Miracle-dz/UniFAR-FTUs huggingface dataset:
Increasing Time in Therapeutic Range of Tacrolimus in the First Year Predicts Better Outcomes in Living-Donor Kidney Transplantation

Background: The aim of the present study was to investigate the impact of time in therapeutic range TTR on long-term outcomes of living kidney transplants. Methods: We included 1,241 living kidney transplants and randomized them into development and validation cohorts with a ratio of 2:1. The tacrolimus TTR percentage was calculated by linear interpolation with a target range (5–10 ng/ml months 0–3, 4–8 ng/ml months 4–12). The optimal TTR cutoff was estimated by the receiver operating characteristic curve analysis on the basis of acute rejection (AR) within 12 months in the development cohort. Outcomes were analyzed between patients with high TTR and low TTR in the development and validation cohorts, respectively. The TTR was also compared with other tacrolimus measures. Results: The optimal TTR cutoff value was 78%. In the development cohort, patients with TTR > 78% had significantly higher rejection- and infection-free survival. TTR < 78% was an independent risk factor for AR (OR: 2.97, 95%CI: 1.82–4.84) and infection (OR: 1.55, 95%CI: 1.08–2.22). Patient and graft survival were significantly higher in those with TTR>78%, and TTR<78% was associated with graft loss (OR: 3.2, 95%CI: 1.38–7.42) and patient death (OR: 6.54, 95%CI: 1.34–31.77). These findings were confirmed in the validation cohort. Furthermore, we divided all included patients into a high and low TTR group. TTR was more strongly associated with patient and graft survival than mean level, standard deviation, and intrapatient variability (IPV). Conclusions: Increasing the TTR of tacrolimus in the first year was associated with improved long-term outcomes in living kidney transplants, and TTR may be a novel valuable strategy to monitor tacrolimus exposure.
Estimating Carbon Flux From Optically Recording Total Particle Volume at Depths Below the Primary Pycnocline

Optical instruments can rapidly determine numbers and characteristics of water column particles with high sensitivity. Here we show the usefulness of optically assessed total particle volume below the main pycnocline to estimate carbon export in two systems: the open subarctic North Atlantic and the Ross Sea, Antarctica. Both regions exhibit seasonally high phytoplankton production and efficient export (i.e., a strong biological pump). Total particle volumes in the mesopelagic (200-300 m) were significantly correlated with those in the overlying surface mixed layer (50 - 60 m), indicating that most particles at depth reflect export from the surface. This connectivity, however, is modulated by the physical structure of the water column and by particle type (e.g., the presence of colonies of the haptophyte Phaeocystis antarctica versus diatoms). Evidence from both regions show that a strong pycnocline can delay or may even prevent particles from settling to deeper layers, which then succumb to disintegration, or microbial and/or zooplankton consumption. Strong katabatic winds in the Ross Sea may deepen the mixed layer, causing a rapid transfer of particles to mesopelagic depths through the mixed-layer pump. Independent estimates of seasonally integrated export production in the Ross Sea, based on upper water column carbon mass balance, were significantly correlated (in the order of shared variance) with 1) total particle volumes from images, 2) particulate organic carbon, and 3) chlorophyll fluorescence, all recorded at a depth range of 200 – 300 m. Carbon export was not significantly correlated with particle abundance measured by a Coulter Counter at the same depth range. Measuring total particle volume below the primary pycnocline is therefore a useful approach to estimate carbon export at least in regions characterized by seasonally high particle export.
Metagenome of Gut Microbiota of Children With Nonalcoholic Fatty Liver Disease

Aim: To investigate the intestinal flora of nonalcoholic fatty liver disease (NAFLD) in Chinese children and adolescents using metagenomic approach. Methods: All participants underwent magnetic resonance spectroscopy (MRS) to quantify liver fat content. Hepatic steatosis was defined as MRS proton density fat fraction (MRS-PDFF) >5%. A total of 58 children and adolescents were enrolled in this study, including 25 obese NAFLD patients, 18 obese non-NAFLD children, and 15 healthy children. Stool samples were collected and analyzed with metagenomics. We used Shannon index to reflect the alpha diversities of gut microbiota. Wilcoxon rank sum test and Kruskal-Wallis test were performed to evaluate alpha diversities between groups. At last, the differences of gut microbiota composition and functional annotations between obese with and without NAFLD and healthy children were assessed by Kruskal-Wallis test. Results: Significant differences in gut microbiota composition and functional annotations among three groups of children and adolescents have been observed. Deep sequencing of gut microbiota revealed high abundance of phylum Proteobacteria (Gammaproteobacteria) in obese NAFLD patients, comparing with the control group. Overall, obese children without NAFLD had less abundant Helicobacter and Helicobacter pylori. Compared to the control group, in obese children with NAFLD, the abundance of Bacteroidetes (Alistipes) were significantly reduced. Faecalibacterium prausnitzii was the only species representing a difference between obese children with and without NAFLD. There were not significant differences in terms of alpha diversity among three groups. Functional annotations demonstrated that several pathways were differentially enriched between groups, including metabolism of other amino acids, replication and repair, folding, sorting, degradation, and glycan biosynthesis and metabolism. Conclusion: Significantly differences are observed in gut microbiota composition and functional annotations between obese children with and without NAFLD in comparison to the healthy children group. The characteristic of gut microbiota in this study may contribute to a further understanding the gut-liver axis of pediatric NAFLD in China.
Does Everyone Pay Attention to People in the Same Way?

AGES: 8–14 The environment around us is constantly changing, so how does the brain adapt to these new and ever-changing situations? Attention helps us filter out distracting information and focus on specific bits of information. For example, when you are at home doing your homework, you might not notice background noises like a dog barking or tra c outside. Not only are researchers interested in how the brain pays attention, but also in how attention is unique for di erent people and for di erent types of information, from simple flashes of light to complex faces. In this article, we will explain the importance of social information, how attention prioritizes social information, and how the amount of attention devoted to social information (known as social attention) varies across di erent people.
Integrating Perception and Optimization for Dexterous Grasping and Manipulation

Dexterous grasping and manipulation of objects are fundamental abilities for robots. Our aim is to endow robots with human-like grasping and manipulation capabilities. Four issues are addressed with the focus on the integration between perception and optimization. This thesis develops approaches that integrate visual/tactile perception with optimization for grasp and manipulation learning.
Comparative study of wild-type and rd10 mice reveals transient intrinsic optical signal response before phosphodiesterase activation in retinal photoreceptors

Transient intrinsic optical signal (IOS) has been observed in stimulus-evoked retinal photoreceptors. This study is to compare IOS changes in wild-type and retinal degeneration 10 (rd10) mouse retinas, to evaluate the effect of cyclic guanosine monophosphate phosphodiesterase on photoreceptor-IOS. Time-lapse near-infrared light microscopy was employed to monitor the spatiotemporal dynamics of the IOS responses in freshly isolated retinas activated by visible light stimulation. Comparative IOS recordings were conducted at postnatal days 14 (P14) and P16. At P14, intrinsic optical signal magnitudes and spatiotemporal dynamics in wild-type and rd10 retinas were similar, indicating that the phosphodiesterase deficiency in rd10 did not affect the formation of photoreceptor-IOS. At P16, IOS magnitude in rd10 significantly decreased compared to that in wild-type, suggesting the IOS sensitivity to the photoreceptor degeneration in rd10. Our experimental results and theoretical analysis indicate that early disc-based stages of the phototransduction cascade before the activation of phosphodiesterase may contribute to the formation of the photoreceptor-IOS responses; and the IOS can be a sensitive biomarker for objective assessment of retinal function. Impact statement Comparative study of wild-type and rd10 mice was implemented to reveal that transient intrinsic optical signal (IOS) was initiated before the phosphodiesterase activation in stimulus-activated photoreceptors and the IOS magnitude was sensitive to photoreceptor degeneration. The photoreceptor-IOS promises a noninvasive biomarker for objective assessment of age-related macular degeneration, retinitis pigmentosa, and other eye diseases that can produce photoreceptor dysfunctions.
Early predictors of perinatal brain damage: the role of neurobiomarkers

Abstract The early detection of perinatal brain damage in preterm and term newborns (i.e. intraventricular hemorrhage, periventricular leukomalacia and perinatal asphyxia) still constitute an unsolved issue. To date, despite technological improvement in standard perinatal monitoring procedures, decreasing the incidence of perinatal mortality, the perinatal morbidity pattern has a flat trend. Against this background, the measurement of brain constituents could be particularly useful in the early detection of cases at risk for short-/long-term brain injury. On this scenario, the main European and US international health-care institutions promoted perinatal clinical and experimental neuroprotection research projects aimed at validating and including a panel of biomarkers in the clinical guidelines. Although this is a promising attempt, there are several limitations that do not allow biomarkers to be included in standard monitoring procedures. The main limitations are: (i) the heterogeneity of neurological complications in the perinatal period, (ii) the small cohort sizes, (iii) the lack of multicenter investigations, (iv) the different techniques for neurobiomarkers assessment, (iv) the lack of consensus for the validation of assays in biological fluids such as urine and saliva, and (v), the lack of reference curves according to measurement technique and biological fluid. In the present review we offer an up-to-date overview of the most promising developments in the use of biomarkers in the perinatal period such as calcium binding proteins (S100B protein), vasoactive agents (adrenomedullin), brain biomarkers (activin A, neuron specific enolase, glial fibrillary acidic protein, ubiquitin carboxyl-terminal hydrolase-L1) and oxidative stress markers.
Harnessing MerTK agonism for targeted therapeutics

ABSTRACT Phagocytosis plays important roles both in homeostasis and under pathological conditions. Fcγ receptor-mediated phagocytosis has been exploited as an integral mechanism for antibody-based therapies. Unlike Fcγ receptor-mediated phagocytosis, MerTK-mediated phagocytic clearance is immunologically silent. Here, we describe a bispecific antibody approach to harness MerTK for targeted clearance without inducing proinflammatory cytokine release associated with Fcγ receptor engagement. We generated bispecific antibodies targeting live B cells or amyloid beta aggregates to demonstrate the feasibility and versatility of this new approach.
Preclinical Detection of Prions in Blood of Nonhuman Primates Infected with Variant Creutzfeldt-Jakob Disease

Variant Creutzfeldt-Jakob disease (vCJD) is caused by prion infection with bovine spongiform encephalopathy and can be transmitted by blood transfusion. Protein misfolding cyclic amplification (PMCA) can detect prions in blood from vCJD patients with 100% sensitivity and specificity. To determine whether PMCA enables prion detection in blood during the preclinical stage of infection, we performed a blind study using blood samples longitudinally collected from 28 control macaques and 3 macaques peripherally infected with vCJD. Our results demonstrate that PMCA consistently detected prions in blood during the entire preclinical stage in all infected macaques, without false positives from noninfected animals, when using the optimized conditions for amplification of macaque prions. Strikingly, prions were detected as early as 2 months postinoculation (>750 days before disease onset). These findings suggest that PMCA has the potential to detect vCJD prions in blood from asymptomatic carriers during the preclinical phase of the disease.
Plasticity in the growth of body segments in relation to height‐for‐age and maternal education in Guatemala

Plasticity in the growth of body segments between populations has been researched in relation to migration, temporal change and high‐altitude studies. We study the within population variation in body segments, thus controlling for some of the environmental and genetic differences that could be at play in between populations studies. We test a version of the thrifty phenotype hypothesis, where the growth of head‐trunk and hand are prioritized due to their functional significance over height and leg growth.
Bayesian machine learning to discover Bruton’s tyrosine kinase inhibitors

Bruton's tyrosine kinase (BTK) has a crucial role in multiple cell signaling pathways including B‐cell antigen receptor (BCR) and Fc receptor (FcR) signaling cascades, which has attracted much attention to find BTK inhibitors to treat autoimmune diseases. In this work, we constructed a Bayesian classification model for virtually seeking novel BTK inhibitors, which showed good performance in terms of screening efficiency and accuracy. Through searching for several chemical libraries including Chembl_17 (1,317,484 compounds), Chembridge (103,473 compounds), and Chemdiv (700,000 compounds) using this model followed by molecular docking and activity prediction, 52 compounds with novel scaffolds were acknowledged as potential BTK inhibitors, which could be promising starting points for further exploration. This study also provided a guide to construct an efficient and effective protocol for virtual screening by integrating machine learning methods.
Autofluorescence spectroscopy in redox monitoring across cell confluencies

Patient-specific therapies require that cells be manufactured in multiple batches of small volumes, making it a challenge for conventional modes of quality control. The added complexity of inherent variability (even within batches) necessitates constant monitoring to ensure comparable end products. Hence, it is critical that new non-destructive modalities of cell monitoring be developed. Here, we study, for the first time, the use of optical spectroscopy in the determination of cellular redox across cell confluencies by exploiting the autofluorescence properties of molecules found natively within cells. This was achieved through a simple retrofitting of a standard inverted fluorescence microscope with a spectrometer output and an appropriate fluorescence filter cube. Through spectral decomposition on the acquired autofluorescence spectra, we are able to further discern the relative contributions of the different molecules, namely flavin adenine dinucleotide (FAD) and reduced nicotinamide adenine dinucleotide (NADH). This is then quantifiable as redox ratios (RR) that represent the extent of oxidation to reduction based upon the optically measured quantities of FAD and NADH. Results show that RR decreases with increasing cell confluency, which we attribute to several inter-related cellular processes. We validated the relationship between RR, metabolism and cell confluency through bio-chemical and viability assays. Live-dead and DNA damage studies were further conducted to substantiate that our measurement process had negligible effects on the cells. In this study, we demonstrate that autofluorescence spectroscopy-derived RR can serve as a rapid, non-destructive and label-free surrogate to cell metabolism measurements. This was further used to establish a relationship between cell metabolism and cellular redox across cell confluencies, and could potentially be employed as an indicator of quality in cell therapy manufacturing.
A mean-field approach to the dynamics of networks of complex neurons, from nonlinear Integrate-and-Fire to Hodgkin–Huxley models

We present a mean-field formalism able to predict the collective dynamics of large networks of conductance-based interacting spiking neurons. We apply this formalism to several neuronal models, from the simplest Adaptive Exponential Integrate-and-Fire model to the more complex Hodgkin-Huxley and Morris-Lecar models. We show that the resulting mean-field models are capable of predicting the correct spontaneous activity of both excitatory and inhibitory neurons in asynchronous irregular regimes, typical of cortical dynamics. Moreover, it is possible to quantitatively predict the populations response to external stimuli in the form of external spike trains. This mean-field formalism therefore provides a paradigm to bridge the scale between population dynamics and the microscopic complexity of the individual cells physiology. NEW & NOTEWORTHY Population models are a powerful mathematical tool to study the dynamics of neuronal networks and to simulate the brain at macroscopic scales. We present a mean-field model capable of quantitatively predicting the temporal dynamics of a network of complex spiking neuronal models, from Integrate-and-Fire to Hodgkin-Huxley, thus linking population models to neurons electrophysiology. This opens a perspective on generating biologically realistic mean-field models from electrophysiological recordings.
Structural and biophysical properties of RIG-I bound to dsRNA with G-U wobble base pairs

ABSTRACT Retinoic acid-inducible gene I (RIG-I) is responsible for innate immunity via the recognition of short double-stranded RNAs in the cytosol. With the clue that G-U wobble base pairs in the influenza A virus’s RNA promoter region are responsible for RIG-I activation, we determined the complex structure of RIG-I ΔCARD and a short hairpin RNA with G-U wobble base pairs by X-ray crystallography. Interestingly, the overall helical backbone trace was not affected by the presence of the wobble base pairs; however, the base pair inclination and helical axis angle changed upon RIG-I binding. NMR spectroscopy revealed that RIG-I binding renders the flexible base pair of the influenza A virus’s RNA promoter region between the two G-U wobble base pairs even more flexible. Binding to RNA with wobble base pairs resulted in a more flexible RIG-I complex. This flexible complex formation correlates with the entropy-favoured binding of RIG-I and RNA, which results in tighter binding affinity and RIG-I activation. This study suggests that the structure and dynamics of RIG-I are tailored to the binding of specific RNA sequences with different flexibility.
Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain

The poly(A) RNA binding proteins MSUT2 and PABPN1 regulate the accumulation of pathological tau in two mouse models of tauopathy. RNA metabolism and abnormal tau in AD Currently, there are no effective treatments for Alzheimer’s disease (AD) and related dementia disorders. Abnormal tau protein correlates with dementia, but the molecular mechanisms whereby tau abnormalities cause neuronal dysfunction and neurodegeneration remain unclear. Wheeler et al. now report that neurons in the brains of Msut2 knockout mice are protected from abnormal tau pathology. MSUT2 and PABPN1, two interacting proteins that facilitate RNA metabolism, were found to modulate the susceptibility of mice to the toxic consequences of abnormal tau deposition in the brain. The authors propose that MSUT2 and PABPN1 may act together to influence deposition of abnormal tau in AD. Brain lesions composed of pathological tau help to drive neurodegeneration in Alzheimer’s disease (AD) and related tauopathies. Here, we identified the mammalian suppressor of tauopathy 2 (MSUT2) gene as a modifier of susceptibility to tau toxicity in two mouse models of tauopathy. Transgenic PS19 mice overexpressing tau, a model of AD, and lacking the Msut2 gene exhibited decreased learning and memory deficits, reduced neurodegeneration, and reduced accumulation of pathological tau compared to PS19 tau transgenic mice expressing Msut2. Conversely, Msut2 overexpression in 4RTauTg2652 tau transgenic mice increased pathological tau deposition and promoted the neuroinflammatory response to pathological tau. MSUT2 is a poly(A) RNA binding protein that antagonizes the canonical nuclear poly(A) binding protein PABPN1. In individuals with AD, MSUT2 abundance in postmortem brain tissue predicted an earlier age of disease onset. Postmortem AD brain tissue samples with normal amounts of MSUT2 showed elevated neuroinflammation associated with tau pathology. We observed co-depletion of MSUT2 and PABPN1 in postmortem brain samples from a subset of AD cases with higher tau burden and increased neuronal loss. This suggested that MSUT2 and PABPN1 may act together in a macromolecular complex bound to poly(A) RNA. Although MSUT2 and PABPN1 had opposing effects on both tau aggregation and poly(A) RNA tail length, we found that increased poly(A) tail length did not ameliorate tauopathy, implicating other functions of the MSUT2/PABPN1 complex in tau proteostasis. Our findings implicate poly(A) RNA binding proteins both as modulators of pathological tau toxicity in AD and as potential molecular targets for interventions to slow neurodegeneration in tauopathies.
Gene‐by‐gene interactions associated with the risk of conotruncal heart defects

The development of conotruncal heart defects (CTDs) involves a complex relationship among genetic variants and maternal lifestyle factors. In this article, we focused on the interactions between 13 candidate genes within folate, homocysteine, and transsulfuration pathways for potential association with CTD risk.