Ligand-independent receptor clustering modulates transmembrane signaling: a new paradigm.

Cell-surface receptors mediate communication between cells and their environment. Lateral membrane organization and dynamic receptor cluster formation are fundamental in signal transduction and cell signaling. However, it is not yet fully understood how receptor clustering modulates a wide variety of physiologically relevant processes. Recent growing evidence indicates that biological responses triggered by membrane receptors can be modulated even in the absence of the natural receptor ligand. We review the most recent findings on how ligand-independent receptor clustering can regulate transmembrane signaling. We discuss the latest technologies to control receptor assembly, such as DNA nanotechnology, optogenetics, and optochemistry, focusing on the biological relevance and unraveling of ligand-independent signaling.

Design of biologically active binary protein 2D materials.

Ordered two-dimensional arrays such as S-layers1,2 and designed analogues3-5 have intrigued bioengineers6,7, but with the exception of a single lattice formed with flexible linkers8, they are constituted from just one protein component. Materials composed of two components have considerable potential advantages for modulating assembly dynamics and incorporating more complex functionality9-12. Here we describe a computational method to generate co-assembling binary layers by designing rigid interfaces between pairs of dihedral protein building blocks, and use it to design a p6m lattice. The designed array components are soluble at millimolar concentrations, but when combined at nanomolar concentrations, they rapidly assemble into nearly crystalline micrometre-scale arrays nearly identical to the computational design model in vitro and in cells without the need for a two-dimensional support. Because the material is designed from the ground up, the components can be readily functionalized and their symmetry reconfigured, enabling formation of ligand arrays with distinguishable surfaces, which we demonstrate can drive extensive receptor clustering, downstream protein recruitment and signalling. Using atomic force microscopy on supported bilayers and quantitative microscopy on living cells, we show that arrays assembled on membranes have component stoichiometry and structure similar to arrays formed in vitro, and that our material can therefore impose order onto fundamentally disordered substrates such as cell membranes. In contrast to previously characterized cell surface receptor binding assemblies such as antibodies and nanocages, which are rapidly endocytosed, we find that large arrays assembled at the cell surface suppress endocytosis in a tunable manner, with potential therapeutic relevance for extending receptor engagement and immune evasion. Our work provides a foundation for a synthetic cell biology in which multi-protein macroscale materials are designed to modulate cell responses and reshape synthetic and living systems.

Bispecific Forkhead Transcription Factor FoxN3 Recognizes Two Distinct Motifs with Different DNA Shapes.

Transcription factors (TFs) control gene expression by binding DNA recognition sites in genomic regulatory regions. Although most forkhead TFs recognize a canonical forkhead (FKH) motif, RYAAAYA, some forkheads recognize a completely different (FHL) motif, GACGC. Bispecific forkhead proteins recognize both motifs, but the molecular basis for bispecific DNA recognition is not understood. We present co-crystal structures of the FoxN3 DNA binding domain bound to the FKH and FHL sites, respectively. FoxN3 adopts a similar conformation to recognize both motifs, making contacts with different DNA bases using the same amino acids. However, the DNA structure is different in the two complexes. These structures reveal how a single TF binds two unrelated DNA sequences and the importance of DNA shape in the mechanism of bispecific recognition.

Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?

Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484T>C and m.11778G>A, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484T>C carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson et al. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.

Nutrition Assessment and Management in Celiac Disease.

Celiac disease (CeD) is the most common immune condition affecting the gastrointestinal tract; it is triggered by gluten and the only available treatment is a strict gluten-free diet (GFD). Therefore, for patients with CeD, adopting a GFD is not a lifestyle choice. The major problem is that a GFD is restrictive and, like all restrictive diets, it has the potential for adverse nutritional outcomes, especially if adopted for a long term. It is well known that GFD can be nutritionally inadequate and is frequently associated with vitamin and mineral deficiencies; it is also associated with excessive sugar and fat intake, particularly when gluten-free substitutes are consumed. Consequently, people with CeD are affected by higher rates of overweight and obesity and metabolic complications, such as fatty liver and cardiovascular disease. Therefore, assessment of nutritional status and diet quality at diagnosis and while on a long-term GFD is key in the management of CeD. This narrative review addresses nutritional considerations in CeD and management of common challenges associated with a GFD.

Establishing risk of vision loss in Leber hereditary optic neuropathy.

We conducted an updated epidemiological study of Leber hereditary optic neuropathy (LHON) in Australia by using registry data to establish the risk of vision loss among different LHON mutations, sex, age at onset, and mitochondrial haplogroup. We identified 96 genetically unrelated LHON pedigrees, including 56 unpublished pedigrees, and updated 40 previously known pedigrees, comprising 620 affected individuals and 4,948 asymptomatic carriers. The minimum prevalence of vision loss due to LHON in Australia in 2020 was one in 68,403 individuals. Although our data confirm some well-established features of LHON, the overall risk of vision loss among those with a LHON mutation was lower than reported previously-17.5% for males and 5.4% for females. Our findings confirm that women, older adults, and younger children are also at risk. Furthermore, we observed a higher incidence of vision loss in children of affected mothers as well as in children of unaffected women with at least one affected brother. Finally, we confirmed our previous report showing a generational fall in prevalence of vision loss among Australian men. Higher reported rates of vision loss in males with a LHON mutation are not supported by our work and other epidemiologic studies. Accurate knowledge of risk is essential for genetic counseling of individuals with LHON mutations. This knowledge could also inform the detection and validation of potential biomarkers and has implications for clinical trials of treatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underpowered study or a false claim of efficacy.

Observation of Strong Nuclear Suppression in Exclusive J/ψ Photoproduction in Au+Au Ultraperipheral Collisions at RHIC.

We report a measurement of exclusive J/ψ and ψ(2s) photoproduction in Au+Au ultraperipheral collisions at sqrt[s_{NN}]=200 GeV using the STAR detector. For the first time, (i) the ψ(2s) photoproduction in midrapidity at the Relativistic Heavy-Ion Collider has been experimentally measured; (ii) nuclear suppression factors are measured for both the coherent and incoherent J/ψ production. At average photon-nucleon center-of-mass energy of 25.0 GeV, the coherent and incoherent J/ψ cross sections of Au nuclei are found to be 71±10% and 36±7%, respectively, of that of free protons. The stronger suppression observed in the incoherent production provides a new experimental handle to study the initial-state parton density in heavy nuclei. Data are compared with theoretical models quantitatively.

The interplay of shape and catalyst distribution in the yield of compressible flow microreactors.

We develop a semi-analytical model for transport in structured catalytic microreactors, where both reactant and product are compressible fluids. Using lubrication and Fick-Jacobs approximations, we reduce the three-dimensional governing equations to an effective one-dimensional set of equations. Our model captures the effect of compressibility, corrugations in the shape of the reactor, and an inhomogeneous catalytic coating of the reactor walls. We show that in the weakly compressible limit (e.g., liquid-phase reactors), the distribution of catalyst does not influence the reactor yield, which we verify experimentally. Beyond this limit, we show that introducing inhomogeneities in the catalytic coating and corrugations to the reactor walls can improve the yield.

A large population study to assess the magnitude of prenatal programming in dairy cattle.

The performance of an adult dairy cow may be influenced by events that occur before her birth. The present study investigated the potential effects of 2 prenatal groups of factors, assisted reproductive technologies and maternal characteristics (e.g., dam parity), on offspring performance during their first lactation in populations of 2 dairy cow breeds: French Holstein and Montbéliarde. The different assisted reproductive technologies studied included the type of semen (conventional or X-sorted) used for AI and the technology of conception used (AI, embryo transfer, or in vitro fertilization). Three maternal characteristics were considered: (1) the dam age at first calving, (2) dam parity number, and (3) indicators of dam udder health during gestation (SCS and events of clinical mastitis). First, we investigated whether heifer survival from 3 d to 18 mo old was associated with any of the prenatal factors considered. We then estimated the associations of these prenatal factors with 8 traits of commercial interest: (1) stature, (2-4) milk, fat, and protein yields, (5) SCS, (6) clinical mastitis, and (7-8) heifer and cow conception rate, all measured on genotyped cows. Linear models were used for this study with the prenatal factors as covariates in the model, and for the 8 traits, phenotypes were adjusted for their corresponding genomic EBV. The results indicated that the survival rate of heifers born from embryo transfer was significantly higher than that of heifers born from AI (probably due to preferential management practices), and the other prenatal factors did not explain large differences in heifer survival. Among the Montbéliarde cows born from AI, those born from X-sorted semen showed a lightly but significantly lower milk yield than those born without X-sorting of the semen (-52 kg of milk in the first lactation). Among the Holstein cows, those born from embryo transfer presented significantly lower milk performance than cows born from AI. Regarding the maternal characteristics, none or very weak associations were found between the dam age at first calving and the offspring performance in both breeds. Dam parity, on the other hand, was associated with offspring performance for milk, fat, and protein yield in both breeds, but not in the same direction. In the Holstein breed, an increase in dam parity was favorable for offspring performance for milk, fat, and protein yield, whereas in the Montbéliarde breed, an increase in dam parity was associated with lower milk and protein yield and no association was found for fat yield. The udder health of the dam during gestation was not or only weakly associated with the traits studied in the offspring. Although some significant associations were identified due to the large sample size, the effects were modest, typically less than 1% of the phenotypic mean, and were not consistently observed across the 2 breeds.

The fecal microbiota of Holstein cows is heritable and genetically correlated to dairy performances.

The fecal microbiota of ruminants constitutes a diversified community that has been phenotypically associated with a variety of host phenotypes, such as production and health. To gain a better understanding of the complex and interconnected factors that drive the fecal bacterial community, we have aimed to estimate the genetic parameters of the diversity and composition of the fecal microbiota, including heritabilities, genetic correlations among taxa, and genetic correlations between fecal microbiota features and host phenotypes. To achieve this, we analyzed a large population of 1,875 Holstein cows originating from 144 French commercial herds and routinely recorded for production, somatic cell score, and fertility traits. Fecal samples were collected from the animals and subjected to 16S rRNA gene sequencing, with reads classified into Amplicon Sequence Variants (ASVs). The estimated α- and ß-diversity indices (i.e., Observed Richness, Shannon index, Bray-Curtis and Jaccard dissimilarity matrices) and the abundances of ASVs, genera, families and phyla, normalized by centered-log ratio (CLR), were considered as phenotypes. Genetic parameters were calculated using either univariate or bivariate animal models. Heritabilities estimates, ranging from 0.08 to 0.31 for taxa abundances and ß-diversity indices, highlight the influence of the host genetics on the composition of the fecal microbiota. Furthermore, genetic correlations estimated within the microbial community and between microbiota features and host traits reveal the complex networks linking all components of the fecal microbiota together and to their host, thus strengthening the holobiont concept. By estimating the heritabilities of microbiota-associated phenotypes, our study quantifies the impact of the host genetics on the fecal microbiota composition. In addition, genetic correlations between taxonomic groups and between taxa abundances and host performance suggest potential applications for selective breeding to improve host traits or promote a healthier microbiota.

Validity of an android device for assessing mobility in people with chronic stroke and hemiparesis: a cross-sectional study.

BACKGROUND: Incorporating instrument measurements into clinical assessments can improve the accuracy of results when assessing mobility related to activities of daily living. This can assist clinicians in making evidence-based decisions. In this context, kinematic measures are considered essential for the assessment of sensorimotor recovery after stroke. The aim of this study was to assess the validity of using an Android device to evaluate kinematic data during the performance of a standardized mobility test in people with chronic stroke and hemiparesis. METHODS: This is a cross-sectional study including 36 individuals with chronic stroke and hemiparesis and 33 age-matched healthy subjects. A simple smartphone attached to the lumbar spine with an elastic band was used to measure participants' kinematics during a standardized mobility test by using the inertial sensor embedded in it. This test includes postural control, walking, turning and sitting down, and standing up. Differences between stroke and non-stroke participants in the kinematic parameters obtained after data sensor processing were studied, as well as in the total execution and reaction times. Also, the relationship between the kinematic parameters and the community ambulation ability, degree of disability and functional mobility of individuals with stroke was studied. RESULTS: Compared to controls, participants with chronic stroke showed a larger medial-lateral displacement (p = 0.022) in bipedal stance, a higher medial-lateral range (p < 0.001) and a lower cranio-caudal range (p = 0.024) when walking, and lower turn-to-sit power (p = 0.001), turn-to-sit jerk (p = 0.026) and sit-to-stand jerk (p = 0.001) when assessing turn-to-sit-to-stand. Medial-lateral range and total execution time significantly correlated with all the clinical tests (p < 0.005), and resulted significantly different between independent and limited community ambulation patients (p = 0.042 and p = 0.006, respectively) as well as stroke participants with significant disability or slight/moderate disability (p = 0.024 and p = 0.041, respectively). CONCLUSION: This study reports a valid, single, quick and easy-to-use test for assessing kinematic parameters in chronic stroke survivors by using a standardized mobility test with a smartphone. This measurement could provide valid clinical information on reaction time and kinematic parameters of postural control and gait, which can help in planning better intervention approaches.

Prevalence of myocardial bridges in the Mexican population: A morphometric and histological analysis.

BACKGROUND: Myocardial bridge (MB) is described as an abnormal band of myocardium covering a variable portion of any coronary artery. METHODS: The current study explores the presence of MB throughout the coronary arterial system and provides a morphometric description through instrumented dissection of a sample of 100 human hearts. The study shows a higher prevalence of MB in the Mexican population than in previous reports. RESULTS: In the total sample (n=100), MB was identified in 96% of it. A total of 421 MBs were observed, with a mean of 4.38mm (±0.28) per dissected heart. The most frequently affected vessel is the anterior interventricular artery where a total of 52 MBs were found, of the total sample studied. DISCUSSION: The high prevalence of MB among Mexican patients could be the result of a genetic association for this population or the neoformation of MB after birth due to lifestyle-associated factors. Further studies are required to better understand the high prevalence of MB among Mexican subjects.

Measurements of the Elliptic and Triangular Azimuthal Anisotropies in Central

The elliptic (v_{2}) and triangular (v_{3}) azimuthal anisotropy coefficients in central ^{3}He+Au, d+Au, and p+Au collisions at sqrt[s_{NN}]=200 GeV are measured as a function of transverse momentum (p_{T}) at midrapidity (|η|<0.9), via the azimuthal angular correlation between two particles both at |η|<0.9. While the v_{2}(p_{T}) values depend on the colliding systems, the v_{3}(p_{T}) values are system independent within the uncertainties, suggesting an influence on eccentricity from subnucleonic fluctuations in these small-sized systems. These results also provide stringent constraints for the hydrodynamic modeling of these systems.

Erratum: Global Polarization of Ξ and Ω Hyperons in Au+Au Collisions at sqrt[s_{NN}]=200 GeV [Phys. Rev. Lett. 126, 162301 (2021)].

This corrects the article DOI: 10.1103/PhysRevLett.126.162301.

Hyperon Polarization along the Beam Direction Relative to the Second and Third Harmonic Event Planes in Isobar Collisions at sqrt[s_{NN}]=200 GeV.

The polarization of Λ and Λ[over ¯] hyperons along the beam direction has been measured relative to the second and third harmonic event planes in isobar Ru+Ru and Zr+Zr collisions at sqrt[s_{NN}]=200 GeV. This is the first experimental evidence of the hyperon polarization by the triangular flow originating from the initial density fluctuations. The amplitudes of the sine modulation for the second and third harmonic results are comparable in magnitude, increase from central to peripheral collisions, and show a mild p_{T} dependence. The azimuthal angle dependence of the polarization follows the vorticity pattern expected due to elliptic and triangular anisotropic flow, and qualitatively disagrees with most hydrodynamic model calculations based on thermal vorticity and shear induced contributions. The model results based on one of existing implementations of the shear contribution lead to a correct azimuthal angle dependence, but predict centrality and p_{T} dependence that still disagree with experimental measurements. Thus, our results provide stringent constraints on the thermal vorticity and shear-induced contributions to hyperon polarization. Comparison to previous measurements at RHIC and the LHC for the second-order harmonic results shows little dependence on the collision system size and collision energy.

Measurement of Sequential ϒ Suppression in Au+Au Collisions at sqrt[s_{NN}]=200 GeV with the STAR Experiment.

We report on measurements of sequential ϒ suppression in Au+Au collisions at sqrt[s_{NN}]=200 GeV with the STAR detector at the Relativistic Heavy Ion Collider (RHIC) through both the dielectron and dimuon decay channels. In the 0%-60% centrality class, the nuclear modification factors (R_{AA}), which quantify the level of yield suppression in heavy-ion collisions compared to p+p collisions, for ϒ(1S) and ϒ(2S) are 0.40±0.03(stat)±0.03(sys)±0.09(norm) and 0.26±0.08(stat)±0.02(sys)±0.06(norm), respectively, while the upper limit of the ϒ(3S) R_{AA} is 0.17 at a 95% confidence level. This provides experimental evidence that the ϒ(3S) is significantly more suppressed than the ϒ(1S) at RHIC. The level of suppression for ϒ(1S) is comparable to that observed at the much higher collision energy at the Large Hadron Collider. These results point to the creation of a medium at RHIC whose temperature is sufficiently high to strongly suppress excited ϒ states.

Beam Energy Dependence of Fifth- and Sixth-Order Net-Proton Number Fluctuations in Au+Au Collisions at RHIC.

We report the beam energy and collision centrality dependence of fifth and sixth order cumulants (C_{5}, C_{6}) and factorial cumulants (κ_{5}, κ_{6}) of net-proton and proton number distributions, from center-of-mass energy (sqrt[s_{NN}]) 3 GeV to 200 GeV Au+Au collisions at RHIC. Cumulant ratios of net-proton (taken as proxy for net-baryon) distributions generally follow the hierarchy expected from QCD thermodynamics, except for the case of collisions at 3 GeV. The measured values of C_{6}/C_{2} for 0%-40% centrality collisions show progressively negative trend with decreasing energy, while it is positive for the lowest energy studied. These observed negative signs are consistent with QCD calculations (for baryon chemical potential, µ_{B}≤110 MeV) which contains the crossover transition range. In addition, for energies above 7.7 GeV, the measured proton κ_{n}, within uncertainties, does not support the two-component (Poisson+binomial) shape of proton number distributions that would be expected from a first-order phase transition. Taken in combination, the hyperorder proton number fluctuations suggest that the structure of QCD matter at high baryon density, µ_{B}∼750 MeV at sqrt[s_{NN}]=3 GeV is starkly different from those at vanishing µ_{B}∼24 MeV at sqrt[s_{NN}]=200 GeV and higher collision energies.

Observation of Directed Flow of Hypernuclei _{Λ}

We report here the first observation of directed flow (v_{1}) of the hypernuclei _{Λ}^{3}H and _{Λ}^{4}H in mid-central Au+Au collisions at sqrt[s_{NN}]=3 GeV at RHIC. These data are taken as part of the beam energy scan program carried out by the STAR experiment. From 165×10^{6} events in 5%-40% centrality, about 8400 _{Λ}^{3}H and 5200 _{Λ}^{4}H candidates are reconstructed through two- and three-body decay channels. We observe that these hypernuclei exhibit significant directed flow. Comparing to that of light nuclei, it is found that the midrapidity v_{1} slopes of _{Λ}^{3}H and _{Λ}^{4}H follow baryon number scaling, implying that the coalescence is the dominant mechanism for these hypernuclei production in the 3 GeV Au+Au collisions.

Beam Energy Dependence of Triton Production and Yield Ratio (N_{t}×N_{p}/N_{d}

We report the triton (t) production in midrapidity (|y|<0.5) Au+Au collisions at sqrt[s_{NN}]=7.7-200 GeV measured by the STAR experiment from the first phase of the beam energy scan at the Relativistic Heavy Ion Collider. The nuclear compound yield ratio (N_{t}×N_{p}/N_{d}^{2}), which is predicted to be sensitive to the fluctuation of local neutron density, is observed to decrease monotonically with increasing charged-particle multiplicity (dN_{ch}/dη) and follows a scaling behavior. The dN_{ch}/dη dependence of the yield ratio is compared to calculations from coalescence and thermal models. Enhancements in the yield ratios relative to the coalescence baseline are observed in the 0%-10% most central collisions at 19.6 and 27 GeV, with a significance of 2.3σ and 3.4σ, respectively, giving a combined significance of 4.1σ. The enhancements are not observed in peripheral collisions or model calculations without critical fluctuation, and decreases with a smaller p_{T} acceptance. The physics implications of these results on the QCD phase structure and the production mechanism of light nuclei in heavy-ion collisions are discussed.

Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Diet may impact important risk factors for endometrial cancer such as obesity and inflammation. However, evidence on the role of specific dietary factors is limited. We investigated associations between dietary fatty acids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: This analysis includes 1,886 incident endometrial cancer cases and 297,432 non-cases. All participants were followed up for a mean of 8.8 years. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of endometrial cancer across quintiles of individual fatty acids estimated from various food sources quantified through food frequency questionnaires in the entire EPIC cohort. The false discovery rate (q-values) was computed to control for multiple comparisons. RESULTS: Consumption of n-6 γ-linolenic acid was inversely associated with endometrial cancer risk (HR comparing 5th with 1st quintileQ5-Q1=0.77, 95% CI = 0.64; 0.92, ptrend=0.01, q-value = 0.15). This association was mainly driven by γ-linolenic acid derived from plant sources (HRper unit increment=0.94, 95%CI= (0.90;0.98), p = 0.01) but not from animal sources (HRper unit increment= 1.00, 95%CI = (0.92; 1.07), p = 0.92). In addition, an inverse association was found between consumption of n-3 α-linolenic acid from vegetable sources and endometrial cancer risk (HRper unit increment= 0.93, 95%CI = (0.87; 0.99), p = 0.04). No significant association was found between any other fatty acids (individual or grouped) and endometrial cancer risk. CONCLUSION: Our results suggest that higher consumption of γ-linolenic acid and α-linoleic acid from plant sources may be associated with lower risk of endometrial cancer.