Miracle-dz/UniFAR-FTUs huggingface dataset:
Renal Outcomes After Simultaneous Liver‐Kidney Transplantation: Results from the US Multicenter Simultaneous Liver‐Kidney Transplantation Consortium

Simultaneous liver‐kidney transplantation (SLKT) is increasingly common in the United States. However, little is known about the renal‐related outcomes following SLKT, which are essential to maximize the health of these allografts. We examined the factors impacting renal function following SLKT. This is an observational multicenter cohort study from the US Multicenter SLKT Consortium consisting of recipients of SLKT aged ≥18 years of transplantations performed between February 2002 and June 2017 at 6 large US centers in 6 different United Network for Organ Sharing regions. The primary outcome was incident post‐SLKT stage 4‐5 chronic kidney disease (CKD) defined as <30 mL/minute/1.73 m2 or listing for kidney transplant. The median age of the recipients (n = 570) was 58 years (interquartile range, 51‐64 years), and 37% were women, 76% were White, 33% had hepatitis C virus infection, 20% had nonalcoholic steatohepatitis (NASH), and 23% had alcohol‐related liver disease; 68% developed ≥ stage 3 CKD at the end of follow‐up. The 1‐year, 3‐year, and 5‐year incidence rates of post‐SLKT stage 4‐5 CKD were 10%, 12%, and 16%, respectively. Pre‐SLKT diabetes mellitus (hazard ratio [HR], 1.45; 95% CI, 1.00‐2.15), NASH (HR, 1.58; 95% CI, 1.01‐2.45), and delayed kidney graft function (HR, 1.72; 95% CI, 1.10‐2.71) were the recipient factors independently associated with high risk, whereas the use of tacrolimus (HR, 0.44; 95% CI, 0.22‐0.89) reduced the risk. Women (β = −6.22 ± 2.16 mL/minute/1.73 m2; P = 0.004), NASH (β = −7.27 ± 3.27 mL/minute/1.73 m2; P = 0.027), and delayed kidney graft function (β = −7.25 ± 2.26 mL/minute/1.73 m2; P = 0.007) were independently associated with low estimated glomerular filtration rate at last follow‐up. Stage 4‐5 CKD is common after SLKT. There remains an unmet need for personalized renal protective strategies, specifically stratified by sex, diabetes mellitus, and liver disease, to preserve renal function among SLKT recipients.
Pancreatic Brsk2 amplifies parasympathetic signals to promote type 2 diabetes

The parasympathetic nervous system (PNS) modulates postprandial glucose metabolism via innervating pancreas; however, its significance in the pathogenesis of type 2 diabetes (T2DM) remains unclear. Here we show that brain-specific serine/threonine-protein kinase 2 (Brsk2), accumulated in obese mouse islets, responds to PNS activation and initiates pre-absorptive insulin release. In inducible mouse models, excessive Brsk2 amplifies parasympathetic signaling to β cells and increases their secretion, ensuing insulin resistance and T2DM. Conversely, Brsk2 inhibition prevents and treats HFD-induced metabolic abnormities via avoiding β-cell oversecretion. Mechanistically, parasympathetic acetylcholine activates cholinergic receptor M3 (Chrm3), then Chrm3 recruits and stabilizes Brsk2, which in turn phosphorylates phospholipase A2 activating protein (Plaa). A Chrm3-Brsk2-Plaa axis stimulates β-cell hypersecretion during both pre-absorptive and absorptive stages in HFD-feeding mice, thus imposing insulin resistance and β-cell dysfunction. Blocking parasympathetic signaling to β cells by Brsk2 protein restoration, autonomic mediation drugs, or vagotomy restricted diabetes development. Moreover, three human BRSK2 variants are associated with hyperinsulinemia, insulin resistance, and T2DM in the Chinese population. These findings reveal that Brsk2 links parasympathetic nervous system to nutrition-overload induced T2DM.
Endothelial Semaphorin 3fb regulates Vegf pathway-mediated angiogenic sprouting

Vessel growth integrates diverse extrinsic signals with intrinsic signaling cascades to coordinate cell migration and sprouting morphogenesis. The pro-angiogenic effects of Vascular Endothelial Growth Factor (VEGF) are carefully controlled during sprouting to generate an efficiently patterned vascular network. We identify crosstalk between VEGF signaling and that of the secreted ligand Semaphorin 3fb (Sema3fb), one of two zebrafish paralogs of mammalian Sema3F. The sema3fb gene is expressed by endothelial cells in actively sprouting vessels. Loss of sema3fb results in abnormally wide and stunted intersegmental vessel artery sprouts. Although the sprouts initiate at the correct developmental time, they have a reduced migration speed. These sprouts have persistent filopodia and abnormally spaced nuclei suggesting dysregulated control of actin assembly. sema3fb mutants show simultaneously higher expression of pro-angiogenic (VEGF receptor 2 (vegfr2) and delta-like 4 (dll4)) and anti-angiogenic (soluble VEGF receptor 1 (svegfr1)/ soluble Fms Related Receptor Tyrosine Kinase 1 (sflt1)) pathway components. We show increased phospho-ERK staining in migrating angioblasts, consistent with enhanced Vegf activity. Reducing Vegfr2 kinase activity in sema3fb mutants rescues angiogenic sprouting. Our data suggest that Sema3fb plays a critical role in promoting endothelial sprouting through modulating the VEGF signaling pathway, acting as an autocrine cue that modulates intrinsic growth factor signaling. Author summary To supply tissues with essential oxygen and nutrients, blood vessel development is carefully orchestrated by positive ‘go’ and negative ‘stop’ growth signals as well as directional cues to shape patterning. Semaphorin proteins are named after the ‘Semaphore’ railway signaling system that directed trains along the appropriate tracks. Our work highlights the role of the Semaphorin 3fb protein in providing a pro-growth signal to developing vessels. Semaphorin 3fb is both produced by, and acts on the precursors of blood vessels as they migrate, a process known as autocrine control. We find that losing Semaphorin 3fb leads to stalled blood vessel growth, indicating it normally acts as a positive signal. It acts via modulating the VEGF growth factor signaling pathway that in turn, controls the migration process. We propose that Semaphorin3b fine-tunes vessel growth, thus ensuring a properly patterned network develops.
Synaptic Plasticity Is Predicted by Spatiotemporal Firing Rate Patterns and Robust to In Vivo-like Variability

Synaptic plasticity, the experience-induced change in connections between neurons, underlies learning and memory in the brain. Most of our understanding of synaptic plasticity derives from in vitro experiments with precisely repeated stimulus patterns; however, neurons exhibit significant variability in vivo during repeated experiences. Further, the spatial pattern of synaptic inputs to the dendritic tree influences synaptic plasticity, yet is not considered in most synaptic plasticity rules. Here, we address the sensitivity of plasticity to trial-to-trial variability and delineate how spatiotemporal synaptic input patterns produce plasticity with in vivo-like conditions using a data-driven computational model with a calcium-based plasticity rule. Using in vivo spike train recordings as inputs, we show that plasticity is strongly robust to trial-to-trial variability of spike timing, and derive general synaptic plasticity rules describing how spatiotemporal patterns of synaptic inputs control the magnitude and direction of plasticity. Specifically, a high temporal input firing rate to a synapse late in a trial correlated with neighboring synaptic activity produces potentiation, while an earlier, moderate firing rate that is negatively correlated with neighboring synaptic activity produces depression. Together, our results reveal that calcium dynamics can unify diverse plasticity rules and reveal how spatiotemporal firing rate patterns control synaptic plasticity.
AATF/Che-1, a new component of paraspeckles, controls R-loops formation and Interferon activation in Multiple Myeloma

Multiple myeloma (MM) is a hematological neoplasm of plasma cells characterized by abnormal production of immunoglobulins. Che-1/AATF (Che-1) is an RNA binding protein involved in transcription regulation and is highly expressed in this malignancy. Here we experimentally show that Che-1 interacts with paraspeckle components, including the lncRNA NEAT1_2 (NEAT1), which serves as the seed for the maintenance of these structures. Che-1 and NEAT1 localize on R-loops, three-stranded RNA:DNA hybrids structures involved in DNA transcription and repair. Depletion of Che-1 produces a marked accumulation of RNA:DNA hybrids sustaining activation of a systemic inflammatory response. We provide evidence that high levels of Unfolded Protein Response (UPR) in MM cells induces RNA:DNA hybrids and an interferon (IFN) gene signature. We found that MM patients exhibit elevated R-loops levels and paraspeckle genes mRNAs increase linearly to MM progression. Strikingly, patients showing elevated IFN genes signature are associated with a marked poor prognosis. Overall, these findings delineate that elevated R-loops accumulation and inflammatory signaling may contribute to MM progression and that Che-1/NEAT1 plays an essential role in maintaining R-loops homeostasis by preventing excessive inflammatory signaling.
Mechanism of tethered agonist-mediated signaling by polycystin-1

Polycystin-1 (PC1) is an important unusual G-protein-coupled receptor (GPCR) with 11 transmembrane (TM) domains and its mutations account for 85% of cases of autosomal dominant polycystic kidney disease (ADPKD). PC1 shares multiple characteristics with Adhesion GPCRs. These include a GPCR proteolysis site that autocatalytically divides these proteins into extracellular, N-terminal and membrane-embedded, C-terminal (CTF) fragments, and a tethered agonist (TA) within the N-terminal stalk of the CTF that is suggested to activate signaling. However, the mechanism by which a TA can activate PC1 is not known. Here, we have combined functional cellular signaling experiments of PC1 CTF expression constructs encoding wild type, stalkless and three different ADPKD stalk variants with all-atom Gaussian accelerated molecular dynamics (GaMD) simulations to investigate TA-mediated signaling activation. Correlations of residue motions and free-energy profiles calculated from the GaMD simulations correlated with the differential signaling abilities of wild type and stalk variants of PC1 CTF. They suggested an allosteric mechanism involving residue interactions connecting the stalk, Tetragonal Opening for Polycystins (TOP) domain and putative pore loop in TA-mediated activation of PC1 CTF. Key interacting residues such as N3074-S3585 and R3848-E4078 predicted from the GaMD simulations were validated by new mutagenesis experiments. Together, these complementary analyses have provided novel insights into a TA-mediated activation mechanism of PC1 CTF signaling, which will be important for future rational drug design targeting PC1. Significance Statement Mutations of polycystin-1 (PC1) are the major cause (85% of cases) of autosomal dominant polycystic kidney disease (ADPKD), which is the fourth leading cause of kidney failure. PC1 is thought to function as an atypical GPCR, yet the mechanism by which PC1 regulates G-protein signaling remains poorly understood. A significant portion of ADPKD mutations of PC1 encode a protein with defects in maturation or reduced function that may be amenable to functional rescue. In this work, we have combined complementary biochemical and cellular assay experiments and accelerated molecular simulations, which revealed a novel allosteric transduction pathway in activation of the PC1 CTF. Our findings shall facilitate future rational drug design efforts targeting the PC1 signaling function.
The road not taken: disconnection of a human-unique cortical pathway in schizophrenia and its effects on naturalistic social cognition

Background Efficient processing of complex and dynamic social scenes relies on intact connectivity of many underlying cortical areas and networks, but how connectivity deficits affect this functioning in social cognition remains unknown. Here we measure these relationships using functionally based localization of social cognition areas, resting-state functional connectivity, and movie-watching data. Methods In 42 schizophrenia participants (SzP) and 41 healthy controls (HC), we measured the functional connectivity of areas localized by face-emotion processing, theory-of-mind, and attention tasks. We quantified the weighted shortest path length between visual and medial prefrontal theory-of-mind areas in both populations to assess the impact of functional connectivity deficits on network structure. We then correlated connectivity along the shortest path in each group with movie-evoked activity in a key node of the theory-of-mind network (TPJp). Results SzP had pronounced connectivity deficits in temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS) areas involved in face-emotion processing (t(81)=4.4, p=0.00002). In HC the shortest path connecting visual and medial prefrontal theory-of-mind areas passed through TPJ-pSTS, whereas in SzP the shortest path passed through prefrontal cortex (PFC). While movie-evoked TPJp activity correlated with connectivity along the TPJ-pSTS pathway in both groups (r=0.43, p=0.002), it additionally correlated with connectivity along the PFC pathway only in SzP (rSzP=0.56, p=0.003). Conclusions Connectivity along the human-unique TPJ-pSTS pathway affects both the network architecture and functioning of areas involved in processing complex dynamic social scenes. These results demonstrate how focal deficits can have widespread impacts across cortex.
cageminer: an R/Bioconductor package to prioritize candidate genes by integrating GWAS and gene coexpression networks

Summary Although genome-wide association studies (GWAS) identify variants associated with traits of interest, they often fail in identifying causative genes underlying a given phenotype. Integrating GWAS and gene coexpression networks can help prioritize high-confidence candidate genes, as the expression profiles of trait-associated genes can be used to mine novel candidates. Here, we present cageminer, the first R package to prioritize candidate genes through the integration of GWAS and coexpression networks. Genes are considered high-confidence candidates if they pass all three filtering criteria implemented in cageminer, namely physical proximity to SNPs, coexpression with known trait-associated genes, and significant changes in expression levels in conditions of interest. Prioritized candidates can also be scored and ranked to select targets for experimental validation. By applying cageminer to a real data set, we demonstrate that it can effectively prioritize candidates, leading to >99% reductions in candidate gene lists. Availability and implementation The package is available at Bioconductor (http://bioconductor.org/packages/cageminer).
Pollen meta-barcoding reveals foraging preferences of honeybees (Apis mellifera L.) along space-time gradient in Japan

The availability of pollen in urban-rural landscapes is an essential factor that influences the population dynamics of insect pollinators. The amount and diversity of pollen play a pivotal role in the foraging ecology of pollinators for their growth and health, but investigations on the spatio-temporal patterns of foraged plants remain rare, especially in cities as neo-ecosystems. Here, we explored the temporal foraging habits of a highly polylectic pollinator (Apis mellifera L.) in a study area, including different landscape classes from rural to urban areas. Mixed-pollen in each month and each location (N = 17) were analysed using DNA meta-barcoding to identify plants visited by honeybees. The results showed that the landscape class (rural, suburban and urban areas) explains spatial variations in the plant composition foraged by honeybees, but not in taxa richness. Furthermore, pollen diversity and plant composition showed a strong seasonal dependence. Furthermore, a higher plant richness and foraged woody taxa was found to occur in spring, which was mainly dominated by the genera Prunus and Acer. In summer and autumn, the genera Trifolium and Plantago of the herbaceous stratum were the most visited plants. The Fabaceae, Rosaceae, Brassicaceae, Plantaginaceae, and Onagraceae plant families were the most frequently observed in all combined samples. The present study contributes to a broader understanding of the ecology and floral preferences of honeybees, on which urban planning can rely to promote biodiversity in cities.
The decoy SNARE Tomosyn sets tonic versus phasic release properties and is required for homeostatic synaptic plasticity

Synaptic vesicle release probability (Pr) is a key presynaptic determinant of synaptic strength established by cell intrinsic properties and further refined by plasticity. To characterize mechanisms that generate Pr heterogeneity between distinct neuronal populations, we examined glutamatergic tonic (Ib) and phasic (Is) motoneurons in Drosophila with stereotyped differences in Pr and synaptic plasticity. We found the decoy SNARE Tomosyn is differentially expressed between these motoneuron subclasses and contributes to intrinsic differences in their synaptic output. Tomosyn expression enables tonic release in Ib motoneurons by reducing SNARE complex formation and suppressing Pr to generate decreased levels of synaptic vesicle fusion and enhanced resistance to synaptic fatigue. In contrast, phasic release dominates when Tomosyn expression is low, enabling high intrinsic Pr at Is terminals at the expense of sustained release and robust presynaptic potentiation. In addition, loss of Tomosyn disrupts the ability of tonic synapses to undergo presynaptic homeostatic potentiation (PHP).
A Herpes Simplex Virus Type-1-derived influenza vaccine induces balanced adaptive immune responses and protects mice from lethal influenza virus challenge

Influenza virus is a major respiratory viral pathogen responsible for the deaths of hundreds of thousands worldwide each year. Current vaccines provide protection primarily by inducing strain-specific antibody responses with the requirement of a match between vaccine strains and circulating strains. It has been suggested that anti-influenza T-cell responses, in addition to antibody responses may provide the broadest protection against different flu strains. Therefore, to address this urgent need, it is desirable to develop a vaccine candidate with an ability to induce balanced adaptive immunity including cell mediated immune responses. A live viral vector technology should exhibit safety, immunogenicity, effectiveness in the presence of pre-existing immunity, and the ability to induce mucosal immune responses. Here, we used VC2, an established Herpes Simplex Virus type 1 vaccine vector, to express the influenza HA protein. We show that this virus is capable of generating potent and specific anti-influenza humoral and cell-mediated immune responses. We further show that a single vaccination with the VC2-derived influenza vaccine protects mice from lethal challenge with influenza virus. Our data support the continued development of VC2-derived influenza vaccines for protection of human populations from both seasonal and pandemic strains of influenza. Finally, our results support the potential of VC2-derived vaccines as a platform for the rapid development of vaccines against emerging and established pathogens, particularly respiratory pathogens.
Constructing a warhead of PROTAC with aptamer for tumor-selective degradation of nucleolin

PROteolysis TArgeting Chimeras (PROTACs) induce targeted protein degradation by hijacking the intracellular ubiquitin proteasome system, thus emerging as a new strategy for drug development. However, although PROTACs are highly efficient for protein degradation, most PROTACs generated lack cell-type selectivity, resulting in potential off-tissue, on-target toxicity. To address this drawback, we herein developed an aptamer-based PROTAC ZL216 using aptamer AS1411 as a targeting ligand for nucleolin, and it showed both excellent serum stability and water solubility. Based on the differential expression of nucleolin on the cell surface, ZL216 can specifically bind to and internalize into breast cancer cells, but not normal breast cells. Furthermore, we revealed that ZL216 promoted the formation of a nucleolin-ZL216-VHL ternary complex in breast cancer cells and potently induced the degradation of nucleolin in vitro and in vivo, thereby inhibiting the proliferation and migration of breast cancer cells. These studies demonstrated the potential of utilizing aptamers to construct PROTACs to achieve the selective degradation of targeted protein in tumor cells and provided a promising strategy for the development of tumor-selective PROTACs.
Mathematical Relationships between Motoneuron Properties Derived by Empirical Data Analysis: Size Determines All Motoneuron Properties

Our understanding of the behaviour of motoneurons (MNs) in mammals partly relies on our knowledge of the relationships between MN membrane properties, such as MN size, resistance, rheobase, capacitance, time constant, axonal conduction velocity and afterhyperpolarization period. Based on scattered but converging evidence, current experimental studies and review papers qualitatively assumed that some of these MN properties are related. Here, we reprocessed the data from 27 experimental studies in cat and rat MN preparations to empirically demonstrate that all experimentally measured MN properties are associated to MN size. Moreover, we expanded this finding by deriving mathematical relationships between each pair of MN properties. These relationships were validated against independent experimental results not used to derive them. The obtained relationships support the classic description of a MN as a membrane equivalent electrical circuit and describe for the first time the association between MN size and MN membrane capacitance and time constant. The obtained relations indicate that motor units are recruited in order of increasing MN size, muscle unit size, MN rheobase, unit force recruitment thresholds and tetanic forces, but underlines that MN size and recruitment order may not be related to motor unit type.
Structure of PINK1 reveals autophosphorylation dimer and provides insights into binding to the TOM complex

Mutations in PINK1 causes autosomal-recessive Parkinson’s disease. Mitochondrial damage results in PINK1 import arrest on the Translocase of the Outer Mitochondrial Membrane (TOM) complex, resulting in the activation of its ubiquitin kinase activity by autophosphorylation and initiation of Parkin-dependent mitochondrial clearance. Herein we report crystal structures of the entire cytosolic domain of insect PINK1. Our structures reveal a dimeric autophosphorylation complex targeting phosphorylation at the invariant Ser205 (human Ser228). The dimer interface requires insert 2, which is unique to PINK1. The structures also reveal how an N-terminal helix binds to the C-terminal extension and provide insights into stabilization of PINK1 on the core TOM complex.
No broad decline of breeding monarch butterflies in North America: implications for conservation efforts

Many insects are in clear decline, with monarch butterflies (Danaus plexippus) drawing particular attention as a flagship species. Falling numbers of overwintering monarchs are well documented, but there has been debate regarding population trends of summer breeding populations. Here, we compile a series of long-term monarch monitoring datasets, some which are analyzed here for the first time, that reveal highly variable responses across the migratory geographic range, but no broad net decline in numbers of breeding monarchs. We also did not find evidence that sampling biased towards natural sites was masking declines at disturbed sites. Overall, our results suggest a robust resiliency in summer populations that thus far has allowed recovery from losses during the winter. Thus, monarchs may not require as much breeding habitat restoration as once thought, and focus should be on conserving the fall and spring migration.