A Comparative Study of Prevalence and Associated Factors of Social Support Among Chinese Shidu Parents and Non-Shidu Parents.

The number of parents in China who have lost their only child, referred to as shidu parents, currently exceeds one million and is increasing by approximately 76,000 annually. Shidu parents face a unique challenge in long-term care, primarily stemming from the sudden and tragic loss of their only child, which leads to a substantial decrease in their social support network. A multi-stage, stratified, and cluster sampling method was employed across various economic belts. Linear regression analysis was utilized to examine factors associated with the social support status of shidu and non-shidu parents. The level of social support decreases as the severity of depression increases. Shidu parents with grandchildren tend to have good social support. The city of Hangzhou exhibits relatively high levels of social support. Married individuals typically report higher levels of social support. It is recommended to prioritize shidu parents without grandchildren as a primary focus for government and societal support. Key recommendations include strengthening social skills training and developing social support networks. Drive economic development, particularly in relatively underdeveloped regions. Strengthen social organizations and community development. Enhancing access to support services, leveraging technology, and encouraging volunteerism for non-married parents.

Extracellular loop 2 of G protein-coupled olfactory receptors is critical for odorant recognition.

G protein-coupled olfactory receptors (ORs) enable us to detect innumerous odorants. They are also ectopically expressed in nonolfactory tissues and emerging as attractive drug targets. ORs can be promiscuous or highly specific, which is part of a larger mechanism for odor discrimination. Here, we demonstrate that the OR extracellular loop 2 (ECL2) plays critical roles in OR promiscuity and specificity. Using site-directed mutagenesis and molecular modeling, we constructed 3D OR models in which ECL2 forms a lid over the orthosteric pocket. We demonstrate using molecular dynamics simulations that ECL2 controls the shape and volume of the odorant-binding pocket, maintains the pocket hydrophobicity, and acts as a gatekeeper of odorant binding. Therefore, we propose the interplay between the specific orthosteric pocket and the variable, less specific ECL2 controls OR specificity and promiscuity. Furthermore, the 3D models created here enabled virtual screening of new OR agonists and antagonists, which exhibited a 70% hit rate in cell assays. Our approach can potentially be generalized to structure-based ligand screening for other G protein-coupled receptors that lack high-resolution 3D structures.

TMEM59 ablation leads to loss of olfactory sensory neurons and impairs olfactory functions via interaction with inflammation.

The olfactory epithelium undergoes constant neurogenesis throughout life in mammals. Several factors including key signaling pathways and inflammatory microenvironment regulate the maintenance and regeneration of the olfactory epithelium. In this study, we identify TMEM59 (also known as DCF1) as a critical regulator to the epithelial maintenance and regeneration. Single-cell RNA-Seq data show downregulation of TMEM59 in multiple epithelial cell lineages with aging. Ablation of TMEM59 leads to apparent alteration at the transcriptional level, including genes associated with olfactory transduction and inflammatory/immune response. These differentially expressed genes are key components belonging to several signaling pathways, such as NF-κB, chemokine, etc. TMEM59 deletion impairs olfactory functions, attenuates proliferation, causes loss of both mature and immature olfactory sensory neurons, and promotes infiltration of inflammatory cells, macrophages, microglia cells and neutrophils into the olfactory epithelium and lamina propria. TMEM59 deletion deteriorates regeneration of the olfactory epithelium after injury, with significant reduction in the number of proliferative cells, immature and mature sensory neurons, accompanied by the increasing number of inflammatory cells and macrophages. Anti-inflammation by dexamethasone recovers neuronal generation and olfactory functions in the TMEM59-KO animals, suggesting the correlation between TMEM59 and inflammation in regulating the epithelial maintenance. Collectively, TMEM59 regulates olfactory functions, as well as neuronal generation in the olfactory epithelium via interaction with inflammation, suggesting a potential role in therapy against olfactory dysfunction associated with inflamm-aging.

Few-Shot Learning for WiFi Fingerprinting Indoor Positioning.

In recent years, deep-learning-based WiFi fingerprinting has been intensively studied as a promising technology for providing accurate indoor location services. However, it still demands a time-consuming and labor-intensive site survey and suffers from the fluctuation of wireless signals. To address these issues, we propose a prototypical network-based positioning system, which explores the power of few-shot learning to establish a robust RSSI-position matching model with limited labels. Our system uses a temporal convolutional network as the encoder to learn an embedding of the individual sample, as well as its quality. Each prototype is a weighted combination of the embedded support samples belonging to its position. Online positioning is performed for an embedded query sample by simply finding the nearest position prototype. To mitigate the space ambiguity caused by signal fluctuation, the Kalman Filter estimates the most likely current RSSI based on the historical measurements and current measurement in the online stage. The extensive experiments demonstrate that the proposed system performs better than the existing deep-learning-based models with fewer labeled samples.

Dopaminergic Projections from the Hypothalamic A11 Nucleus to the Spinal Trigeminal Nucleus Are Involved in Bidirectional Migraine Modulation.

Clinical imaging studies have revealed that the hypothalamus is activated in migraine patients prior to the onset of and during headache and have also shown that the hypothalamus has increased functional connectivity with the spinal trigeminal nucleus. The dopaminergic system of the hypothalamus plays an important role, and the dopamine-rich A11 nucleus may play an important role in migraine pathogenesis. We used intraperitoneal injections of glyceryl trinitrate to establish a model of acute migraine attack and chronicity in mice, which was verified by photophobia experiments and von Frey experiments. We explored the A11 nucleus and its downstream pathway using immunohistochemical staining and neuronal tracing techniques. During acute migraine attack and chronification, c-fos expression in GABAergic neurons in the A11 nucleus was significantly increased, and inhibition of DA neurons was achieved by binding to GABA A-type receptors on the surface of dopaminergic neurons in the A11 nucleus. However, the expression of tyrosine hydroxylase and glutamic acid decarboxylase proteins in the A11 nucleus of the hypothalamus did not change significantly. Specific destruction of dopaminergic neurons in the A11 nucleus of mice resulted in severe nociceptive sensitization and photophobic behavior. The expression levels of the D1 dopamine receptor and D2 dopamine receptor in the caudal part of the spinal trigeminal nucleus candalis of the chronic migraine model were increased. Skin nociceptive sensitization of mice was slowed by activation of the D2 dopamine receptor in SP5C, and activation of the D1 dopamine receptor reversed this behavioral change. GABAergic neurons in the A11 nucleus were activated and exerted postsynaptic inhibitory effects, which led to a decrease in the amount of DA secreted by the A11 nucleus in the spinal trigeminal nucleus candalis. The reduced DA bound preferentially to the D2 dopamine receptor, thus exerting a defensive effect against headache.

Proteomics profiling reveals mitochondrial damage in the thalamus in a mouse model of chronic migraine.

BACKGROUND: Migraine, a complex brain disorder, is regarded as a possible clinical manifestation of brain energy dysfunction. The trigeminovascular system is considered the basis for the pathogenesis of migraine, hence we depicted the proteomics profiling of key regions in this system, then focusing on protein alterations related to mitochondrial function. The aim of this study is to illustrate the role of mitochondria in migraine. METHODS: A mouse model of chronic migraine (CM) was established by repeated nitroglycerin (NTG) stimulation and evaluated by von-Frey filaments, a hot plate and a light-dark box. Differentially expressed proteins (DEPs) in some subcortical brain regions of the trigeminovascular system were screened through liquid chromatography-tandem mass spectrometry (LC‒MS/MS) to analyse the specificity of key signaling pathways in different brain regions. And then mitochondrial function, structure and dynamics were determined by qPCR, ELISA, and transmission electron microscope (TEM). Finally, the effect of mitochondrial intervention-Urolithin A (UA) on CM was investigated. RESULTS: Repeated NTG injection triggered photophobia, periorbital and hind paw allodynia in mice. The proteomics profiling of CM model showed that 529, 109, 163, 152 and 419 DEPs were identified in the thalamus, hypothalamus, periaqueductal grey (PAG), trigeminal ganglion (TG) and trigeminocervical complex (TCC), respectively. The most significant changes in the brain region-specific pathways pointed to thalamic mitochondrial impairment. NTG induced mitochondrial structural disruption, dysfunction and homeostatic dysregulation, which could be partially attenuated by UA intervention. CONCLUSION: Our findings highlight the involvement of mitochondrial damage in the thalamus in central sensitization of CM, which provides evidence of possible metabolic mechanisms in migraine pathophysiology.

Improving the Accuracy of Estimates of Indoor Distance Moved Using Deep Learning-Based Movement Status Recognition.

As a result of the development of wireless indoor positioning techniques such as WiFi, Bluetooth, and Ultra-wideband (UWB), the positioning traces of moving people or objects in indoor environments can be tracked and recorded, and the distances moved can be estimated from these data traces. These estimates are very useful in many applications such as workload statistics and optimized job allocation in the field of logistics. However, due to the uncertainties of the wireless signal and corresponding positioning errors, accurately estimating movement distance still faces challenges. To address this issue, this paper proposes a movement status recognition-based distance estimating method to improve the accuracy. We divide the positioning traces into segments and use an encoder-decoder deep learning-based model to determine the motion status of each segment. Then, the distances of these segments are calculated by different distance estimating methods based on their movement statuses. The experiments on the real positioning traces demonstrate the proposed method can precisely identify the movement status and significantly improve the distance estimating accuracy.

Synthesis and biological evaluation of open-chain analogs of cyclic peptides as inhibitors of cellular Shp2 activity.

A series of open-chain analogs of cyclic peptides was designed and synthesized using sansalvamide A as a model compound. All compounds exhibited low antitumor activity. Furthermore, the evaluation of their inhibitory potency toward IMPDH, SHP2, ACHE, proteasome, MAGL, and cathepsin B showed that all of the compounds were potent against protein tyrosine phosphatase Shp2. Specifically, compounds 1a, 1d, 2b, and 2f were found to inhibit SHP2 with IC50 values in the low micromolar range and good selectivity. Based on the molecular docking results, the binding modes of the chain cyclic peptides in the active center of SHP2 were discussed.

Lgr5+ cells are required and dynamically participate in olfactory epithelium regeneration: a revisiting shows Lgr5 expression in multiple cell lineages.

Olfactory sensory neurons (OSNs) located in the olfactory epithelium (OE) detect thousands of volatile environmental odors to form the sense of smell. OSNs are generated from basal cells, which show the characteristics of progenitor/stem cells. In the mammalian OE, persistent neurogenesis occurs during lifetime, providing a unique model to study the tissue turnover and fate determination of stem cells. Methods: Immunohistochemical analysis and RNAscope in situ hybridization indicated the localization of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) in the intact and injured OE. Lineage tracing was conducted to analyze the dynamic role of Lgr5+ cells in the OE homeostasis and regeneration. We also used DTR-driven genetic depletion of Lgr5+ cells and lentivirus-mediated Lgr5 downregulation to demonstrate the essential role of Lgr5+ cells in the OE regeneration. Results: We show that Lgr5 marks horizontal basal cells (HBCs) in the OE of adults but not newborns. We revisit the role of Lgr5+ cells in the OE homeostasis and regeneration, and find that Lgr5+ cells participate in the OE homeostasis from neonatal to one-month-old age, as well as in the OE regeneration post injury. During the OE regeneration, Lgr5 is transiently expressed in apical supporting cells, immature neurons, and mature sensory neurons. The Lgr5+ cells become or generate HBCs in the regenerated OE. DTR-driven cell depletion shows that Lgr5+ cells are not necessary in the adult OE homeostasis, but required in the recovery of OE from injury. Lgr5 down-regulation by lentiviral infection also demonstrates the essential role of Lgr5 expression in the OE regeneration. Conclusion: Our study elucidates the role of Lgr5+ cells in the OE homeostasis and regeneration, potentially providing a candidate to cell-based therapy against olfactory dysfunction.

Potent Uncompetitive Inhibitors of Nicotinamide N-Methyltransferase (NNMT) as In Vivo Chemical Probes.

NNMT uses SAM as a cofactor to catalyze the methylation of nicotinamide, producing 1-methylnicotinamide. Recent studies have shown that NNMT upregulation in cancer-associated fibroblasts (CAFs) is required to maintain the CAF phenotype in high-grade serous carcinoma. These observations suggest that NNMT should be evaluated as a therapeutic target, especially in cancer. Although several small-molecule inhibitors of NNMT have been identified, there remains a need for highly potent and selective inhibitors with excellent in vivo activity and ADME properties that can be used as reliable chemical probes. We have identified azaindoline carboxamide 38 as a selective and potent NNMT inhibitor with favorable PK/PD and safety profiles as well as excellent oral bioavailability and pharmaceutical properties. Our mechanistic studies indicate that 38 binds uncompetitively with SAM but competitively with nicotinamide consistent with its binding in the nicotinamide binding site and likely forming a positive interaction with SAM.

Screening of NogoA/NTR-related differential genes in rat sciatic nerve injury signal pathway.

AIM: To screen the differential genes in NogoA/NTR-related pathways that associate with sciatic nerve injury. RESULTS: There was no difference in the expression of NogoA, NTR and Ntrk2. Differential genes existed in 11 differential pathways that include NogoA, NTR and Ntrk2. Pathways closely related to sciatic nerve injury are MAPK, endophagocytosis, apoptosis, neurotrophin signaling and inflammatory mediators. NTRK1, FASLG, LDLR ADRB1 and HTR2A in model rats were downregulated compared with control rats, IL1R1, CSF1R, BCL2L1 and HRH1 in model rats were upregulated compared with control rats. CONCLUSION: MAPK, endophagocytic, apoptotic, neurotrophic factor and inflammatory mediators of ductal mediators may be involved in the sciatic nerve injury in rats. The differentially expressed genes in these pathways may play important roles in sciatic nerve injury.

The measurement of dorsal radial tilt by x-ray and computed tomography.

OBJECTIVE: We conducted this study to define and measure the dorsal radial tilt, and to guide the reduction of distal radius fractures and the pre-bending of steel plates used in surgery. METHODS: The dorsal radial tilt was measured using both computed tomography (CT) and x-ray from both left and right side. The differences and correlations of the data measured by those two methods and from two sides were analyzed. RESULTS: The tilts measured by x-ray were significantly bigger than those measured by CT from the left side (t=55.51, p < 0.01) and from the right side (t=49.81, p < 0.01). The tilts measured by those two methods from the left and right sides were correlated (r=0.85, p < 0.01; r=0.81, p < 0.01). The dorsal radial tilts measured from the left side were not significantly different from those measured from the right side by CT (t=1.49, p > 0.05) and by x-ray (t=1.51, p > 0.05). The dorsal radial tilts measured from the left side by CT were significantly different from those measured from the right side by x-ray (t=43.07, p < 0.01), and these two sets of data were correlated (r=0.71, p < 0.01). The dorsal radial tilts measured from the left side by x-ray was significantly different from that measured from right side by CT (t=40.43, p < 0.01), and those two sets of data were also correlated (r=0.75, p < 0.01). CONCLUSIONS: The dorsal radial tilts measured from one side by one method can be used to estimate the tilts measured from the other side / the same side by the same method / the other method.

The measurement of dorsal radial tilt by x-ray and computed tomography

SUMMARY OBJECTIVE: We conducted this study to define and measure the dorsal radial tilt, and to guide the reduction of distal radius fractures and the pre-bending of steel plates used in surgery. METHODS: The dorsal radial tilt was measured using both computed tomography (CT) and x-ray from both left and right side. The differences and correlations of the data measured by those two methods and from two sides were analyzed. RESULTS: The tilts measured by x-ray were significantly bigger than those measured by CT from the left side (t=55.51, p < 0.01) and from the right side (t=49.81, p < 0.01). The tilts measured by those two methods from the left and right sides were correlated (r=0.85, p < 0.01; r=0.81, p < 0.01). The dorsal radial tilts measured from the left side were not significantly different from those measured from the right side by CT (t=1.49, p > 0.05) and by x-ray (t=1.51, p > 0.05). The dorsal radial tilts measured from the left side by CT were significantly different from those measured from the right side by x-ray (t=43.07, p < 0.01), and these two sets of data were correlated (r=0.71, p < 0.01). The dorsal radial tilts measured from the left side by x-ray was significantly different from that measured from right side by CT (t=40.43, p < 0.01), and those two sets of data were also correlated (r=0.75, p < 0.01). Conclusions: The dorsal radial tilts measured from one side by one method can be used to estimate the tilts measured from the other side / the same side by the same method / the other method.

RESUMO OBJETIVO: Realizamos este estudo para definir e medir a inclinação radial dorsal, e para orientar a redução das fraturas do raio distal e a pré-flexão das chapas de aço utilizadas na cirurgia. MÉTODOS: A inclinação radial dorsal foi medida usando tomografia computadorizada (TC) e raios X dos lados esquerdo e direito. As diferenças e correlações dos dados medidos por esses dois métodos e de dois lados foram analisadas. RESULTADOS: As inclinações medidas por raios X foram significativamente maiores que as medidas pela TC do lado esquerdo (t=55,51, p<0,01) e do lado direito (t=49,81, p<0,01). As inclinações medidas por esses dois métodos dos lados esquerdo e direito foram correlacionadas (r=0,85, p<0,01; r=0,81, p<0,01). As inclinações radiais dorsais medidas a partir do lado esquerdo não foram significativamente diferentes das medidas do lado direito por CT (t=1,49, p>0,05) e por raios X (t=1,51, p>0,05). As inclinações radiais dorsais medidas a partir do lado esquerdo por TC foram significativamente diferentes das medidas a partir do lado direito por raios X (t=43,07, p<0,01), e esses dois conjuntos de dados foram correlacionados (r=0,71, p<0,01). As inclinações radiais dorsais medidas a partir do lado esquerdo por raios X foram significativamente diferentes das medidas do lado direito por CT (t=40,43, p<0,01), e esses dois conjuntos de dados também foram correlacionados (r=0,75, p<0,01). CONCLUSÕES: As inclinações radiais dorsais medidas de um lado por um método podem ser usadas para estimar as inclinações medidas do outro lado/o mesmo lado pelo mesmo método/o outro método.