Miracle-dz/UniFAR-FTUs huggingface dataset:
Knee osteoarthritis has doubled in prevalence since the mid-20th century

Significance Knee osteoarthritis is a highly prevalent, disabling joint disease with causes that remain poorly understood but are commonly attributed to aging and obesity. To gain insight into the etiology of knee osteoarthritis, this study traces long-term trends in the disease in the United States using large skeletal samples spanning from prehistoric times to the present. We show that knee osteoarthritis long existed at low frequencies, but since the mid-20th century, the disease has doubled in prevalence. Our analyses contradict the view that the recent surge in knee osteoarthritis occurred simply because people live longer and are more commonly obese. Instead, our results highlight the need to study additional, likely preventable risk factors that have become ubiquitous within the last half-century. Knee osteoarthritis (OA) is believed to be highly prevalent today because of recent increases in life expectancy and body mass index (BMI), but this assumption has not been tested using long-term historical or evolutionary data. We analyzed long-term trends in knee OA prevalence in the United States using cadaver-derived skeletons of people aged ≥50 y whose BMI at death was documented and who lived during the early industrial era (1800s to early 1900s; n = 1,581) and the modern postindustrial era (late 1900s to early 2000s; n = 819). Knee OA among individuals estimated to be ≥50 y old was also assessed in archeologically derived skeletons of prehistoric hunter-gatherers and early farmers (6000–300 B.P.; n = 176). OA was diagnosed based on the presence of eburnation (polish from bone-on-bone contact). Overall, knee OA prevalence was found to be 16% among the postindustrial sample but only 6% and 8% among the early industrial and prehistoric samples, respectively. After controlling for age, BMI, and other variables, knee OA prevalence was 2.1-fold higher (95% confidence interval, 1.5–3.1) in the postindustrial sample than in the early industrial sample. Our results indicate that increases in longevity and BMI are insufficient to explain the approximate doubling of knee OA prevalence that has occurred in the United States since the mid-20th century. Knee OA is thus more preventable than is commonly assumed, but prevention will require research on additional independent risk factors that either arose or have become amplified in the postindustrial era.
MegaVoltage Cone Beam Computed Tomography with a standard medical linear accelerator

Accurate patient positioning is vital for improved clinical outcomes for cancer treatments using radiotherapy. This project has developed Mega Voltage Cone Beam CT using a standard medical linear accelerator to allow 3D imaging of the patient position at treatment time with no additional hardware required. Providing 3D imaging functionality at no further cost allows enhanced patient position verification on older linear accelerators and in developing countries where access to new technology is limited.
Blocking Energy‐Loss Pathways for Ideal Fluorescent Organic Light‐Emitting Diodes with Thermally Activated Delayed Fluorescent Sensitizers

Organic light‐emitting diodes (OLEDs) based on thermally activated delayed fluorescence‐sensitized fluorescence (TSF) offer the possibility of attaining an ultimate high efficiency with low roll‐off utilizing noble‐metal free, easy‐to‐synthesize, pure organic fluorescent emitters. However, the performances of TSF‐OLEDs are still unsatisfactory. Here, TSF‐OLEDs with breakthrough efficiencies even at high brightnesses by suppressing the competitive deactivation processes, including direct charge recombination on conventional fluorescent dopants (CFDs) and Dexter energy transfer from the host to the CFDs, are demonstrated. On the one hand, electronically inert terminal‐substituents are introduced to protect the electronically active core of the CFDs; on the other hand, delicate device structures are designed to provide multiple energy‐funneling paths. As a result, unprecedentedly high maximum external quantum efficiency/power efficiency of 24%/71.4 lm W−1 in a green TSF‐OLED are demonstrated, which remain at 22.6%/52.3 lm W−1 even at a high luminance of 5000 cd m−2. The work unlocks the potential of TSF‐OLEDs, paving the way toward practical applications.
mTORC1 activates SREBP-2 by suppressing cholesterol trafficking to lysosomes in mammalian cells

Significance Through unknown mechanisms mTORC1 triggers translocation of SREBP-2, an endoplasmic reticulum (ER) resident protein, to the Golgi to produce mature SREBP-2, which translocates to the nucleus to act as a transcription factor. Low ER cholesterol is a well-known inducer of SREBP-2 activation. We thus investigated whether mTORC1 activates SREBP-2 by reducing ER cholesterol levels. We report that, in cultured mammalian cells, an increase in mTORC1 activity is accompanied by a decrease in ER cholesterol and by SREBP-2 activation. Conversely, a decrease in mTORC1 activity coincides with higher ER cholesterol and lower SERBP-2 activity. We demonstrate that, by suppressing autophagy and by maintaining endosomal recycling, mTORC1 actively prevents membrane-derived cholesterol from reaching lysosomes, thereby reducing cholesterol ER and activating SREBP-2. mTORC1 is known to activate sterol regulatory element-binding proteins (SREBPs) including SREBP-2, a master regulator of cholesterol synthesis. Through incompletely understood mechanisms, activated mTORC1 triggers translocation of SREBP-2, an endoplasmic reticulum (ER) resident protein, to the Golgi where SREBP-2 is cleaved to translocate to the nucleus and activate gene expression for cholesterol synthesis. Low ER cholesterol is a well-established trigger for SREBP-2 activation. We thus investigated whether mTORC1 activates SREBP-2 by reducing cholesterol delivery to the ER. We report here that mTORC1 activation is accompanied by low ER cholesterol and an increase of SREBP-2 activation. Conversely, a decrease in mTORC1 activity coincides with a rise in ER cholesterol and a decrease in SERBP-2 activity. This rise in ER cholesterol is of lysosomal origin: blocking the exit of cholesterol from lysosomes by U18666A or NPC1 siRNA prevents ER cholesterol from increasing and, consequently, SREBP-2 is activated without mTORC1 activation. Furthermore, when mTORC1 activity is low, cholesterol is delivered to lysosomes through two membrane trafficking pathways: autophagy and rerouting of endosomes to lysosomes. Indeed, with dual blockade of both pathways by Atg5−/− and dominant-negative rab5, ER cholesterol fails to increase when mTORC1 activity is low, and SREBP-2 is activated. Conversely, overexpressing constitutively active Atg7, which forces autophagy and raises ER cholesterol even when mTORC1 activity is high, suppresses SREBP-2 activation. We conclude that mTORC1 actively suppresses autophagy and maintains endosomal recycling, thereby preventing endosomes and autophagosomes from reaching lysosomes. This results in a reduction of cholesterol in the ER and activation of SREBP-2.
Antagonism correlates with metabolic similarity in diverse bacteria

Significance Diverse species from all over the bacterial tree of life produce antibiotics to limit the growth of competitors and thereby enhance their resource availability. Here we examined the pairwise inhibition between bacterial species from natural settings. We find that bacteria mainly inhibit the growth of metabolically similar and evolutionary related species, in line with Darwin’s age old competition-relatedness hypothesis. We further find that inhibiting the growth of other species is associated with a generalist lifestyle, suggesting a trade-off between specialists efficiently growing on few resources and generalists who are able to use many resources but have to inhibit the specialists to obtain them. In the Origin of Species, Charles R. Darwin [Darwin C (1859) On the Origin of Species] proposed that the struggle for existence must be most intense among closely related species by means of their functional similarity. It has been hypothesized that this similarity, which results in resource competition, is the driver of the evolution of antagonism among bacteria. Consequently, antagonism should mostly be prevalent among phylogenetically and metabolically similar species. We tested the hypothesis by screening for antagonism among all possible pairwise interactions between 67 bacterial species from 8 different environments: 2,211 pairs of species and 4,422 interactions. We found a clear association between antagonism and phylogenetic distance, antagonism being most likely among closely related species. We determined two metabolic distances between our strains: one by scoring their growth on various natural carbon sources and the other by creating metabolic networks of predicted genomes. For both metabolic distances, we found that the probability of antagonism increased the more metabolically similar the strains were. Moreover, our results were not compounded by whether the antagonism was between sympatric or allopatric strains. Intriguingly, for each interaction the antagonizing strain was more likely to have a wider metabolic niche than the antagonized strain: that is, larger metabolic networks and growth on more carbon sources. This indicates an association between an antagonistic and a generalist strategy.
Graphene–Graphene Interactions: Friction, Superlubricity, and Exfoliation

Graphite's lubricating properties due to the “weak” interactions between individual layers have long been known. However, these interactions are not weak enough to allow graphite to readily exfoliate into graphene on a large scale. Separating graphite layers down to a single sheet is an intense area of research as scientists attempt to utilize graphene's superlative properties. The exfoliation and processing of layered materials is governed by the friction between layers. Friction on the macroscale can be intuitively understood, but there is little understanding of the mechanisms involved in nanolayered materials. Using molecular dynamics and a new forcefield, graphene's unusual behavior in a superlubric state is examined, and the energy dissipated between two such surfaces sliding past each other is shown. The dependence of friction on temperature and surface roughness is described, and agreement with experiment is reported. The accuracy of the simulated behavior enables the processes that drive exfoliation of graphite into individual graphene sheets to be described. Taking into account the friction between layers, a peeling mechanism of exfoliation is predicted to be of lower energy cost than shearing.
Staufen1 inhibits MyoD translation to actively maintain muscle stem cell quiescence

Significance This work addresses a fundamental mechanism for the translational control of a master regulator of myogenic differentiation, MyoD, by the RNA binding protein Staufen1. We show that muscle stem cells express the MyoD transcript in the quiescent state in vivo but block its translation through direct repression by Staufen1. Loss of this translational repression leads to MyoD translation and cell cycle entry, highlighting a novel role for MyoD in regulating the exit from quiescence. This mechanism of direct translational repression enables the cells to exist poised for activation and cell cycle entry. These data provide insight in the translational control of muscle stem cell quiescence. Tissue regeneration depends on the timely activation of adult stem cells. In skeletal muscle, the adult stem cells maintain a quiescent state and proliferate upon injury. We show that muscle stem cells (MuSCs) use direct translational repression to maintain the quiescent state. High-resolution single-molecule and single-cell analyses demonstrate that quiescent MuSCs express high levels of Myogenic Differentiation 1 (MyoD) transcript in vivo, whereas MyoD protein is absent. RNA pulldowns and costainings show that MyoD mRNA interacts with Staufen1, a potent regulator of mRNA localization, translation, and stability. Staufen1 prevents MyoD translation through its interaction with the MyoD 3′-UTR. MuSCs from Staufen1 heterozygous (Staufen1+/−) mice have increased MyoD protein expression, exit quiescence, and begin proliferating. Conversely, blocking MyoD translation maintains the quiescent phenotype. Collectively, our data show that MuSCs express MyoD mRNA and actively repress its translation to remain quiescent yet primed for activation.
3D Printing of Liquid Crystal Elastomeric Actuators with Spatially Programed Nematic Order

Liquid crystal elastomers (LCEs) are soft materials capable of large, reversible shape changes, which may find potential application as artificial muscles, soft robots, and dynamic functional architectures. Here, the design and additive manufacturing of LCE actuators (LCEAs) with spatially programed nematic order that exhibit large, reversible, and repeatable contraction with high specific work capacity are reported. First, a photopolymerizable, solvent‐free, main‐chain LCE ink is created via aza‐Michael addition with the appropriate viscoelastic properties for 3D printing. Next, high operating temperature direct ink writing of LCE inks is used to align their mesogen domains along the direction of the print path. To demonstrate the power of this additive manufacturing approach, shape‐morphing LCEA architectures are fabricated, which undergo reversible planar‐to‐3D and 3D‐to‐3D′ transformations on demand, that can lift significantly more weight than other LCEAs reported to date.
Improving Decision Making in Intensive Care

textabstractMany decisions are made during a day’s work in critical care. Should this octogenarian with pneumonia and cancer be admitted to the ICU or left on the ward with palliative care? And if admitted to the ICU, will she benefit from being ventilated or should she only be treated with antibiotics and inotropes? How long should we continue administrating antibiotics in a patient with peritonitis due to anastomotic leakage after low anterior resection? Will antibiotics do the job or does he have to go back to the operating theatre? Should we give more fluids in a patient with shock, should we start vasoconstrictors or vasodilators or should we accept this low blood pressure? Continue treatment with a curative intent or accept the inevitable? Act on a laboratory result or stop ‘just treating the numbers’?
Flat central density profiles from scalar field dark matter halos

Scalar elds endowed with a cosh potential behave in the linear regime, exactly as the cold dark matter (CDM) model. Thus, the scalar eld dark matter (SFDM) hypothesis predicts the same structure formation as the CDM model. This means that CDM and SFDM are equivalent from the cosmological point of view. The free parameters of the SFDM model are determined by cosmological observations. In previous work we showed that if we use such parameters, the scalar eld collapses forming stable objects with a mass around 10 12 M . In the present work we use analytical solutions of the at and weak eld limit of the Einstein-Klein-Gordon equations and show that the SFDM density prole corresponds to a halo with an almost at central density and that it coincides with the CDM model in a broad outer region. This result could solve the problem of the density cusp DM halo in galaxies without any additional hypothesis, thus supporting the viability of the SFDM model.
Rapid diagnostic testing platform for iron and vitamin A deficiency

Significance We demonstrate a technology that we believe could transform the way nutritional deficiency testing is done worldwide. Micronutrient deficiencies such as vitamin A and iron affect a third of the world’s population with consequences such as blindness, higher child mortality, anemia, poor pregnancy outcomes, and reduced work capacity. Our testing platform simultaneously quantifies concentrations of ferritin, retinol-binding protein, and C-reactive protein, allowing one to diagnose iron and vitamin A deficiency and inflammation status (to better inform and help with the interpretation of the result) in about 15 min. Our approach combines multiple florescent markers and immunoassay approaches on a single test strip, allowing us to span the five orders of magnitude difference in the physiological range of these markers. Micronutrient deficiencies such as those of vitamin A and iron affect a third of the world’s population with consequences such as night blindness, higher child mortality, anemia, poor pregnancy outcomes, and reduced work capacity. Many efforts to prevent or treat these deficiencies are hampered by the lack of adequate, accessible, and affordable diagnostic methods that can enable better targeting of interventions. In this work, we demonstrate a rapid diagnostic test and mobile enabled platform for simultaneously quantifying iron (ferritin), vitamin A (retinol-binding protein), and inflammation (C-reactive protein) status. Our approach, enabled by combining multiple florescent markers and immunoassay approaches on a single test, allows us to provide accurate quantification in 15 min even though the physiological range of the markers of interest varies over five orders of magnitude. We report sensitivities of 88%, 100%, and 80% and specificities of 97%, 100%, and 97% for iron deficiency (ferritin <15 ng/mL or 32 pmol/L), vitamin A deficiency (retinol-binding protein <14.7 μg/mL or 0.70 μmol/L) and inflammation status (C-reactive protein >3.0 μg/mL or 120 nmol/L), respectively. This technology is suitable for point-of-care use in both resource-rich and resource-limited settings and can be read either by a standard laptop computer or through our previously developed NutriPhone technology. If implemented as either a population-level screening or clinical diagnostic tool, we believe this platform can transform nutritional status assessment and monitoring globally.
Musical training sharpens and bonds ears and tongue to hear speech better

Significance Musical training is a good thing, but does it benefit us in hearing speech in noise as has been suggested? If so, what is the brain mechanism behind this? Here we provide evidence of musician advantage on speech in noise perception at not only the behavioral level but also the level of neural representations of phonemes and functional connectivity. Results implicate better speech encoding in both auditory and speech motor regions, as well as stronger cross-modal auditory–motor integration in musicians than nonmusicians when processing speech, especially in noisy conditions. The idea that musical training improves speech in noise perception by enhancing auditory–motor integration is intriguing, with applications in alleviating speech perception difficulties in aging populations and hearing disorders. The idea that musical training improves speech perception in challenging listening environments is appealing and of clinical importance, yet the mechanisms of any such musician advantage are not well specified. Here, using functional magnetic resonance imaging (fMRI), we found that musicians outperformed nonmusicians in identifying syllables at varying signal-to-noise ratios (SNRs), which was associated with stronger activation of the left inferior frontal and right auditory regions in musicians compared with nonmusicians. Moreover, musicians showed greater specificity of phoneme representations in bilateral auditory and speech motor regions (e.g., premotor cortex) at higher SNRs and in the left speech motor regions at lower SNRs, as determined by multivoxel pattern analysis. Musical training also enhanced the intrahemispheric and interhemispheric functional connectivity between auditory and speech motor regions. Our findings suggest that improved speech in noise perception in musicians relies on stronger recruitment of, finer phonological representations in, and stronger functional connectivity between auditory and frontal speech motor cortices in both hemispheres, regions involved in bottom-up spectrotemporal analyses and top-down articulatory prediction and sensorimotor integration, respectively.
Are uric acid values surrogate for insulin resistance in apparently healthy subjects across a spectrum of body mass index?

Background: The concept of insulin resistance initially proposed in diabetic patients requiring high doses of insulin is now known to be associated with major public health problems, including obesity, hypertension, coronary artery disease, and metabolic syndrome. Serum uric acid (SUA) values are also elevated in the above conditions and proposed to reflect the insulin-resistant state. Objective: To determine whether SUA levels can be used as a surrogate for insulin resistance calculated as homeostatic model assessment insulin resistance (HOMA-IR) in apparently healthy, normal weight, overweight, and obese population. Materials and Methods: A cross-sectional study done in 150 subjects of both genders aged 20-40 years was divided equally based on their body mass index into three groups namely normal weight, overweight, and obese as per National Institutes of Health classification. Fasting plasma glucose, fasting serum insulin, and SUA were estimated. HOMA-IR was calculated. Results: Mean waist circumference, waist-hip ratio, fasting insulin, fasting glucose, uric acid, and HOMA-IR were found to be elevated in both overweight and obese groups. Mean uric acid levels were 4.9 mg/dL, 5.4 mg/dL, and 6.3 mg/dL and mean HOMA-IR values are 2.2, 3.3, and 7.3, respectively, in normal weight, overweight, and obese subjects. Significant correlation of uric acid with insulin resistance calculated as HOMA-IR was not found in any of the three groups. Conclusion: There was an incremental increase in fasting glucose, fasting insulin, uric acid, and HOMA-IR from normal weight to overweight to obese subjects in a systematic proportion. Significant correlation of uric acid with fasting insulin and insulin resistance was not seen and hence cannot be used as the surrogate marker for insulin resistance in the apparently healthy population.
Islet cells share promoter hypomethylation independently of expression, but exhibit cell-type–specific methylation in enhancers

Significance We have studied the dynamics of DNA methylation in pancreatic α- and β-cells and reached surprising insights into the establishment of islet cell identity. Different islet cell types share lack of methylation in cell-type–specific gene promoters, while DNA methylation differences between islet cell types are concentrated in enhancer regions. The findings support the fundamental role of enhancer methylation in determining cell identity, and have implications for the understanding of islet cell plasticity in diabetes. DNA methylation at promoters is an important determinant of gene expression. Earlier studies suggested that the insulin gene promoter is uniquely unmethylated in insulin-expressing pancreatic β-cells, providing a classic example of this paradigm. Here we show that islet cells expressing insulin, glucagon, or somatostatin share a lack of methylation at the promoters of the insulin and glucagon genes. This is achieved by rapid demethylation of the insulin and glucagon gene promoters during differentiation of Neurogenin3+ embryonic endocrine progenitors, regardless of the specific endocrine cell-type chosen. Similar methylation dynamics were observed in transgenic mice containing a human insulin promoter fragment, pointing to the responsible cis element. Whole-methylome comparison of human α- and β-cells revealed generality of the findings: genes active in one cell type and silent in the other tend to share demethylated promoters, while methylation differences between α- and β-cells are concentrated in enhancers. These findings suggest an epigenetic basis for the observed plastic identity of islet cell types, and have implications for β-cell reprogramming in diabetes and diagnosis of β-cell death using methylation patterns of circulating DNA.