Heralded Three-Photon Entanglement from a Single-Photon Source on a Photonic Chip.

In the quest to build general-purpose photonic quantum computers, fusion-based quantum computation has risen to prominence as a promising strategy. This model allows a ballistic construction of large cluster states which are universal for quantum computation, in a scalable and loss-tolerant way without feed forward, by fusing many small n-photon entangled resource states. However, a key obstacle to this architecture lies in efficiently generating the required essential resource states on photonic chips. One such critical seed state that has not yet been achieved is the heralded three-photon Greenberger-Horne-Zeilinger (3-GHZ) state. Here, we address this elementary resource gap, by reporting the first experimental realization of a heralded 3-GHZ state. Our implementation employs a low-loss and fully programmable photonic chip that manipulates six indistinguishable single photons of wavelengths in the telecommunication regime. Conditional on the heralding detection, we obtain the desired 3-GHZ state with a fidelity 0.573±0.024. Our Letter marks an important step for the future fault-tolerant photonic quantum computing, leading to the acceleration of building a large-scale optical quantum computer.

A computational framework for predicting novel drug indications using graph convolutional network with contrastive learning.

Inferring potential drug indications plays a vital role in the drug discovery process. It can be time-consuming and costly to discover novel drug indications through biological experiments. Recently, graph learning-based methods have gained popularity for this task. These methods typically treat the prediction task as a binary classification problem, focusing on modeling associations between drugs and diseases within a graph. However, labeled data for drug indication prediction is often limited and expensive to acquire. Contrastive learning addresses this challenge by aligning similar drug-disease pairs and separating dissimilar pairs in the embedding space. Thus, we developed a model called DrIGCL for drug indication prediction, which utilizes graph convolutional networks and contrastive learning. DrIGCL incorporates drug structure, disease comorbidities, and known drug indications to extract representations of drugs and diseases. By combining contrastive and classification losses, DrIGCL predicts drug indications effectively. In multiple runs of hold-out validation experiments, DrIGCL consistently outperformed existing computational methods for drug indication prediction, particularly in terms of top-k. Furthermore, our ablation study has demonstrated a significant improvement in the predictive capabilities of our model when utilizing contrastive learning. Finally, we validated the practical usefulness of DrIGCL by examining the predicted novel indications of Aspirin. The prediction model's code is available at https://github.com/yuxunluo9/DrIGCL.

Microwave Ablation versus Surgical Resection for US-detected Multifocal T1N0M0 Papillary Thyroid Carcinoma: A 10-Center Study.

Background Microwave ablation (MWA) is currently under preliminary investigation for the treatment of multifocal papillary thyroid carcinoma (PTC) and has shown promising treatment efficacy. Compared with surgical resection (SR), MWA is minimally invasive and could preserve thyroid function. However, a comparative analysis between MWA and SR is warranted to draw definitive conclusions. Purpose To compare MWA and SR for preoperative US-detected T1N0M0 multifocal PTC in terms of overall and 1-, 3-, and 5-year progression-free survival rates and complication rates. Materials and Methods In this retrospective study, 775 patients with preoperative US-detected T1N0M0 multifocal PTC treated with MWA or SR across 10 centers between May 2015 and December 2021 were included. Propensity score matching (PSM) was performed for patients in the MWA and SR groups, followed by comparisons between the two groups. The primary outcomes were overall and 1-, 3-, and 5-year progression-free survival (PFS) rates and complication rates. Results After PSM, 229 patients (median age, 44 years [IQR 36.5-50.5 years]; 179 female) in the MWA group and 453 patients (median age, 45 years [IQR 37-53 years]; 367 female) in the SR group were observed for a median of 20 months (range, 12-74 months) and 26 months (range, 12-64 months), respectively. MWA resulted in less blood loss, shorter incision length, and shorter procedure and hospitalization durations (all P < .001). There was no evidence of differences in overall and 1-, 3-, or 5-year PFS rates (all P > .05) between MWA and SR (5-year rate, 77.2% vs 83.1%; P = .36) groups. Permanent hoarseness (2.2%, P = .05) and hypoparathyroidism (4.0%, P = .005) were encountered only in the SR group. Conclusion There was no evidence of a significant difference in PFS rates between MWA and SR for US-detected multifocal T1N0M0 PTC, and MWA resulted in fewer complications. Therefore, MWA is a feasible option for selected patients with multifocal T1N0M0 PTC. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.

Predicting associations between drugs and G protein-coupled receptors using a multi-graph convolutional network.

Developing new drugs is an expensive, time-consuming process that frequently involves safety concerns. By discovering novel uses for previously verified drugs, drug repurposing helps to bypass the time-consuming and costly process of drug development. As the largest family of proteins targeted by verified drugs, G protein-coupled receptors (GPCR) are vital to efficiently repurpose drugs by inferring their associations with drugs. Drug repurposing may be sped up by computational models that predict the strength of novel drug-GPCR pairs interaction. To this end, a number of models have been put forth. In existing methods, however, drug structure, drug-drug interactions, GPCR sequence, and subfamily information couldn't simultaneously be taken into account to detect novel drugs-GPCR relationships. In this study, based on a multi-graph convolutional network, an end-to-end deep model was developed to efficiently and precisely discover latent drug-GPCR relationships by combining data from multi-sources. We demonstrated that our model, based on multi-graph convolutional networks, outperformed rival deep learning techniques as well as non-deep learning models in terms of inferring drug-GPCR relationships. Our results indicated that integrating data from multi-sources can lead to further advancement.

trans-Palmitoleic acid promotes adipose thermogenesis to reduce obesity via hypothalamic FFAR1 signaling.

Diet-induced thermogenesis (DIT) is crucial for maintaining body weight homeostasis, and the role of dietary fatty acids in modulating DIT is essential. However, the underlying mechanism of fatty acid regulated diet-induced thermogenesis remains elusive. Utilizing the diet- and genetic ablation-induced obese mice models, we found that the C16 unsaturated fatty acids, trans-palmitoleic acid (TPA) and cis-palmitoleic acid (CPA), significantly increased the energy expenditure by promoting the thermogenesis of brown adipose tissues and the production of beige cells in white adipose. As a result, there is a significant reduction in the occurrence of obesity, associated hepatic steatosis and hyperglycemia. Notably, TPA exhibited more potent effects on promoting DIT and alleviating obesity than CPA did. Using inhibitor and gene deletion mice models, we unveiled that TPA acted as a signaling molecule to play a biological function, which could be sensed by the hypothalamic FFAR1 to activate the sympathetic nervous system in promoting adipose tissue thermogenesis. Together, these results demonstrate the underlying mechanism of free fatty acids associated-DIT and will provide fresh insights into the roles of trans-fatty acids in the development of obesity.

STK16 promoted colorectal cancer progress in a c-MYC signaling-dependent manner.

BACKGROUND: Colorectal cancer standed as a global health challenge, ranking third in cancer incidence and second in cancer-related deaths worldwide. A deeper understanding of the intricate mechanisms driving colorectal cancer development was pressing need. STK16 had garnered attention in recent researches, while its involvement in cancer had been minimally explored. c-MYC had emerged as a key player in cancer biology. Due to its complex structure, multifunctionality, and intricate interactions, directly inhibiting the activity of c-MYC proves to be challenging. Hence, current research was directing efforts towards modulating c-MYC expression levels. METHODS: Immunoblot, Immunohistochemistry and immunoprecipitation assays were conducted to assess the indicated protein expression levels. RT-PCR was performed to detect the corresponding mRNA expression levels. The proliferation, migration, invasion, and colony formation abilities of the specified cancer cells were investigated using CCK8 assays, Brdu assays, transwell assays, and colony formation assays, respectively. Cellular and animal experiments were performed to investigate the correlation between STK16 signaling and c-MYC signaling. RESULTS: STK16 plays a positive regulatory role in the progression of colorectal cancer. Delving into the molecular mechanisms, we unveiled that STK16 phosphorylated c-MYC at serine 452, a pivotal event hindering the ubiquitin-proteasome pathway degradation of c-MYC. Importantly, colorectal cancer proliferation mediated by STK16 was found to be dependent on the phosphorylation of c-MYC at S452. Furthermore, the researchers demonstrated that STK16 knockout or pharmacological inhibition significantly curtailed colorectal cancer proliferation and c-MYC expression in in vivo animal models. CONCLUSION: We discovered that STK16 phosphorylates c-MYC at serine 452, hindering its degradation via the ubiquitin-proteasome pathway. STK16 inhibition, either genetically or pharmacologically, effectively curtails cancer growth and c-MYC expression in vivo. These findings highlight STK16 as a potential therapeutic target for colorectal cancer.

Protein-enriched soup and weekly exercise improve muscle health: A randomized trial in mid-to-old age with inadequate protein intake.

BACKGROUND: Prior research has highlighted the synergistic impact of protein supplementation on muscle function post-exercise in adults; however, evidence supporting the combined effects were less robust and inconsistent on those with protein insufficiency. This investigation aims to explore efficacy of protein-enriched soup coupled with exercise on muscle health and metabolism in middle-aged and older adults with suboptimal protein intake. METHODS: An open-label, 12-week, randomized controlled trial involving participants with insufficient protein intake (<1.0 g/kg/day) was done. The intervention group consumed protein-enriched soup (24-30 g protein daily) and 1-h weekly exercise, while controls received health education. Assessments included laboratory tests, functional assessments, and body composition. RESULTS: In this trial, 97 out of 100 randomized participants (mean age: 64.65 ± 4.84 years, 81.8% female) completed the study (47 in intervention group and 50 in control group). Compared results of baselines, at 1 and 3 months of intervention, significant improvements in waist circumference (83.48 ± 10.22 vs. 82.5 ± 9.88 vs. 82.37 ± 9.42 cm, P for trend = 0.046), 6-min walking distance (525.65 ± 58.46 vs. 534.47 ± 51.87 vs. 552.02 ± 57.66 m, P for trend = 0.001), five-time sit-to-stand time (7.63 ± 1.63 vs. 6.81 ± 1.8 vs. 6.4 ± 1.42 s, P for trend <0.001), grip strength (26.74 ± 6.54 vs. 27.53 ± 6.99 vs. 28.52 ± 7.09 kg, P for trend <0.001), and MNA score (26.8 ± 2.14 vs. 27.73 ± 1.74 vs. 27.55 ± 1.72, P for trend <0.001) were discerned within the intervention group. The intervention demonstrated a significant reduction in serum triglyceride (105.32 ± 49.84 vs. 101.36 ± 42.58 vs. 93.43 ± 41.49 mg/dL, P for trend = 0.023), increased HDL-C (60.04 ± 16.21 vs. 60 ± 17.37 vs. 62.55 ± 18.27 mg/dL, P for trend = 0.02), and DHEA-S levels (97.11 ± 54.39 vs. 103.39 ± 56.75 vs. 106.83 ± 60.56 µg/dL, P for trend = 0.002). Serum myostatin did not differ in both groups, but serum leptin levels significantly increased (9118.88 ± 5811.68 vs. 11508.97 ± 7151.08 vs. 11220.80 ± 7190.71 pg/mL, P for trend = 0.016) in controls. The intervention group showed greater improvements in 6 min walking distance (ß = 0.71, 95% CI: 6.88 to 40.79, P = 0.006), five-time sit-to-stand test (ß = -0.87, 95% CI: -1.59 to -0.15, P = 0.017), MNA score (ß = 0.96, 95% CI: 0.20 to 1.71, P = 0.013), serum triglycerides (ß = -15.01, 95% CI: -27.83 to -2.20, P = 0.022), LDL-C (ß = -9.23, 95% CI: -16.98 to -1.47, P = 0.020), and DHEA-S levels (ß = 9.98, 95% CI: 0.45 to 19.51, P = 0.04) than controls. CONCLUSIONS: Protein-enriched soup with weekly exercise over 12 weeks significantly improved physical performance, lipid profile, and DHEA-S levels among middle-aged and older adults with inadequate protein intake, while studies assessing long-term benefits of the intervention are needed.

Efficacy and safety of antibiotics for treatment of leptospirosis: a systematic review and network meta-analysis.

BACKGROUND: Leptospirosis, an important zoonotic bacterial disease, commonly affects resource-poor populations and results in significant morbidity and mortality worldwide. The value of antibiotics in leptospirosis remains unclear, as evidenced by the conflicting opinions published. METHODS: We conducted a search in the PubMed, Web of Science, and Cochrane Library databases for studies. These studies included clinical trials and retrospective studies that evaluated the efficacy or safety of antibiotics for leptospirosis treatment. The primary outcomes assessed were defervescence time, mortality rate, and hospital stays. Subgroup analyses were performed based on whether there were cases involving children and whether there were cases of severe jaundice. Safety was defined as the prevalence of adverse events associated with the use of antibiotics. p scores were utilized to rank the efficacy of the antibiotics. RESULTS: There are included 9 randomized controlled trials (RCTs), 1 control trial (CT), and 3 retrospective studies (RS) involving 920 patients and 8 antibiotics. Six antibiotics resulted in significantly shorter defervescence times compared to the control, namely cefotaxime (MD, - 1.88; 95% CI = - 2.60 to - 1.15), azithromycin (MD, - 1.74; 95% CI = - 2.52 to - 0.95), doxycycline (MD, - 1.53; 95% CI = - 2.05 to - 1.00), ceftriaxone (MD, - 1.22; 95% CI = - 1.89 to - 0.55), penicillin (MD, - 1.22; 95% CI = - 1.80 to - 0.64), and penicillin or ampicillin (MD, - 0.08; 95% CI = - 1.01 to - 0.59). The antibiotics were not effective in reducing the mortality and hospital stays. Common adverse reactions to antibiotics included Jarisch-Herxheimer reaction, rash, headache, and digestive reactions (nausea, vomiting, diarrhea, abdominal pain, and others). CONCLUSIONS: Findings recommend that leptospirosis patients be treated with antibiotics, which significantly reduced the leptospirosis defervescence time. Cephalosporins, doxycycline, and penicillin are suggested, and azithromycin may be a suitable alternative for drug-resistant cases. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022354938.

Asymmetric segregation of maternal mRNAs and germline-related determinants in Cephalochordate embryos: implications for the evolution of early patterning events in chordates.

How animal embryos determine their early cell fates is an important question in developmental biology. In various model animals asymmetrically localized maternal transcripts play important roles in axial patterning and cell fate specification. Cephalochordates (amphioxus), which have three living genera (Asymmetron, Epigonichthys, Branchiostoma), are an early branching chordate lineage and thus occupy a key phylogenetic position for understanding the evolution of chordate developmental mechanisms. It has been shown that in the zygote of Brachiostoma amphioxus, which possess bilateral gonads flanking both sides of their trunk region, maternal transcripts of germline determinants form a compact granule. During early embryogenesis this granule is inherited by a single blastomere that subsequently gives rise to a cluster of cells displaying typical characteristics of primordial germ cells (PGC). These PGCs then come to lie in the tailbud region and proliferate during posterior elongation of the larva to join in the gonad anlagen at the ventral tip of the developing myomeres in amphioxus larvae. However, in Asymmetron and Epigonichthys amphioxus, whose gonads are present only on the right side of their body, nothing is known about their PGC development or the cellular/morphogenetic processes resulting in the asymmetric distribution of gonads. Using conserved germline determinants as markers, we show that similarly to Brachiostoma amphioxus, Asymmetron also employ a preformation mechanism to specify their PGCs, suggesting that this mechanism represents an ancient trait dating back to the common ancestor of Cephalochordates. Surprisingly, we found that Asymmetron PGCs are initially deposited on both sides of the body during early larval development; however, the left side PGCs cease to exist in young juveniles, suggesting that PGCs are eliminated from the left body side during larval development or following metamorphosis. This is reminiscent of the PGC development in the sea urchin embryo, and we discuss the implications of this observation for the evolution of developmental mechanisms.

Identification of Novel FZD4 Mutations in Familial Exudative Vitreoretinopathy and Investigating the Pathogenic Mechanisms of FZD4 Mutations.

Purpose: The purpose of this study is to report five novel FZD4 mutations identified in familial exudative vitreoretinopathy (FEVR) and to analyze and summarize the pathogenic mechanisms of 34 of 96 reported missense mutations in FZD4. Methods: Five probands diagnosed with FEVR and their family members were enrolled in the study. Ocular examinations and targeted gene panel sequencing were conducted on all participants. Plasmids, each carrying 29 previously reported FZD4 missense mutations and five novel mutations, were constructed based on the selection of mutations from each domain of FZD4. These plasmids were used to investigate the effects of mutations on protein expression levels, Norrin/ß-catenin activation capacity, membrane localization, norrin binding ability, and DVL2 recruitment ability in HEK293T, HEK293STF, and HeLa cells. Results: All five novel mutations (S91F, V103E, C145S, E160K, C377F) responsible for FEVR were found to compromise Norrin/ß-catenin activation of FZD4 protein. After reviewing a total of 34 reported missense mutations, we categorized all mutations based on their functional changes: signal peptide mutations, cysteine mutations affecting disulfide bonds, extracellular domain mutations influencing norrin binding, transmembrane domain (TM) 1 and TM7 mutations impacting membrane localization, and intracellular domain mutations affecting DVL2 recruitment. Conclusions: We expanded the spectrum of FZD4 mutations relevant to FEVR and experimentally demonstrated that missense mutations in FZD4 can be classified into five categories based on different functional changes.

Shank3 deficiency elicits autistic-like behaviors by activating p38α in hypothalamic AgRP neurons.

BACKGROUND: SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38α, a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38α are involved in the development of autism caused by Shank3 mutations or deficiency. METHODS: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3-/-) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38α in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38α. T180A and Y182F mutations expressed inactive p38α. RESULTS: We found that Shank3 controls stereotypic behavior and sociability by regulating p38α activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3-/- mice. Consistently, overexpression of p38α in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38α in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. In contrast, activated p38α in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. LIMITATIONS: We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38α in AgRP neurons. CONCLUSIONS: These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38α signaling in AgRP neurons, suggesting that p38α signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism.

Electroacupuncture alters brain network functional connectivity in subacute stroke: A randomised crossover trial.

BACKGROUND: Electroacupuncture (EA) is a promising rehabilitation treatment for upper-limb motor recovery in stroke patients. However, the neurophysiological mechanisms underlying its clinical efficacy remain unclear. This study aimed to explore the immediate modulatory effects of EA on brain network functional connectivity and topological properties. METHODS: The randomized, single-blinded, self-controlled two-period crossover trial was conducted among 52 patients with subacute subcortical stroke. These patients were randomly allocated to receive either EA as the initial intervention or sham electroacupuncture (SEA) as the initial intervention. After a washout period of 24 hours, participants underwent the alternate intervention (SEA or EA). Resting state electroencephalography signals were recorded synchronously throughout both phases of the intervention. The functional connectivity (FC) of the parietofrontal network and small-world (SW) property indices of the whole-brain network were compared across the entire course of the two interventions. RESULTS: The results demonstrated that EA significantly altered ipsilesional parietofrontal network connectivity in the alpha and beta bands (alpha: F = 5.05, P = .011; beta: F = 3.295, P = .047), whereas no significant changes were observed in the SEA group. When comparing between groups, EA significantly downregulated ipsilesional parietofrontal network connectivity in both the alpha and beta bands during stimulation (alpha: t = -1.998, P = .049; beta: t = -2.342, P = .022). Significant differences were also observed in the main effects of time and the group × time interaction for the SW index (time: F = 5.516, P = .026; group × time: F = 6.892, P = .01). In terms of between-group comparisons, the EA group exhibited a significantly higher SW index than the SEA group at the post-stimulation stage (t = 2.379, P = .018). CONCLUSION: These findings suggest that EA downregulates ipsilesional parietofrontal network connectivity and enhances SW properties, providing a potential neurophysiological mechanism for facilitating motor performance in stroke patients.

Heterochronous multiple primary prostate cancer and lymphoma: A case report.

BACKGROUND: Multiple primary malignant tumors (MPMTs) are rare type of cancer, especially when solid tumors are the first and lymphoma is the second primary malignancy. We report a patient with heterochronous MPMTs consisting of prostate cancer and rectal diffuse large B-cell lymphoma (DLBCL). CASE SUMMARY: We report a 77-year-old male patient diagnosed with prostate cancer who was treated with radiation therapy and one year of endocrine therapy with bicalutamide (50 mg per day) and an extended-release implant of goserelin (1/28 d). Seven years later, rectal DLBCL with lung metastases was found. CONCLUSION: Although rare, the possibility of prostate cancer combined with a double primary cancer of DLBCL can provide a deeper understanding.

Correlation of Gut Microbiota with Children Obesity and Weight Loss.

Children obesity is a serious public health problem drawing much attention around the world. Recent research indicated that gut microbiota plays a vital role in children obesity, and disturbed gut microbiota is a prominent characteristic of obese children. Diet and exercise are efficient intervention for weight loss in obesity children, however, how the gut microbiota is modulated which remains largely unknown. To characterize the feature of gut microbiota in obese children and explore the effect of dietary and exercise on gut microbiota in simple obese children, 107 healthy children and 86 obese children were recruited, and among of the obese children 39 received the dietary-exercise combined weight loss intervention (DEI). The gut microbiota composition was detected by the 16S amplicon sequencing method. The gut microbiota composition was significantly different between obese children and the healthy cohort, and DEI significantly reduced the body weight and ameliorated the gut microbiota dysbiosis. After DEI, the abundance of the Akkermansia muciniphila was increased, while the abundance of the Sutterella genus was decreased in simple obese children. Our results may provide theoretical reference for future personalized obesity interventions based on gut microbiota. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01088-3.

Thyroid hormone deprival and TSH/TSHR signaling deficiency lead to central hypothyroidism-associated intestinal dysplasia.

BACKGROUND: Central hypothyroidism (CH) is characterized by low T4 levels and reduced levels or bioactivity of circulating TSH. However, there is a lack of studies on CH-related intestinal maldevelopment. In particular, the roles of TH and TSH/TSHR signaling in CH-related intestinal maldevelopment are poorly understood. Herein, we utilized Tshr-/- mice as a congenital hypothyroidism model with TH deprival and absence of TSHR signaling. METHODS: The morphological characteristics of intestines were determined by HE staining, periodic acid-shiff staining, and immunohistochemical staining. T4 was administrated into the offspring of homozygous mice from the fourth postnatal day through weaning or administrated after weaning. RT-PCR was used to evaluate the expression of markers of goblet cells and intestinal digestive enzymes. Single-cell RNA-sequencing analysis was used to explore the cell types and gene profiles of metabolic alternations in early-T4-injected Tshr-/- mice. KEY FINDINGS: Tshr deletion caused significant growth retardation and intestinal maldevelopment, manifested as smaller and more slender small intestines due to reduced numbers of stem cells and differentiated epithelial cells. Thyroxin supplementation from the fourth postnatal day, but not from weaning, significantly rescued the abnormal intestinal structure and restored the decreased number of proliferating intestinal cells in crypts of Tshr-/- mice. Tshr-/- mice with early-life T4 injections had more early goblet cells and impaired metabolism compared to Tshr+/+ mice. SIGNIFICANCE: TH deprival leads to major defects of CH-associated intestinal dysplasia while TSH/TSHR signaling deficiency promotes the differentiation of goblet cells and impairs nutrition metabolism.

Characterization of a novel heterozygous frameshift variant in NDP gene that causes familial exudative vitreoretinopathy in female patients.

Familial exudative vitreoretinopathy (FEVR) is a severe inherited disease characterized by defective retinal vascular development. With genetic and clinical heterogeneity, FEVR can be inherited in different patterns and characterized by phenotypes ranging from moderate visual defects to complete vision loss. This study was conducted to unravel the genetic and functional etiology of a 4-month-old female FEVR patient. Targeted gene panel and Sanger sequencing were utilized for genetic evaluation. Luciferase assays, western blot, quantitive real-time PCR, and immunocytochemistry were performed to verify the functional defects in the identified candidate variant. Here, we report a 4-month-old girl with bilateral retinal folds and peripheral avascularization, and identified a novel frameshift heterozygous variant c.37dup (p.Leu13ProfsTer13) in NDP. In vitro experiments revealed that the Leu13ProfsTer13 variant led to a prominent decrease in protein levels instead of mRNA levels, resulting in compromised Norrin/ß-catenin signaling activity. Human androgen receptor assay further revealed that a slight skewing of X chromosome inactivation could partially cause FEVR. Thus, the pathogenic mechanism by which heterozygous frameshift or nonsense variants in female carriers cause FEVR might largely result from a loss-of-function variant in one X chromosome allele and a slightly skewed X-inactivation. Further recruitment of more FEVR-affected females carrying NDP variants and genotype-phenotype correlation analysis can ultimately offer valuable information for the prognosis prediction of FEVR.

Induced Mesenchymal Stem Cells-Small Extracellular Vesicles Alleviate Post-stroke Cognitive Impairment by Rejuvenating Senescence of Neural Stem Cells.

Ischemic stroke is typified by hypoxia and a cascade of pathophysiological events, including metabolic dysfunction, ionic dysregulation, excitotoxicity, inflammatory infiltration, and oxidative stress. These ultimately result in neuronal apoptosis or necrosis with constrained neuroregenerative capabilities. In this study, neural stem cells (NSCs) under conditions of oxygen-glucose deprivation (OGD) in vitro and following middle cerebral artery occlusion (MCAO) in vivo were explored. Transcriptome sequencing revealed a decline in NSC differentiation and neurogenesis after OGD exposure, which was related to cellular senescence. This observation was corroborated by increased senescence markers in the MCAO mouse model, reduction in NSC numbers, and decline in neurogenesis. Importantly, iMSC-sEVs (induced mesenchymal stem cells-small extracellular vesicles) have the therapeutic potential to alleviate NSC senescence and rejuvenate their regenerative capacities both in vitro and in vivo. Moreover, iMSC-sEVs contribute to the recovery of cognitive function and synapse loss caused by MCAO.

Pcolce2 overexpression promotes supporting cell reprogramming in the neonatal mouse cochlea.

Hair cell (HC) damage is a leading cause of sensorineural hearing loss, and in mammals supporting cells (SCs) are unable to divide and regenerate HCs after birth spontaneously. Procollagen C-endopeptidase enhancer 2 (Pcolce2), which encodes a glycoprotein that acts as a functional procollagen C protease enhancer, was screened as a candidate regulator of SC plasticity in our previous study. In the current study, we used adeno-associated virus (AAV)-ie (a newly developed adeno-associated virus that targets SCs) to overexpress Pcolce2 in SCs. AAV-Pcolce2 facilitated SC re-entry into the cell cycle both in cultured cochlear organoids and in the postnatal cochlea. In the neomycin-damaged model, regenerated HCs were detected after overexpression of Pcolce2, and these were derived from SCs that had re-entered the cell cycle. These findings reveal that Pcolce2 may serve as a therapeutic target for the regeneration of HCs to treat hearing loss.

A novel deep-learning based weighted feature fusion architecture for precise classification of pressure injury.

Introduction: Precise classification has an important role in treatment of pressure injury (PI), while current machine-learning or deeplearning based methods of PI classification remain low accuracy. Methods: In this study, we developed a deeplearning based weighted feature fusion architecture for fine-grained classification, which combines a top-down and bottom-up pathway to fuse high-level semantic information and low-level detail representation. We validated it in our established database that consist of 1,519 images from multi-center clinical cohorts. ResNeXt was set as the backbone network. Results: We increased the accuracy of stage 3 PI from 60.3% to 76.2% by adding weighted feature pyramid network (wFPN). The accuracy for stage 1, 2, 4 PI were 0.870, 0.788, and 0.845 respectively. We found the overall accuracy, precision, recall, and F1-score of our network were 0.815, 0.808, 0.816, and 0.811 respectively. The area under the receiver operating characteristic curve was 0.940. Conclusions: Compared with current reported study, our network significantly increased the overall accuracy from 75% to 81.5% and showed great performance in predicting each stage. Upon further validation, our study will pave the path to the clinical application of our network in PI management.

Prediction of survival and analysis of prognostic factors for patients with AFP negative hepatocellular carcinoma: a population-based study.

PURPOSE: Hepatocellular carcinoma (HCC) has a poor prognosis, and alpha-fetoprotein (AFP) is widely used to evaluate HCC. However, the proportion of AFP-negative individuals cannot be disregarded. This study aimed to establish a nomogram of risk factors affecting the prognosis of patients with AFP-negative HCC and to evaluate its diagnostic efficiency. PATIENTS AND METHODS: Data from patients with AFP-negative initial diagnosis of HCC (ANHC) between 2004 and 2015 were collected from the Surveillance, Epidemiology, and End Results database for model establishment and validation. We randomly divided overall cohort into the training or validation cohort (7:3). Univariate and multivariate Cox regression analysis were used to identify the risk factors. We constructed nomograms with overall survival (OS) and cancer-specific survival (CSS) as clinical endpoint events and constructed survival analysis by using Kaplan-Meier curve. Also, we conducted internal validation with Receiver Operating Characteristic (ROC) analysis and Decision curve analysis (DCA) to validate the clinical value of the model. RESULTS: This study included 1811 patients (1409 men; 64.7% were Caucasian; the average age was 64 years; 60.7% were married). In the multivariate analysis, the independent risk factors affecting prognosis were age, ethnicity, year of diagnosis, tumor size, tumor grade, surgery, chemotherapy, and radiotherapy. The nomogram-based model related C-indexes were 0.762 (95% confidence interval (CI): 0.752-0.772) and 0.752 (95% CI: 0.740-0.769) for predicting OS, and 0.785 (95% CI: 0.774-0.795) and 0.779 (95% CI: 0.762-0.795) for predicting CSS. The nomogram model showed that the predicted death was consistent with the actual value. The ROC analysis and DCA showed that the nomogram had good clinical value compared with TNM staging. CONCLUSION: The age(HR:1.012, 95% CI: 1.006-1.018, P-value < 0.001), ethnicity(African-American: HR:0.946, 95% CI: 0.783-1.212, P-value: 0.66; Others: HR:0.737, 95% CI: 0.613-0.887, P-value: 0.001), tumor diameter(HR:1.006, 95% CI: 1.004-1.008, P-value < 0.001), year of diagnosis (HR:0.852, 95% CI: 0.729-0.997, P-value: 0.046), tumor grade(Grade 2: HR:1.124, 95% CI: 0.953-1.326, P-value: 0.164; Grade 3: HR:1.984, 95% CI: 1.574-2.501, P-value < 0.001; Grade 4: HR:2.119, 95% CI: 1.115-4.027, P-value: 0.022), surgery(Liver Resection: HR:0.193, 95% CI: 0.160-0.234, P-value < 0.001; Liver Transplant: HR:0.102, 95% CI: 0.072-0.145, P-value < 0.001), chemotherapy(HR:0.561, 95% CI: 0.471-0.668, P-value < 0.001), and radiotherapy(HR:0.641, 95% CI: 0.463-0.887, P-value:0.007) were independent prognostic factors for patients with ANHC. We developed a nomogram model for predicting the OS and CSS of patients with ANHC, with a good predictive performance.