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TRα1 mutant suppresses KLF9 to cause endometrial metaplasia with ectopic IL-33 expression leading to uterine fibrosis and infertility
Abstract Thyroid hormone receptors (TRs) mediate the genomic actions of thyroid hormone. Mutations of THRA gene cause a human disease known as resistance to thyroid hormone (RTHα). We created a mouse model expressing a dominant negative mutated TRα1 (Thra1PV/+ mice) that exhibits growth retardation, bone abnormalities, constipation, and anemia, as found in RTHα patients. In addition, female Thra1PV/+ mice exhibit decreased fertility. In the present study, we aimed to characterize the molecular events leading to infertility. Histologically, there was progressive uterine atrophy in Thra1PV/+ mutant mice, characterized by squamous metaplasia of the endometrial mucosa and endometrial fibrosis. RNA-seq analysis of laser-captured micro-dissected endometrium and spatial transcriptomics revealed a key role for Krüppel-like factor (Klf9), a directly-regulated TR target gene, in normal endometrial differentiation. Klf9 was suppressed in the endometrium of mice harboring mutated TRα1 and pathway analysis revealed that deficient Klf9 signaling was associated with squamous differentiation, consistent with the endometrial metaplasia observed histologically. Further, we showed that this metaplastic endometrial mucosa was the source of ectopic IL-33, which was associated with increased T-cell infiltrates, destruction of glands, and endometrial fibrosis. Our studies provide new insights to understand uterine epithelial morphogenesis and how thyroid dysfunction could lead to female infertility.
Geometric morphometrics approach for classifying children’s nutritional status on out of sample data
Prognostic impact of moderate to severe anemia associated with renal dysfunction in patients with heart failure
Dimethyl fumarate effects on paraquat-induced hepatotoxicity in mice via anti-oxidative, anti-inflammatory, and anti-apoptotic activities
The computerized algorithm for renal assessment improves diagnostic accuracy of renal impairment in hospitalized patients
Abstract In hospitalized patients, acute kidney injury (AKI) is an important adverse event associated with high mortality and medical costs. Accurate diagnosis and timely management of AKI are essential for improving the outcomes of in-hospital AKI, and delayed diagnosis or misdiagnosis hinders advancements in AKI care. To ameliorate this problem, several electronic AKI alert systems have been proposed but have shown inconsistent effects on AKI outcomes. Before electronic systems can improve AKI outcomes, it is important to confirm their diagnostic accuracy. The purposes of the present study were to establish an easy-to-construct computerized algorithm for the diagnosis of renal impairment and to test its accuracy. The present study retrospectively included 1551 patients hospitalized in Wanfang Hospital with serum creatinine (SCr) levels > 1.3 mg/dL. A computerized algorithm was constructed to identify AKI events and chronic kidney disease (CKD) in these patients. Previous SCr tests were reviewed to define baseline SCr levels. A SCr level increased > 1.5 times from baseline was defined as AKI. An estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m 2 for > 90 days was defined as CKD. Discharge diagnoses made by the attending physicians were defined as “clinician’s diagnoses.” The researcher’s diagnoses, made by experienced nephrologists according to the same criteria, were the gold standard to which the computerized algorithms and the clinician’s diagnoses were compared. The diagnoses made by the computerized algorithm and clinician were compared with the researcher’s diagnoses to define their accuracy. Among the included patients, the mean age was 73.0 years; in-hospital mortality was 14.8%, and AKI was present in 28.6% of patients. Regarding the diagnostic accuracy for AKI, the computerized algorithm achieved a sensitivity of 85.6% and a specificity of 98.8%. The main cause of false-negative (FN) AKI diagnosis was AKI occurring prior to the outpatient visit, before the indexed hospitalization. Regarding the diagnostic accuracy for CKD, the computerized algorithm achieved a sensitivity of 94.7% and specificity of 100%. The main cause of FN CKD diagnosis was the lack of previous eGFR records. The computerized algorithm exhibited significantly superior accuracy compared to the clinician’s diagnoses for both AKI (95.0% vs. 57.0%) and CKD (96.5% vs. 73.6%). We developed a simple and easy-to-construct computerized algorithm for the diagnosis of renal impairment that demonstrated significantly improved diagnostic accuracy for AKI and CKD compared to that of clinicians. In the future, an algorithmic approach for the differential diagnosis of AKI and a decision guide should be incorporated into this system.
Kinematic characteristics in patients with subcortical vascular cognitive impairment: a quantitative analysis of digitized spiral drawing metrics
GATFELPA integrates graph attention networks and enhanced label propagation for robust community detection
Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation
De novo design of protein minibinder agonists of TLR3
Abstract Toll-like Receptor 3 (TLR3) is a pattern recognition receptor that initiates antiviral immune responses upon binding double-stranded RNA (dsRNA). Several nucleic acid-based TLR3 agonists have been explored clinically as vaccine adjuvants in cancer and infectious disease, but present substantial manufacturing and formulation challenges. Here, we use computational protein design to create novel miniproteins that bind to human TLR3 with nanomolar affinities. Cryo-EM structures of two minibinders in complex with TLR3 reveal that they bind the target as designed, although one partially unfolds due to steric competition with a nearby N-linked glycan. Multivalent forms of both minibinders induce NF-κB signaling in TLR3-expressing cell lines, demonstrating that they may have therapeutically relevant biological activity. Our work provides a foundation for the development of specific, stable, and easy-to-formulate protein-based agonists of TLRs and other pattern recognition receptors.
Machine learning-enhanced high-resolution exposure assessment of ultrafine particles
Construction of functional covalent organic framework films by modulator and solvent induced polymerization
Versatile nitrate-respiring heterotrophs are previously concealed contributors to sulfur cycle
Abstract Heterotrophic denitrifiers play crucial roles in global carbon and nitrogen cycling. However, their inability to oxidize sulfide renders them vulnerable to this toxic molecule, which inhibits the key enzymatic reaction responsible for reducing nitrous oxide (N2O), thereby raising greenhouse gas emissions. Here, we applied microcosm incubations, community-isotope-corrected DNA stable-isotope probing, and metagenomics to characterize a cohort of heterotrophic denitrifiers in estuarine sediments that thrive by coupling sulfur oxidation with denitrification through chemolithoheterotrophic metabolism. Remarkably, ecophysiology experiments from enrichments demonstrate that such heterotrophs expedite denitrification with sulfur acting as alternative electron sources and substantially curtail N2O emissions in both organic-rich and organic-limited environments. Their flexible, non-sulfur-dependent physiology may confer competitive advantages over conventional heterotrophic denitrifiers in detoxifying sulfide, adapting to organic matter fluctuations, and mitigating greenhouse gas emissions. Our study provides insights into the ecological role of heterotrophic denitrifiers in microbial communities with implications for sulfur cycling and climate change.
Measuring mean radiant temperature for indoor comfort assessment using low-resolution optical sensors
Degeneracy-breaking and long-lived multimode microwave electromechanical systems enabled by cubic silicon-carbide membrane crystals
NSm is a critical determinant for bunyavirus transmission between vertebrate and mosquito hosts
Abstract Bunyavirales is a very large order including viruses infecting a variety of taxonomic groups such as arthropods, vertebrates, plants, and protozoa. Some bunyaviruses are transmitted between vertebrate hosts by blood-sucking arthropods and cause major diseases in humans and animals. It is not understood why only some bunyaviruses have evolved the capacity to be transmitted by arthropod vectors. Here we show that only vector-borne bunyaviruses express a non-structural protein, NSm, whose function has so far remained largely elusive. Using as experimental system Bunyamwera virus (BUNV) and its invertebrate host, Aedes aegypti, we show that NSm is dispensable for viral replication in mosquito cells in vitro but is absolutely required for successful infection in the female mosquito following a blood meal. More specifically, NSm is required for cell-to-cell spread and egress from the mosquito midgut, a known barrier to viral infection. Notably, the requirement for NSm is specific to the midgut; bypassing this barrier by experimental intrathoracic infection of the mosquito eliminates the necessity of NSm for virus spread in other tissues, including the salivary glands. Overall, we unveiled a key evolutionary process that allows the transmission of vector-borne bunyaviruses between arthropod and vertebrate hosts.
Cell adhesion and spreading on fluid membranes through microtubules-dependent mechanotransduction
STICI: Split-Transformer with integrated convolutions for genotype imputation
Regeneration in the absence of canonical neoblasts in an early branching flatworm
Abstract The remarkable regenerative abilities of flatworms are closely linked to neoblasts – adult pluripotent stem cells that are the only division-competent cell type outside of the reproductive system. Although the presence of neoblast-like cells and whole-body regeneration in other animals has led to the idea that these features may represent the ancestral metazoan state, the evolutionary origin of both remains unclear. Here we show that the catenulid Stenostomum brevipharyngium , a member of the earliest-branching flatworm lineage, lacks conventional neoblasts despite being capable of whole-body regeneration and asexual reproduction. Using a combination of single-nuclei transcriptomics, in situ gene expression analysis, and functional experiments, we find that cell divisions are not restricted to a single cell type and are associated with multiple fully differentiated somatic tissues. Furthermore, the cohort of germline multipotency genes, which are considered canonical neoblast markers, are not expressed in dividing cells, but in the germline instead, and we experimentally show that they are neither necessary for proliferation nor regeneration. Overall, our results challenge the notion that canonical neoblasts are necessary for flatworm regeneration and open up the possibility that neoblast-like cells may have evolved convergently in different animals, independent of their regenerative capacity.
Single-cell profiling of penta- and tetradactyl mouse limb buds identifies mesenchymal progenitors controlling digit numbers and identities
Abstract The cellular interactions controlling digit numbers and identities have remained largely elusive. Here, we leverage the anterior digit and identity loss in Grem1 tetradactyl mouse limb buds to identify early specified limb bud mesenchymal progenitor (LMP) populations whose size and distribution is governed by spatial modulation of BMP activity and SHH signaling. D istal-autopodial LMPs (dLMP) express signature genes required for autopod and digit development, and alterations affecting the dLMP population size prefigure the changes in digit numbers that characterize specific congenital malformations. A second, p eripheral LMP (pLMP) population is anteriorly biased and reduction/loss of its asymmetric distribution underlies the loss of middle digit asymmetry and identities in Grem1 tetradactyl and pig limb buds. pLMPs depend on BMP activity, while dLMPs require GREM1-mediated BMP antagonism. Taken together, the spatial alterations in GREM1 antagonism in mouse mutant and evolutionarily diversified pig limb buds tunes BMP activity, which impacts dLMP and pLMP populations in an opposing manner.