on 0-100 scores were 24.5, 24.5, 25.4, 13.6, 21.5, 20.5, 16.9, and 14.3, respectively. Anchor-based WPMI estimates were 9.7 for the Physical Component Summary score and 7.6 for the Mental Component Summary score (using norm-based T-score metric). For FACIT-Fatigue (range 0-52), WPMI estimates ranged from 9.7 to 11.3 points. For RASIQ (range 0-100), anchor-based WPMI was determined as a change between -32.7 and -21.7 points for the Joint Pain scale, -26.7 to -23.7 for the Joint Stiffness scale, and -21.1 to -17.4 for the Impact scale. CONCLUSIONS: This study derived WPMI thresholds for SF-36v2, FACIT-Fatigue, and RASIQ among patients with RA, using multiple anchors. Derivation of WPMI thresholds for these PRO instruments will enable their broader use in evaluating and interpreting treatment benefit in future RA studies.

When assessing medical treatments in clinical trials, it is important to understand whether the treatment improves symptoms or impacts of a disease to an extent which is meaningful for patients. Patients are often asked to complete questionnaires about their symptoms throughout clinical trials to measure if and how symptoms change. Questionnaire responses are used to calculate a score that is compared before and after treatment. This study was designed to investigate how much scores in three questionnaires (SF-36v2, FACIT-Fatigue, and RASIQ) changed for patients with rheumatoid arthritis who reported experiencing meaningful symptom improvement based on data from two clinical trials. As the RASIQ is a new questionnaire that was designed specifically for rheumatoid arthritis, this research is particularly important for interpretation of RASIQ results.