Observation of magnetic amplification using dark spins.

Quantum amplification enables the enhancement of weak signals and is of great importance for precision measurements, such as biomedical science and tests of fundamental symmetries. Here, we observe a previously unexplored magnetic amplification using dark noble-gas nuclear spins in the absence of pump light. Such dark spins exhibit remarkable coherence lasting up to 6 min and the resilience against the perturbations caused by overlapping alkali-metal gas. We demonstrate that the observed phenomenon, referred to as "dark spin amplification," significantly magnifies magnetic field signals by at least three orders of magnitude. As an immediate application, we showcase an ultrasensitive magnetometer capable of measuring subfemtotesla fields in a single 500-s measurement. Our approach is generic and can be applied to a wide range of noble-gas isotopes, and we discuss promising optimizations that could further improve the current signal amplification up to [Formula: see text] with [Formula: see text]Ne, [Formula: see text] with [Formula: see text]Xe, and [Formula: see text] with [Formula: see text]He. This work unlocks opportunities in precision measurements, including searches for ultralight dark matter with sensitivity well beyond the supernova-observation constraints.

Structural Pharmacology of TRPV4 Antagonists.

The nonselective calcium-permeable Transient Receptor Potential Cation Channel Subfamily V Member4 (TRPV4) channel regulates various physiological activities. Dysfunction of TRPV4 is linked to many severe diseases, including edema, pain, gastrointestinal disorders, lung diseases, and inherited neurodegeneration. Emerging TRPV4 antagonists show potential clinical benefits. However, the molecular mechanisms of TRPV4 antagonism remain poorly understood. Here, cryo-electron microscopy (cryo-EM) structures of human TRPV4 are presented in-complex with two potent antagonists, revealing the detailed binding pockets and regulatory mechanisms of TRPV4 gating. Both antagonists bind to the voltage-sensing-like domain (VSLD) and stabilize the channel in closed states. These two antagonists induce TRPV4 to undergo an apparent fourfold to twofold symmetry transition. Moreover, it is demonstrated that one of the antagonists binds to the VSLD extended pocket, which differs from the canonical VSLD pocket. Complemented with functional and molecular dynamics simulation results, this study provides crucial mechanistic insights into TRPV4 regulation by small-molecule antagonists, which may facilitate future drug discovery targeting TRPV4.

Structural insights into the orthosteric inhibition of P2X receptors by non-ATP analog antagonists.

P2X receptors are extracellular ATP-gated ion channels that form homo- or heterotrimers and consist of seven subtypes. They are expressed in various tissues, including neuronal and nonneuronal cells, and play critical roles in physiological processes such as neurotransmission, inflammation, pain, and cancer. As a result, P2X receptors have attracted considerable interest as drug targets, and various competitive inhibitors have been developed. However, although several P2X receptor structures from different subtypes have been reported, the limited structural information of P2X receptors in complex with competitive antagonists hampers the understanding of orthosteric inhibition, hindering the further design and optimization of those antagonists for drug discovery. We determined the cryogenic electron microscopy (cryo-EM) structures of the mammalian P2X7 receptor in complex with two classical competitive antagonists of pyridoxal-5'-phosphate derivatives, pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) and pyridoxal phosphate-6-azophenyl-2',5'-disulfonic acid (PPADS), and performed structure-based mutational analysis by patch-clamp recording as well as molecular dynamics (MD) simulations. Our structures revealed the orthosteric site for PPADS/PPNDS, and structural comparison with the previously reported apo- and ATP-bound structures showed how PPADS/PPNDS binding inhibits the conformational changes associated with channel activation. In addition, structure-based mutational analysis identified key residues involved in the PPNDS sensitivity of P2X1 and P2X3, which are known to have higher affinity for PPADS/PPNDS than other P2X subtypes.

Improving Magnetic Resonance Imaging and Chemodynamic Therapy Properties via Tuning the Fe(II)/Fe(III) Ratio in Hydrophilic Single-Atom Nanobowls.

We developed an intrinsic hydrophilic single-atom iron nanobowl (Fe-SANB) for magnetic resonance imaging (MRI)-guided tumor microenvironment-triggered cancer therapy. Benefiting from the sufficient exposure of Fe single atoms and the intrinsic hydrophilicity of the bowl-shaped structure, the Fe-SANBs exhibited a superior performance for T1-weighted MRI with an r1 value of 11.48 mM-1 s-1, which is 3-fold higher than that of the commercial Gd-DTPA (r1 = 3.72 mM-1 s-1). After further coembedding Gd single atoms in the nanobowls, the r1 value can be greatly improved to 19.54 mM-1 s-1. In tumor microenvironment (TME), the Fe-SANBs can trigger pH-induced Fenton-like activity to generate highly toxic hydroxyl radicals for high-efficiency chemodynamic therapy (CDT). Both the MRI and CDT efficiency of these nanobowls can be optimized by tuning the ratio of Fe(II)/Fe(III) in the Fe-SANBs via controlling the calcination temperature. Furthermore, the generation of •OH at the tumor site can be accelerated via the photothermal effect of Fe-SANBs, thus promoting CDT efficacy. Both in vitro and in vivo results confirmed that our nanoplatform exhibited high T1-weighted MRI contrast, robust biocompatibility, and satisfactory tumor treatment, providing a potential nanoplatform for MRI-guided TME-triggered precise cancer therapy.

[Value of the human chorionic gonadotropin stimulation test in the diagnosis of disorder of sexual development in children]. / äººç»’æ¯›è†œä¿ƒæ€§è ºæ¿€ç´ æ¿€å‘è¯•éªŒåœ¨æ€§å‘è‚²å¼‚å¸¸å„¿ç«¥ä¸­çš„è¯Šæ–­ä½œç”¨è¯„ä¼°.

OBJECTIVES: To investigate the value of the human chorionic gonadotropin (hCG) stimulation test in the diagnosis of disorder of sexual development (DSD) in children. METHODS: A retrospective analysis was conducted on 132 children with DSD. According to the karyotype, they were divided into three groups: 46,XX group (n=10), 46,XY group (n=87), and sex chromosome abnormality group (n=35). The above groups were compared in terms of sex hormone levels before and after hCG stimulation test, and the morphological manifestation of the impact of testicular tissue on the results of the hCG stimulation test was analyzed. RESULTS: There was no significant difference in the multiple increase of testosterone after stimulation among the three groups (P>0.05). In the 46,XY group, the children with 5α-reductase type 2 deficiency had a testosterone-to-dihydrotestosterone ratio higher than that of the 46,XY DSD children with other causes. Morphological analysis showed that DSD children with testicular tissue demonstrated a significantly higher multiple increase in testosterone after stimulation compared to children without testicular tissue (P<0.05). CONCLUSIONS: The hCG stimulation test has an important value in assessing the presence and function of testicular interstitial cells in children with different types of DSD, and it is recommended to perform the hCG stimulation test for DSD children with unclear gonadal type.

Comparative Analysis of Enbloc or Piecemeal Removal After Enbloc Resection of Gastrointestinal Stromal Tumors.

OBJECTIVE: To investigate the safety and prognosis of enbloc or piecemeal removal after enbloc resection of a gastric GIST by comparing the clinical data of endoscopic en block resection and piecemeal removal (EP) and en block resection and complete removal (EC) of gastric GISTs. METHODS: A total of 111 (43 endoscopic piecemeal, and 68 complete removal) patients with gastric GIST's ≥ 2 cm in diameter who underwent endoscopic therapy from January 2016 to June 2020 at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. In all cases, it was ensured that the tumor was intact during the resection, however, it was divided into EP group and EC group based on whether the tumor was completely removed or was cut into pieces which were then removed. The patients' recurrence-free survival rate and recurrence-free survival (RFS) were recorded. RESULTS: There was no statistically significant difference in RFS rates between the two groups (P = 0.197). The EP group had relatively high patient age, tumor diameter, risk classification, and operation time. However, there was no statistically significant difference in the number of nuclear fission images, postoperative hospitalization time, postoperative fasting time, complication rate and complication grading between the two groups (P > 0.05). CONCLUSION: Endoscopic piecemeal removal after en block resection of gastric GIST is safe and effective and achieves similar clinical outcomes as complete removal after en block resection.

Macrophage-enriched Sectm1a promotes efficient efferocytosis to attenuate ischemia/reperfusion-induced cardiac injury.

Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage-enriched gene, as a modulator of macrophage efferocytosis in I/R-injured hearts. Upon myocardial I/R, Sectm1a-KO mice exhibited impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhanced macrophage efferocytosis and improved cardiac function. Mechanistically, SECTM1A could elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor α (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of the Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury.

Databases and computational methods for the identification of piRNA-related molecules: A survey.

Piwi-interacting RNAs (piRNAs) are a class of small non-coding RNAs (ncRNAs) that plays important roles in many biological processes and major cancer diagnosis and treatment, thus becoming a hot research topic. This study aims to provide an in-depth review of computational piRNA-related research, including databases and computational models. Herein, we perform literature analysis and use comparative evaluation methods to summarize and analyze three aspects of computational piRNA-related research: (i) computational models for piRNA-related molecular identification tasks, (ii) computational models for piRNA-disease association prediction tasks, and (iii) computational resources and evaluation metrics for these tasks. This study shows that computational piRNA-related research has significantly progressed, exhibiting promising performance in recent years, whereas they also suffer from the emerging challenges of inconsistent naming systems and the lack of data. Different from other reviews on piRNA-related identification tasks that focus on the organization of datasets and computational methods, we pay more attention to the analysis of computational models, algorithms, and performances that aim to provide valuable references for computational piRNA-related identification tasks. This study will benefit the theoretical development and practical application of piRNAs by better understanding computational models and resources to investigate the biological functions and clinical implications of piRNA.

Alfalfa MsbHLH115 confers tolerance to cadmium stress through activating the iron deficiency response in Arabidopsis thaliana.

Cadmium (Cd) pollution severely affects plant growth and development, posing risks to human health throughout the food chain. Improved iron (Fe) nutrients could mitigate Cd toxicity in plants, but the regulatory network involving Cd and Fe interplay remains unresolved. Here, a transcription factor gene of alfalfa, MsbHLH115 was verified to respond to iron deficiency and Cd stress. Overexpression of MsbHLH115 enhanced tolerance to Cd stress, showing better growth and less ROS accumulation in Arabidopsis thaliana. Overexpression of MsbHLH115 significantly enhanced Fe and Zn accumulation and did not affect Cd, Mn, and Cu concentration in Arabidopsis. Further investigations revealed that MsbHLH115 up-regulated iron homeostasis regulation genes, ROS-related genes, and metal chelation and detoxification genes, contributing to attenuating Cd toxicity. Y1H, EMSA, and LUC assays confirmed the physical interaction between MsbHLH115 and E-box, which is present in the promoter regions of most of the above-mentioned iron homeostasis regulatory genes. The transient expression experiment showed that MsbHLH115 interacted with MsbHLH121pro. The results suggest that MsbHLH115 may directly regulate the iron-deficiency response system and indirectly regulate the metal detoxification response mechanism, thereby enhancing plant Cd tolerance. In summary, enhancing iron accumulation through transcription factor regulation holds promise for improving plant tolerance to Cd toxicity, and MsbHLH115 is a potential candidate for addressing Cd toxicity issues.

Differences in the perceptions of patients with primary biliary cholangitis and physicians from various hospital departments: An online survey.

OBJECTIVES: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease that affects the quality of life (QoL) of patients. This study aimed to evaluate the differences in perceptions of PBC among physicians from different hospital departments and patients with PBC. METHODS: An online survey regarding the general knowledge, diagnosis, and management of PBC was completed by physicians and patients. RESULTS: A total of 239 patients with PBC and 239 physicians from eight hospital departments (gastroenterology, infectious diseases, rheumatology, hepatobiliary surgery, pathology, clinical laboratory, ultrasound, and radiology) completed the survey. The results showed that physicians from departments other than gastroenterologists and rheumatologists lacked knowledge of PBC, and that junior gastroenterologists were uncertain about the diagnostic and treatment pathways of PBC. Importantly, the lack of knowledge significantly impacted the QoL of patients, especially the emotional scores of PBC-40 (odds ratio -2.556, 95% confidence interval -3.852 to -1.260, P < 0.001). In addition, there was a perceived knowledge gap between patients and gastroenterologists. CONCLUSIONS: Physicians must improve their awareness of PBC. Patient education and patient-physician communication are important for improving the patient's QoL.

PABPC1L induces IDO1 to promote tryptophan metabolism and immune suppression in renal cell carcinoma.

The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance despite having extensive T-cell infiltration. Elucidation of the mechanisms underlying immune evasion could help identify therapeutic strategies to boost the efficacy of immune checkpoint blockade (ICB) in RCC. This study uncovered a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine 2,3-dioxygenase 1 (IDO1), a prospective target for immunotherapy. PABPC1L was markedly upregulated in RCC, and high PABPC1L expression correlated with unfavorable prognosis and resistance to ICB. PABPC1L bolstered tryptophan metabolism by upregulating IDO1, inducing T-cell dysfunction and Treg infiltration. PABPC1L enhanced the stability of JAK2 mRNA, leading to increased JAK2-STAT1 signaling that induced IDO1 expression. Additionally, PABPC1L-induced activation of the JAK2-STAT1 axis created a positive feedback loop to promote PABPC1L transcription. Conversely, loss of PABPC1L diminished IDO1 expression, mitigated cytotoxic T-cell suppression, and enhanced responsiveness to anti-PD-1 therapy in patient-derived xenograft models. These findings reveal the crucial role of PABPC1L in facilitating immune evasion in RCC and indicate that inhibiting PABPC1L could be a potential immunotherapeutic approach in combination with ICB to improve patient outcomes.

A shared mechanism for TNP-ATP recognition by members of the P2X receptor family.

P2X receptors (P2X1-7) are non-selective cation channels involved in many physiological activities such as synaptic transmission, immunological modulation, and cardiovascular function. These receptors share a conserved mechanism to sense extracellular ATP. TNP-ATP is an ATP derivative acting as a nonselective competitive P2X antagonist. Understanding how it occupies the orthosteric site in the absence of agonism may help reveal the key allostery during P2X gating. However, TNP-ATP/P2X complexes (TNP-ATP/human P2X3 (hP2X3) and TNP-ATP/chicken P2X7 (ckP2X7)) with distinct conformations and different mechanisms of action have been proposed. Whether these represent species and subtype variations or experimental differences remains unclear. Here, we show that a common mechanism of TNP-ATP recognition exists for the P2X family members by combining enhanced conformation sampling, engineered disulfide bond analysis, and covalent occupancy. In this model, the polar triphosphate moiety of TNP-ATP interacts with the orthosteric site, while its TNP-moiety is deeply embedded in the head and dorsal fin (DF) interface, creating a restrictive allostery in these two domains that results in a partly enlarged yet ion-impermeable pore. Similar results were obtained from multiple P2X subtypes of different species, including ckP2X7, hP2X3, rat P2X2 (rP2X2), and human P2X1 (hP2X1). Thus, TNP-ATP uses a common mechanism for P2X recognition and modulation by restricting the movements of the head and DF domains which are essential for P2X activation. This knowledge is applicable to the development of new P2X inhibitors.

Dual-Catalyzed Stereodivergent Electrooxidative Homocoupling of Benzoxazolyl Acetate.

The development of a reliable strategy for stereodivergent radical reactions that allows convenient access to all stereoisomers of homocoupling adducts with multiple stereogenic centers remains an unmet goal in organic synthesis. Herein, we describe a dual-catalyzed electrooxidative C(sp3)-H/C(sp3)-H homocoupling with complete absolute and relative stereocontrol for the synthesis of molecules with contiguous quaternary stereocenters in a general and predictable manner. The stereodivergent electrooxidative homocoupling reaction is achieved by synergistically utilizing two distinct chiral catalysts that convert identical racemic substrates into inherently distinctive reactive chiral intermediates, dictate enantioselective radical addition, and allow access to the full complement of stereoisomeric products via simple catalyst permutation. The successful execution of the dual-electrocatalytic strategy programmed via electrooxidative activation provides a significant conceptual advantage and will serve as a useful foundation for further research into cooperative stereocontrolled radical transformations and diversity-oriented synthesis.

Molecular Mechanism Analysis of the Effect of Hederagenin Combined with L-OHP on Chemosensitivity of AGS/L-OHP Based on Network Pharmacology.

AIMS AND OBJECTIVES: This study aimed to evaluate the pharmacological mechanism of Hederagenin (HD) combined with oxaliplatin (L-OHP) in treating gastric cancer (GC) through network pharmacology combined with experimental verification. MATERIAL AND METHODS: Network pharmacology methods were used to screen potential targets for HD, L-OHP, and GC-related targets from public databases, and the intersection of the three gene sets was taken. Cross genes were analyzed through protein-protein interaction (PPI) networks to predict core targets, and related pathways were predicted through GO and KEGG enrichment analysis. The experimental results were verified by the in vitro experiments. HD was applied on AGS/L-OHP cells, and then cellular chemosensitivity and the expressions of P-gp, Survivin, Bcl-2, p-Akt, and p-PI3K genes were detected. Wound assay and Transwell Chamber assay were employed to detect the effect of HD on AGS/L-OHP cells. Nude mice xenograft models transfected using AGS/L-OHP cells were also treated with HD in order to verify the results. The size and weight of the tumor, as well as the expressions of P-gp, Survivin, Bcl-2, p- Akt and p-PI3K genes, were also measured. RESULTS: KEGG analysis showed that the anti-gastric cancer effect of HD was mediated mainly by PI3K-Akt signaling pathways. The PI3K-Akt signaling pathway containing more enriched genes may play a greater role in anti-gastric cancer. It was observed that for AGS/L-OHP cells jointly treated with HD and L-OHP, their activity, migration and invasion were significantly lower than those treated only using HD or L-OHP group. Moreover, expressions of p-Akt, p- PI3K, Bcl-2, P-gp, and Survivin for the HD+L-OHP group decreased significantly. Results of the in vivo experiments showed that the sizes and weights of tumors in the HD+L-OHP group were the lowest compared to the HD group and L-OHP group. CONCLUSION: Our findings suggest that HD may reduce the resistance of AGS/L-OHP cells to LOHP by regulating the PI3K/Akt signaling pathway.

Impact of rGO modified with FAS on corrosion protection performance of inorganic phosphate bonded coating.

In this paper, inorganic phosphate bonded coatings (IPBCs) via embedding reduced graphene oxide (rGO) modified with heptadecafluoro-1,1,2,2-tetradecyl trimethoxysilane (FAS) were prepared through sol-gel method. Aim of this paper is to research the corrosion resistance of IPBCs with the addition of rGO modified with FAS. Firstly, the Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy (Raman) and surface morphology of GO and rGO modified with and without FAS were characterized. Results indicated that the hydrophobic -CF2- and -CF3 groups were successfully introduced into GO and rGO after modification. And IPBCs with rGO-FAS exhibited higher hydrophobicity and corrosion resistance than IPBCs with the addition of GO or GO-FAS. That is because the hydrophobicity and the introduction of low surface energy material is conducive to overcoming the interaction of rGO itself, thus rGO can be better utilized and played, which resulting the excellent corrosion performance of IPBC@rGO-FAS.

Evaluation of the Robustness Verification of Downstream Production Process for Inactivated SARS-CoV-2 Vaccine and Different Chromatography Medium Purification Effects.

BACKGROUND: Large-scale vaccine production requires downstream processing that focuses on robustness, efficiency, and cost-effectiveness. METHODS: To assess the robustness of the current vaccine production process, three batches of COVID-19 Omicron BA.1 strain hydrolytic concentrated solutions were selected. Four gel filtration chromatography media (Chromstar 6FF, Singarose FF, Bestarose 6B, and Focurose 6FF) and four ion exchange chromatography media (Maxtar Q, Q Singarose, Diamond Q, and Q Focurose) were used to evaluate their impact on vaccine purification. The quality of the vaccine was assessed by analyzing total protein content, antigen content, residual Vero cell DNA, residual Vero cell protein, and residual bovine serum albumin (BSA). Antigen recovery rate and specific activity were also calculated. Statistical analysis was conducted to evaluate process robustness and the purification effects of the chromatography media. RESULTS: The statistical analysis revealed no significant differences in antigen recovery (p = 0.10), Vero HCP residue (p = 0.59), Vero DNA residue (p = 0.28), and BSA residue (p = 0.97) among the three batches of hydrolytic concentrated solutions processed according to the current method. However, a significant difference (p < 0.001) was observed in antigen content. CONCLUSIONS: The study demonstrated the remarkable robustness of the current downstream process for producing WIBP-CorV vaccines. This process can adapt to different batches of hydrolytic concentrated solutions and various chromatography media. The research is crucial for the production of inactivated SARS-CoV-2 vaccines and provides a potential template for purifying other viruses.

Ethnobotanical study on medicinal plants used by the Yi people in Xiaoliangshan, Yunnan Province, SW China.

ETHNOPHARMACOLOGICAL RELEVANCE: The Yi people in the Xiaoliangshan region in southwest China have a unique practice of combining ritual treatment and traditional medicine to care for patients. Despite increasing urbanization in the area, they have managed to preserve their distinctive lifestyle and extensive knowledge of traditional medicinal plants, setting them apart from other regions. However, there is a lack of systematic documentation on the knowledge of traditional medicinal plants used by the Yi people in Xiaoliangshan. AIM OF THE STUDY: This research aims to achieve the following objectives: 1. Document the diversity of medicinal plants used by the Yi people and explore their therapeutic usages. 2. Evaluate and analyze the main types of diseases with a high incidence in the local area and identify the types of medicinal plants used to treat these diseases. 3. Explore the underlying geographical and human factors influencing both disease prevalence and medicinal plant usage. METHODS: Ethnobotanical research methods were used to record and analyze the medicinal plants used by the Yi in Xiaoliangshan. Experts identified all plant specimens collected during ethnobotanical field surveys. The types of diseases treated by medicinal plants were classified according to the International Classification of Primary Care -2nd. RESULTS: A total of 125 medicinal plants were recorded after interviewing 193 participants. Of the medicinal plants identified, those with over 100 use reports were Paris polyphylla (202 use reports), Taxillus sutchuenensis (183), Artemisia indica (149), and Papaver somniferum (113). A total of 14 disease categories were recorded, with those related to the following categories having higher Informant Consensus factor values (ICF ≥0.85): Pregnancy, Childbearing, Family Planning, General and Unspecified, Urological, Respiratory, Musculoskeletal, and Skin. The highest quantity of medicinal plants is utilized to improve specific diseases and health problems, namely those related to Digestion, Skin, and Musculoskeletal. Fewer plant species were utilized for diseases or health issues associated with Eyes, Psychological, or Pregnancy, Childbearing, and Family Planning. The use reports from the informants also revealed how some medicinal plants are used to treat a variety of diseases or health issues. For instance, Malva pusilla is used for inducing abortion, treating postpartum hemorrhage, and joint sprains; Artemisia indica is used for treating malaria; Argentina lineata is used to remedy tuberculosis and malaria. Taxillus sutchuenensis is used for dealing with cold, pneumonia, and other ailments. CONCLUSIONS: The Yi people in Xiaoliangshan have a rich knowledge of traditional medicinal plants. Decoction and wine brewing are the most common processing methods used for these plants, which are utilized to treat a wide range of diseases. The characteristics of the medicinal use of the Yi people reflects the alpine mountainous environment in which they live, and their medical practices are closely related to traditional healing culture. This study enhances our understanding of the Yi traditional medicine via documentation and offers a valuable reference for future research and the development of new drugs.