Modulations of ocean-atmosphere interactions on squid abundance over Southwest Atlantic.

Anthropogenic shifts in seas are reshaping fishing trends, with significant implications for aquatic food sources throughout this century. Examining a 21-year abundance dataset of Argentine shortfin squids Illex argentinus paired with a regional oceanic analysis, we noted strong correlations between squid annual abundance and sea surface temperature (SST) in January and February and eddy kinetic energy (EKE) from March to May in the Southwest Atlantic. A deeper analysis revealed combined ocean-atmosphere interactions, pinpointed as the primary mode in a rotated empirical orthogonal function analysis of SST. This pattern produced colder SST and amplified EKE in the surrounding seas, factors crucial for the unique life stages of squids. Future projections from the CMIP6 archive indicated that this ocean-atmosphere pattern, referred to as the Atlantic symmetric pattern, would persist in its cold SST phase, promoting increased squid abundance. However, rising SSTs due to global warming might counteract the abundance gains. Our findings uncover a previously unrecognized link between squids and specific environmental conditions governed by broader ocean-atmosphere interactions in the Southwest Atlantic. Integrating these insights with seasonal and decadal projections can offer invaluable information to stakeholders in squid fisheries and marine conservation under a changing climate.

How different face mask types affect interpersonal distance perception and threat feeling in social interaction.

Due to the easing of the pandemic, public policies no longer mandated people to wear masks. People can choose to no wear or wear different types of masks based on personal preferences and safety perceptions during daily interaction. Available information about the influence of face mask type on interpersonal distance (IPD) by different aging populations is still lacking. Thus, this study aimed to investigate the face mask type (no wear, cloth, medical and N95 mask) and age group effect of avatars (children, adults and older adults) on IPD perception, threat feeling and physiological skin conductance response under active and passive approaching. One hundred participants with a range from 20 to 35 years old were recruited for this study. Twelve avatars (three age groups*four face mask conditions) were created and applied in a virtual reality environment. The results showed that age group, mask type and approach mode had significant effects on IPD and subjective threat feeling. A non-significant effect was found on skin conductance responses. Participants maintained a significantly longer IPD when facing the older adults, followed by adults and then children. In the passive approach condition, people tended to maintain a significantly greater comfort distance than during the active approach. For the mask type effect, people kept a significantly largest and shortest IPD when facing an avatar with no mask or the N95 mask, respectively. A non-significant IPD difference was found between the N95 and medical mask. Additionally, based on the subjective threat feeling, facing an avatar wearing a medical mask generated the lowest threat feeling compared to the others. The findings of this study indicated that wearing medical masks provided a benefit in bringing people closer for interaction during specific situations. Understanding that mask-wearing, especially medical one, brought to shortest IPD when compared to the unmasked condition can be utilized to enhance safety measures in crowded public spaces and health-care settings. This information could guide the development of physical distancing recommendations, taking into account both the type of mask and the age groups involved, to ensure the maintenance of appropriate distances.

Correction: First-principles modeling of the highly dynamical surface structure of a MoS2 catalyst with S-vacancies.

Correction for 'First-principles modeling of the highly dynamical surface structure of a MoS2 catalyst with S-vacancies' by Po-Yuan Wang et al., Phys. Chem. Chem. Phys., 2022, 24, 24166-24172, https://doi.org/10.1039/D2CP03384D.

Intratumoral delivery of TransCon™ TLR7/8 Agonist promotes sustained anti-tumor activity and local immune cell activation while minimizing systemic cytokine induction.

BACKGROUND: Intratumoral (IT) delivery of toll-like receptor (TLR) agonists has shown encouraging anti-tumor benefit in preclinical and early clinical studies. However, IT delivery of TLR agonists may lead to rapid effusion from the tumor microenvironment (TME), potentially limiting the duration of local inflammation and increasing the risk of systemic adverse events. METHODS: To address these limitations, TransCon™ TLR7/8 Agonist-an investigational sustained-release prodrug of resiquimod that uses a TransCon linker and hydrogel technology to achieve sustained and predictable IT release of resiquimod-was developed. TransCon TLR7/8 Agonist was characterized for resiquimod release in vitro and in vivo, in mice and rats, and was assessed for anti-tumor efficacy and pharmacodynamic activity in mice. RESULTS: Following a single IT dose, TransCon TLR7/8 Agonist mediated potent tumor growth inhibition which was associated with sustained resiquimod release over several weeks with minimal induction of systemic cytokines. TransCon TLR7/8 Agonist monotherapy promoted activation of antigen-presenting cells in the TME and tumor-draining lymph nodes, with evidence of activation and expansion of CD8+ T cells in the tumor-draining lymph node and TME. Combination of TransCon TLR7/8 Agonist with systemic immunotherapy further promoted anti-tumor activity in TransCon TLR7/8 Agonist-treated tumors. In a bilateral tumor setting, combination of TransCon TLR7/8 Agonist with systemic IL-2 potentiated tumor growth inhibition in both injected and non-injected tumors and conferred protection against tumor rechallenge following complete regressions. CONCLUSIONS: Our findings show that a single dose of TransCon TLR7/8 Agonist can mediate sustained local release of resiquimod in the TME and promote potent anti-tumor effects as monotherapy and in combination with systemic immunotherapy, supporting TransCon TLR7/8 Agonist as a novel intratumoral TLR agonist for cancer therapy. A clinical trial to evaluate the safety and efficacy of TransCon TLR7/8 Agonist, as monotherapy and in combination with pembrolizumab, in cancer patients is currently ongoing (transcendIT-101; NCT04799054).

First-principles modeling of the highly dynamical surface structure of a MoS2 catalyst with S-vacancies.

Vacancy sites, e.g., S-vacancies, are essential for the performance of MoS2 catalysts. As earlier studies have revealed that the size and shape of the S-vacancies may affect the catalytic activity, we have studied the behavior and mobility of such vacancies on MoS2 using DFT calculations and kinetic Monte-Carlo (kMC) simulations. The diffusion barriers for the S-vacancies are highly dependent on the immediate environment: isolated single S-vacancies are found to be immobile. In contrast, small nS-vacancies formed from n = 2 to 5 neighboring S-vacancies are often highly dynamic systems that can move within a confined area. Large extended nS-vacancies are generally unstable and transform quickly into alternating patterns of S-atoms and vacancy sites. These results illustrate the importance of recognizing MoS2 (but also other catalysts) as dynamic structures when trying to tune their catalytic performances by introducing specific defect structures.

Musculoskeletal symptoms and associated factors among manual porcelain workers at different workstations: a cross-sectional study.

OBJECTIVES: To investigate the prevalence of work-related musculoskeletal disorders (WMSDs) symptoms and to identify the associated factors (individual, and work-related) among manual porcelain workers at different workstations. The risk level of each workstation was also assessed based on the working postures for the purpose of improving occupational health. METHODS: In total, 349 workers were recruited for this cross-sectional study. The Nordic Musculoskeletal Questionnaire (NMQ) was used to collect data on WMSDs symptoms in nine body regions. The relationship between individual/occupational factors and WMSDs symptoms was determined using multiple logistic regression analysis. The Rapid Entire Body Assessment (REBA) method was applied to classify the risk level of working postures at the five workstations (shaping, trimming, glazing, painting, and burning). RESULTS: The prevalence of musculoskeletal discomfort in at least one body region within the past 12 months was 69.1% among the participants: the neck (49.3%), lower back (43.8%), and shoulders (27.5%). Sex, work experience, daily working hours, perceived work fatigue, and workstation, were significantly associated with WMSDs symptoms in different body regions. The REBA indicated that 57.8% and 32.5% of the working postures were in the medium- and above high-risk levels, respectively. CONCLUSION: The findings of this study showed a high occurrence of WMSDs symptoms among manual porcelain workers and suggested that both individual and work-related characteristics should be considered to improve occupational health. Furthermore, urgent ergonomic intervention is needed to avoid awkward working postures that cause WMSDs symptoms in porcelain workers, particularly at the shaping and burning workstations.

A comparative evaluation of the four measurement methods for comfort and reachability distance perceptions.

This study aimed to evaluate the precision, accuracy, and reliability of the common measurement methods for collecting comfort and reachability distances. Four measurement methods were applied in the study: real-life measurement, virtual reality (VR) simulation, the media method, and the paper-and-pencil test. Forty participants were recruited, who were required to determine their comfort and reachability distances when approached by, or actively approaching, confederates under the four methods. The relative error magnitude and mean absolute difference were used to evaluate the precision and accuracy of the methods, respectively. Then, intraclass correlation coefficients were applied to evaluate the reliability of the methods. The ANOVA results showed that the confederate's gender, method, and pattern all had significant effects on the comfort and reachability distances. The distance obtained by the paper-and-pencil test was the smallest, while the distance measured by the media method was larger. The real-life measurement had high reliability, but its precision performance was worse than that of both the VR simulation and the active media method. The VR simulation had the best precision and reliability, while the measurement value tended to be overestimated. The media method in the passive pattern showed the worst precision, accuracy, and reliability performance among the four methods. The active media method performed well except for accuracy when collecting distance data. The paper-and-pencil test showed erroneous results regarding the precision and reliability performance. These findings provide scientific reference suggestions for the selection of measuring methods for collecting comfort and reachability distances.

Maternal high-fructose diet induced early-onset retinopathy via the suppression of synaptic plasticity mediated by mitochondrial dysfunction.

Retinopathy is a leading cause of blindness, and there is currently no cure. Earlier identification of the progression of retinopathy could provide a better chance for intervention. Diet has profound effects on retinal function. A maternal high-fructose diet (HFD) triggers diseases in multiple organs. However, whether maternal HFD impairs retinal function in adult offspring is currently unknown. By using the rodent model of maternal HFD during pregnancy and lactation, our data indicated a reduced b-wave of electroretinography (ERG) in HFD female offspring at 3 mo of age compared with age-matched offspring of dams fed regular chow (ND). Immunofluorescence and Western blot analyses indicated that the distributions and expressions of synaptophysin, postsynaptic density protein 95 (PSD95), and phospho(p)-Ca2+/calmodulin-stimulated protein kinase IIα (CaMKIIα) were significantly suppressed in the HFD group. Furthermore, the ATP content and the mitochondrial respiratory protein, Mt CPX 4-2, were decreased. Moreover, the expressions of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the retina of the HFD group were downregulated. Treatment with coenzyme Q10 (Q10), a key mediator of the electron transport chain, effectively reversed these abovementioned dysfunctions. Together, these results suggested that maternal HFD impaired retinal function in adult female offspring. The mechanism underlying early-onset retinopathy may involve the reduction in the capacity of mitochondrial energy production and the suppression of synaptic plasticity. Most importantly, mitochondria could be a feasible target to reprogram maternal HFD-damaged retinal function.NEW & NOTEWORTHY In this study, we provide novel evidence that maternal high-fructose diet during gestation and lactation could induce early-onset retinopathy in adult female offspring. Of note, the insufficient energy content, downregulated mitochondrial respiratory complex 4-2, and impaired mitochondrial biogenesis might contribute to the decrease of synaptic plasticity resulting in retinal function suppression. Oral application with coenzyme Q10 for 4 wk could at least partially reverse the aforementioned molecular events and retinal function.

Dendritic Cell Expression of Retinal Aldehyde Dehydrogenase-2 Controls Graft-versus-Host Disease Lethality.

Recent studies have underscored the critical role of retinoic acid (RA) in the development of lineage-committed CD4 and CD8 T cells in vivo. We have shown that under acute graft-versus-host disease (GVHD) inflammatory conditions, RA is upregulated in the intestine and is proinflammatory, as GVHD lethality was attenuated when donor allogeneic T cells selectively expressed a dominant negative RA receptor α that blunted RA signaling. RA can function in an autocrine and paracrine fashion, and as such, the host cell lineage responsible for the production of RA metabolism and the specific RA-metabolizing enzymes that potentiate GVHD severity are unknown. In this study, we demonstrate that enhancing RA degradation in the host and to a lesser extent donor hematopoietic cells by overexpressing the RA-catabolizing enzyme CYP26A1 reduced GVHD. RA production is facilitated by retinaldehyde isoform-2 (RALDH2) preferentially expressed in dendritic cells (DCs). Conditionally deleted RA-synthesizing enzyme RALDH2 in host or to a lesser extent donor DCs reduced GVHD lethality. Improved survival in recipients with RALDH2-deleted DCs was associated with increased T cell death, impaired T effector function, increased regulatory T cell frequency, and augmented coinhibitory molecule expression on donor CD4+ T cells. In contrast, retinaldehydrogenase isoform-1 (RALDH1) is dominantly expressed in intestinal epithelial cells. Unexpectedly, conditional host intestinal epithelial cells RALDH1 deletion failed to reduce GVHD. These data demonstrate the critical role of both donor and especially host RALDH2+ DCs in driving murine GVHD and suggest RALDH2 inhibition or CYP26A1 induction as novel therapeutic strategies to prevent GVHD.

Salivary AMY1 Copy Number Variation Modifies Age-Related Type 2 Diabetes Risk.

BACKGROUND: Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain. METHODS: We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk. RESULTS: We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR. CONCLUSIONS: We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age.

An Evaluation of Posture Recognition Based on Intelligent Rapid Entire Body Assessment System for Determining Musculoskeletal Disorders.

Determining the potential risks of musculoskeletal disorders through working postures in a workplace is expensive and time-consuming. A novel intelligent rapid entire body assessment (REBA) system based on convolutional pose machines (CPM), entitled the Quick Capture system, was applied to determine the risk levels. The aim of the study was to validate the feasibility and reliability of the CPM-based REBA system through a simulation experiment. The reliability was calculated from the differences of motion angles between the CPM-based REBA and a motion capture system. Results show the data collected by the Quick Capture system were consistent with those of the motion capture system; the average of root mean squared error (RMSE) was 4.77 and the average of Spearman's rho (ρ) correlation coefficient in the different 12 postures was 0.915. For feasibility evaluation, the linear weighted Cohen's kappa between the REBA score obtained by the Quick Capture system and those from the three experts were used. The result shows good agreement, with an average proportion agreement index (P0) of 0.952 and kappa of 0.738. The Quick Capture system does not only accurately analyze working posture, but also accurately determines risk level of musculoskeletal disorders. This study suggested that the Quick Capture system could be applied for a rapid and real-time on-site assessment.

Anti-neuroinflammation ameliorates systemic inflammation-induced mitochondrial DNA impairment in the nucleus of the solitary tract and cardiovascular reflex dysfunction.

BACKGROUND: Decreased heart rate variability (HRV) leads to cardiovascular diseases and increased mortality in clinical studies. However, the underlying mechanisms are still inconclusive. Systemic inflammation-induced neuroinflammation is known to impair the autonomic center of cardiovascular regulation. The dynamic stability of blood pressure and heart rate (HR) is regulated by modulation of the reciprocal responses of sympathetic and parasympathetic tone by the baroreflex, which is controlled by the nucleus of the solitary tract (NTS). METHODS: Systemic inflammation was induced by E. coli lipopolysaccharide (LPS, 1.2 mg/kg/day, 7 days) peritoneal infusion via an osmotic minipump in normotensive Sprague-Dawley rats. Systolic blood pressure (SBP) and HR were measured by femoral artery cannulation and recorded on a polygraph under anesthesia. The low-frequency (LF; 0.25-0.8 Hz) and high-frequency (HF; 0.8-2.4 Hz) components of SBP were adopted as the indices for sympathetic vasomotor tone and parasympathetic vasomotor tone, while the baroreflex effectiveness index (BEI) was adopted from the analysis of SBP and pulse interval (PI). The plasma levels of proinflammatory cytokines and mitochondrial DNA (mtDNA) oxidative damage were analyzed by ELISA. Protein expression was evaluated by Western blot. The distribution of oxidative mtDNA was probed by immunofluorescence. Pharmacological agents were delivered via infusion into the cisterna magna with an osmotic minipump. RESULTS: The suppression of baroreflex sensitivity was concurrent with increased SBP and decreased HR. Neuroinflammatory factors, including TNF-α, CD11b, and Iba-1, were detected in the NTS of the LPS group. Moreover, indices of mtDNA damage, including 8-OHdG and γ-H2AX, were significantly increased in neuronal mitochondria. Pentoxifylline or minocycline intracisternal (IC) infusion effectively prevented mtDNA damage, suggesting that cytokine and microglial activation contributed to mtDNA damage. Synchronically, baroreflex sensitivity was effectively protected, and the elevated blood pressure was significantly relieved. In addition, the mtDNA repair mechanism was significantly enhanced by pentoxifylline or minocycline. CONCLUSION: These results suggest that neuronal mtDNA damage in the NTS induced by neuroinflammation could be the core factor in deteriorating baroreflex desensitization and subsequent cardiovascular dysfunction. Therefore, the enhancement of base excision repair (BER) signaling in mitochondria could be a potential therapeutic strategy for cardiovascular reflex dysregulation.

Development of a Genetic Score to Predict an Increase in HDL Cholesterol Concentration After a Dietary Intervention in Adults with Metabolic Syndrome.

BACKGROUND: Dietary intervention (DI) is a primary strategy to attenuate some of the metabolic abnormalities associated with metabolic syndrome (MetS), including low HDL cholesterol. There is no biomarker that can identify individuals who respond to DI by increasing HDL cholesterol. OBJECTIVE: The aim of this study was to assess the predictive power of a genetic predisposition score (GPS) in Mexican adults with MetS to identify HDL cholesterol responders to DI. METHODS: This study followed a prospective cohort design. Sixty-seven Mexican adults aged 20-60 y (21% men) with BMI ≥25 and ≤39.9 kg/m², who had at least 3 of 5 positive criteria for MetS, were included. Participants consumed a low saturated fat diet for 2.5 mo (<7% energy as saturated fat, <200 mg of cholesterol/d) and reduced their usual diet by ∼440 kcal/d, a reduction in total energy intake of about 25%. Anthropometry and serum biochemical markers, including HDL cholesterol, were measured before and after DI. A multilocus GPS was constructed using previously reported genetic variants associated with response to diet in subjects with MetS. GPS values, designed to predict the response of HDL cholesterol to the DI, were computed for each individual as the sum of the number of effect alleles across 14 SNPs. RESULTS: Individuals were dichotomized as high and low GPS according to median GPS (-2.12) and we observed a difference in HDL cholesterol changes on DI of +3 mg/dL (6.3%) in subjects with low GPS, whereas those with high GPS had HDL cholesterol decreases of -3 mg/dL (-7.9%) (P = 0.04). CONCLUSIONS: Individuals with low GPS showed greater increases in their HDL cholesterol than those with high GPS. Therefore, the GPS can be useful for predicting the HDL cholesterol response to diet.

Toward Closing the Gap between Hexoses and N-Acetlyhexosamines: Experimental and Computational Studies on the Collision-Induced Dissociation of Hexosamines.

Motivated by the fundamental difference in the reactivity of hexoses and N-acetylhexosamines under collision-induced dissociation (CID) mass spectrometry conditions, we have investigated the CID of two hexosamines, glucosamine (GlcN) and galactosamine (GalN), experimentally and computationally. Both hexosamines undergo ring-opening and then dissociate via the 0,2A and the 0,3A (0,3X) cross-ring cleavage channels. The preference for the ring-opening is similar to the behavior of N-acetylhexosamines and explains why the two anomers of the same sugar give the same mass spectrum. While the spectrum for GlcN is dominated by the 0,2A signal, the signal intensities for both 0,2A and the 0,3A (0,3X) dissociation channels are comparable for GalN, which allows GlcN and GalN to be distinguished easily. Calculations at MP2 level of theory indicate that this is related to the differences in the relative barrier heights for the 0,2A and the 0,3A (0,3X) cross-ring cleavage channels. This, in return, reflects the circumstance that the 0,2A cross-ring cleavage barriers are different for the two sugars, while the barriers of all other dissociation channels are comparable. While the mechanisms of the cross-ring dissociation channels of hexoses are well described using the retro-aldol mechanism in the literature, this study proposes a new mechanism for the 0,3A (0,3X) cross-ring cleavage of hexosamines that involves the formation of an epoxy intermediate or a zwitterionic intermediate.

A systematic analysis highlights multiple long non-coding RNAs associated with cardiometabolic disorders.

Genome-wide association studies (GWAS) have identified many susceptibility loci for cardiometabolic disorders. Most of the associated variants reside in non-coding regions of the genome including long non-coding RNAs (lncRNAs), which are thought to play critical roles in diverse biological processes. Here, we leveraged data from the available GWAS meta-analyses on lipid and obesity-related traits, blood pressure, type 2 diabetes, and coronary artery disease and identified 179 associated single-nucleotide polymorphisms (SNPs) in 102 lncRNAs (p-value < 2.3 × 10-7). Of these, 55 SNPs, either the lead SNP or in strong linkage disequilibrium with the lead SNP in the related loci, were selected for further investigations. Our in silico predictions and functional annotations of the SNPs as well as expression and DNA methylation analysis of their lncRNAs demonstrated several lncRNAs that fulfilled predefined criteria for being potential functional targets. In particular, we found evidence suggesting that LOC157273 (at 8p23.1) is involved in regulating serum lipid-cholesterol. Our results showed that rs4841132 in the second exon and cg17371580 in the promoter region of LOC157273 are associated with lipids; the lncRNA is expressed in liver and associates with the expression of its nearby coding gene, PPP1R3B. Collectively, we highlight a number of loci associated with cardiometabolic disorders for which the association may act through lncRNAs.

Stimulatory Action of Telmisartan, an Antagonist of Angiotensin II Receptor, on Voltage-Gated Na⁺ Current: Experimental and Theoretical Studies.

Telmisartan (Tel) is recognized as a non-peptide blocker of AT1R. Whether this agent has any direct effects on ion currents remains unexplored. In whole-cell current recordings, addition of Tel increased the peak amplitude of voltage-gated Na⁺ (NaV) current (INa) accompanied by the increased time constant of INa inactivation in differentiated NSC-34 motor neuron-like cells. Tel-stimulated INa in these cells is unlinked to either blockade of AT1R or activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). In order to explore how this compound affects the amplitude and kinetics of INa in neurons, a Hodgkin-Huxley-based (HH-based) model designed to mimic effect of Tel on the functional activities of neurons was computationally created in this study. In this framework, the parameter for h inactivation gating variable, which was changed in a stepwise fashion, was implemented to predict changes in membrane potentials (V) as a function of maximal Na⁺ (GNa), K⁺ conductance (GK), or both. As inactivation time course of INa was increased, the bifurcation point of V versus GNa became lower, and the range between subcritical and supercritical values at the bifurcation of V versus GK correspondingly became larger. During a slowing in INa inactivation, the critical boundary between GNa and GK was shifted towards the left. Simulation studies demonstrated that progressive slowing in the inactivation time course of INa resulted in unanticipated increase of neuronal excitability by mimicking the effect of Tel in neuronal cells. Collectively, Tel can directly interact with the NaV channel to increase peak INa as well as to slow INa inactivation. It is thus highly likely that the effects of Tel or its structurally similar drugs could be another intriguing mechanism underlying their pharmacological actions in neurons or neuroendocrine cells occurring in vivo.

Enhancement Effect of a Variable Topology of a Membrane-Tethered Anti-Poly(ethylene glycol) Antibody on the Sensitivity for Quantifying PEG and PEGylated Molecules.

Sensitive quantification of the pharmacokinetics of poly(ethylene glycol) (PEG) and PEGylated molecules is critical for PEGylated drug development. Here, we developed a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) for PEG by tethering an anti-PEG antibody (AGP3) via tethers with different dimensions on the surface of 293T cells (293T/S-αPEG, short-type cells; 293T/L-αPEG, long-type cells; 293T/SL-αPEG, hybrid-type cells) to improve the binding capacity and detection limit for free PEG and PEGylated molecules. The binding capacity of hybrid-type cells for PEG-like molecules (CH3-PEG5K-FITC (FITC = fluorescein isothiocyanate) and eight-arm PEG20K-FITC) was at least 10-80-fold greater than that of 293T cells expressing anti-PEG antibodies with uniform tether lengths. The detection limit of free PEG (OH-PEG3K-NH2 and CH3-PEG5K-NH2) and PEG-like molecule (CH3-PEG5K-FITC, CH3-PEG5K-SHPP, and CH3-PEG5K-NIR797) was14-137 ng mL-1 in the hybrid-type cell-based sandwich ELISA. 293T/SL-αPEG cells also had significantly higher sensitivity for quantification of a PEGylated protein (PegIntron) and multiarm PEG macromolecules (eight-arm PEG20K-NH2 and eight-arm PEG40K-NH2) at 3.2, 16, and 16 ng mL-1, respectively. Additionally, the overall binding capacity of 293T/SL-αPEG cells for PEGylated macromolecules was higher than that of 293T/S-αPEG or 293T/L-αPEG cells. Anchoring anti-PEG antibodies on cells via variable-length tethers for cell-based sandwich ELISA, therefore, provides a sensitive, high-capacity method for quantifying free PEG and PEGylated molecules.

Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site.

Genome-wide association studies (GWAS) have identified hundreds of genetic variants that are associated with lipid phenotypes. However, data supporting a functional role for these variants in the context of lipid metabolism are scarce. We investigated the association of the lipoprotein lipase (LPL) variant rs13702 with plasma lipids and explored its potential for functionality. The rs13702 minor allele had been predicted to disrupt a microRNA (miR) recognition element (MRE) seed site (MRESS) for the human microRNA-410 (miR-410). Furthermore, rs13702 is in linkage disequilibrium (LD) with several SNPs identified by GWAS. We performed a meta-analysis across ten cohorts of participants that showed a statistically significant association of rs13702 with triacylglycerols (TAG) (p = 3.18 × 10(-42)) and high-density lipoprotein cholesterol (HDL-C) (p = 1.35 × 10(-32)) with each copy of the minor allele associated with 0.060 mmol/l lower TAG and 0.041 mmol/l higher HDL-C. Our data showed that an LPL 3' UTR luciferase reporter carrying the rs13702 major T allele was reduced by 40% in response to a miR-410 mimic. We also evaluated the interaction between intake of dietary fatty acids and rs13702. Meta-analysis demonstrated a significant interaction between rs13702 and dietary polyunsaturated fatty acid (PUFA) with respect to TAG concentrations (p = 0.00153), with the magnitude of the inverse association between dietary PUFA intake and TAG concentration showing -0.007 mmol/l greater reduction. Our results suggest that rs13702 induces the allele-specific regulation of LPL by miR-410 in humans. This work provides biological and potential clinical relevance for previously reported GWAS variants associated with plasma lipid phenotypes.

Dissecting the role of retinoic acid receptor isoforms in the CD8 response to infection.

Vitamin A deficiency leads to increased susceptibility to a spectrum of infectious diseases. The studies presented dissect the intrinsic role of each of the retinoic acid receptor (RAR) isoforms in the clonal expansion, differentiation, and survival of pathogen-specific CD8 T cells in vivo. The data show that RARα is required for the expression of gut-homing receptors on CD8(+) T cells and survival of CD8(+) T cells in vitro. Furthermore, RARα is essential for survival of CD8(+) T cells in vivo following Listeria monocytogenes infection. In contrast, RARß deletion leads to modest deficiency in Ag-specific CD8(+) T cell expansion during infection. The defective survival of RARα-deficient CD8(+) T cells leads to a deficiency in control of L. monocytogenes expansion in the spleen. To our knowledge, these are the first comparative studies of the role of RAR isoforms in CD8(+) T cell immunity.

Taiwanese adult foot shape classification using 3D scanning data.

This study classifies the foot shapes of Taiwanese using 3D foot scanning data from 2000 males and 1000 females. Nine foot dimensions relative to foot length and absolute measures in the common foot length categories were applied to compare the gender differences. Using foot breadth in % foot length (% FL), ball of foot length in % FL and arch height in % FL as feature parameters, three foot shape types for males and females can be classified. Significant gender differences were found in seven of the nine foot dimensions. Females had greater ball of foot length than males (0.2% FL). When comparing feet of the same foot length, males had greater breadth, girth and height dimensions than females, except for toe height. In addition, ethnic differences in foot shape were also observed. The findings can provide very useful information for building gender-specific shoe lasts and designing footwear insoles. PRACTITIONER SUMMARY: 3D foot scanning data of 2000 males and 1000 females were classified into three different footshapes for males and females, respectively. Gender and ethnic differences on foot shape were also compared. The finding scan provide very useful information for gender-specific shoe last design and footwear production.