Single-Slice Hounsfield Unit (HU) Value of the Chinese Proximal Humerus on Routine Chest CT: A Study on Opportunistically Screening for Low Bone Density / Valor de Unidad Hounsfield (HU) de Corte Único del Húmero Proximal Chino en una Tomografía Computarizada de Tórax de Rutina: Un Estudio sobre la Detección Oportunista de Baja Densidad Ósea

SUMMARY: A Study on Relationship between Single-Slice Hounsfield Unit(HU) value of the Chinese proximal humerus and Bone Mineral Density(BMD) Using Routine Chest CT and Dual-energy X-ray Absorptiometry(DEXA) was performed. Data were collected from 240 individuals who underwent DEXA and routine chest CT scans (including full images of the proximal humerus) on the same day at 967 Hospitals between January 2019 and December 2021. The method of measuring single-slice HU values of the proximal humerus on routine chest CT scans exhibited high reliability and repeatability (intraclass correlation coefficient > 0.961, P < 0.001). A strong positive correlation was observed between single-slice HU values of the proximal humerus and DEXA results, with the 20-mm HU value demonstrating the highest correlation. Across different BMI groups, the Area Under Curve (AUC) for the 20-mm HU value was consistently the largest (AUC=0.701- 0.813, P< 0.05). Therefore, the 20-mm HU value can be considered a reliable reference for the opportunistic screening of low BMD, with reference values of -4HU for underweight individuals, -13HU for normal weight individuals, -7HU for overweight individuals, and -16HU for obese individuals. Values below these thresholds indicate a risk of low BMD. This study enriches the Chinese BMD data and offers a swift and effective approach for opportunistically screening low BMD.

Se realizó un estudio sobre la relación entre el valor de la Unidad Hounsfield (HU) de corte único del húmero proximal chino y la densidad mineral ósea (DMO) mediante TC de tórax de rutina y absorciometría de rayos X de energía dual (DEXA). Se recopilaron datos de 240 personas que se sometieron a DEXA y tomografías computarizadas de rutina de tórax (incluidas imágenes completas del húmero proximal) el mismo día en 967 hospitales entre enero de 2019 y diciembre de 2021. El método para medir los valores de HU de un solo corte del húmero proximal en las tomografías computarizadas de tórax mostraron alta confiabilidad y repetibilidad (coeficiente de correlación intraclase > 0,961, P < 0,001). Se observó una fuerte correlación positiva entre los valores de HU de un solo corte del húmero proximal y los resultados de DEXA, demostrando el valor de HU de 20 mm la correlación más alta. En diferentes grupos de IMC, el área bajo la curva (AUC) para el valor HU de 20 mm fue consistentemente el más grande (AUC = 0,701-0,813, P <0,05). Por lo tanto, el valor de HU de 20 mm puede considerarse una referencia fiable para el cribado oportunista de DMO baja, con valores de referencia de -4 HU para personas con bajo peso, -13 HU para personas con peso normal, -7 HU para personas con sobrepeso y -16 HU para personas obesas. Los valores por debajo de estos umbrales indican un riesgo de DMO baja. Este estudio es un aporte para los datos chinos sobre la DMO y ofrece un enfoque rápido y eficaz para detectar de forma oportunista la DMO baja.

Expression analysis and biological regulation of silencing regulatory protein 6 (SIRT6) in cutaneous squamous cell carcinoma

Abstract Background Cutaneous squamous cell carcinoma (CSCC) is one of the most common types of skin cancer worldwide. Therefore, the identification of biomarkers associated with CSCC progression could aid in the early detection of high-risk squamous cell carcinoma and the development of novel therapeutic strategies. Objective This study aimed to investigate the expression patterns of silent mating type Information Regulation 2 homolog 6 (SIRT6) in CSCC and its clinical significance. Methods The protein expression level of SIRT6 in tissues was detected by immunohistochemistry, and the correlation between SIRT6 expression and clinicopathological parameters in CSCC patients was analyzed. The relative expression of SIRT6 in CSCC cell lineage and tissue specimens was determined by western blotting and PCR. The effect of SIRT6 silencing on cell proliferation was evaluated using cell counting kit 8. Wound healing, transwell method, and flow cytometry were used to investigate the migration, invasion, and cell cycle distribution/apoptosis of CSCC cells after SIRT6 silencing, respectively. Western blot was used to detect the expression of EMT (Epithelial-Mesenchymal Transition), cycle, apoptosis, and other related proteins. Results The high expression of SIRT6 was correlated with the location of cancer tissue and Broder staging in CSCC patients. Knockdown of SIRT6 inhibited the proliferation, migration, invasion and EMT of CSCC cells, and promoted their apoptosis, with cells blocked in G1 phase. Study limitations No animal experiments were conducted to further verify the results. Conclusion Decreased expression of SIRT6 can inhibit the occurrence and development of CSCC.

Investigating Morphological Changes of the Hippocampus After Prolonged Aerobic Exercise in Mice: Neural Function and Learning Capabilities / Investigación de los Cambios Morfológicos del Hipocampo Después De un Ejercicio Aeróbico Prolongado en Ratones: Función Neuronal y Capacidades de Aprendizaje

SUMMARY: Both the academic and popular worlds have paid close attention to the link between exercise and cognitive performance. It is increasingly important to understand the numerous mechanisms by which exercise might influence cognitive abilities in view of the continuous societal issues caused by aging populations and the prevalence of disorders associated to cognitive decline. A rising amount of evidence showing a favorable association between physical activity and cognitive well-being serves as the foundation for the justification for studying the effects of exercise on cognitive function and learning ability. The study employed an 8-week treadmill based on exercise on male adults C57BL/6 mice. The exercise group were engaged in 5 sessions a week gradually increasing the intensity of the protocol by 5 % each week. The Mice cognitive assessments were done using Morris Water Maze and Novel Object Recognition tests. The long term-impact on learning ability were further assessed through immmohistochemistry and molecular analysis of the hippocampal and prefrontal cortex tissues of the animals' brain tissues. The findings showed improved spatial learning abilities, recognition memory, and heighted synaptic plasticity indicated by elevated synaptic makers. The study underscores the role of long-term aerobic exercise in augmenting cognitive performance. It not only contributes to the understanding of the interplay between neuroplasticity and cognitive benefits but also the growing body of research on the impact of exercise on cognitive function.

Tanto el mundo académico como el popular han prestado mucha atención al vínculo entre el ejercicio y el rendimiento cognitivo. Es cada vez más importante comprender los numerosos mecanismos por los cuales el ejercicio podría influir en las capacidades cognitivas en vista de los continuos problemas sociales causados por el envejecimiento de la población y la prevalencia de trastornos asociados al deterioro cognitivo. Una cantidad cada vez mayor de evidencia que muestra una asociación favorable entre la actividad física y el bienestar cognitivo sirve como base para justificar el estudio de los efectos del ejercicio sobre la función cognitiva y la capacidad de aprendizaje. El estudio se realizó en ratones machos adultos C57BL/6 utilizándose en los ejercicios una cinta rodante durante 8 semanas. El grupo de ejercicio realizó 5 sesiones por semana aumentando gradualmente la intensidad del protocolo en un 5 % cada semana. Las evaluaciones cognitivas de los ratones se realizaron utilizando las pruebas Morris Water Maze y Novel Object Recognition. El impacto a largo plazo en la capacidad de aprendizaje se evaluó mediante inmunohistoquímica y análisis molecular de los tejidos del hipocampo y la corteza prefrontal de los tejidos cerebrales de los animales. Los hallazgos mostraron mejoras en las habilidades de aprendizaje espacial, la memoria de reconocimiento y una mayor plasticidad sináptica indicada por unos creadores sinápticos elevados. El estudio subraya el papel del ejercicio aeróbico a largo plazo para aumentar el rendimiento cognitivo. No sólo contribuye a la comprensión de la interacción entre la neuroplasticidad y los beneficios cognitivos, sino también al creciente conjunto de investigaciones sobre el impacto del ejercicio en la función cognitiva.

Comparison of Anatomically of Medial Plantar Flap versus Reverse Sural Fasciocutaneous Flap in the Treatment of Skin Defects After Cutaneous Squamous Cell Carcinoma Excision

SUMMARY: To compare the advantages and disadvantages of reverse sural fasciocutaneous flap (RSFF) versus medial plantar flap (MPF) in the treatment of skin defects after excision of squamous cell carcinoma (SCC) of the heel. The research participants were 80 SCC patients admitted to Lishui People's Hospital between January 2019 and April 2022, who were assigned to RSFF group (n=37) and MPF group (n=43) according to the flap type. After a one-year follow-up, the survival, flap necrosis and ulceration, as well as pain and tactile sensation recovery of both groups were counted. At the last follow-up, the clinical response was evaluated, and Short-Form 36 Item Health Survey (SF-36) and appearance satisfaction surveys were conducted. No patients died in either group, and one patient in each group developed flap necrosis. The MPF group had better sensory recovery and a lower incidence of flap ulceration (P0.05). The cosmetic satisfaction was higher in MPF group than in RSFF group (P<0.05). MPF contributes to beautiful appearance, better sensory recovery, and low risk of long-term ulceration, while RSFF is suitable for lesions with large defects or those located at the lateral heel.

El objetivo del estudio fue comparar las ventajas y desventajas del colgajo fasciocutáneo sural inverso (RSFF) versus el colgajo plantar medial (MPF) en el tratamiento de defectos de la piel después de la escisión de un carcinoma de células escamosas (CCE) del talón. Los participantes de la investigación fueron 80 pacientes con CCE ingresados en el Hospital Popular de Lishui entre enero de 2019 y abril de 2022, que fueron asignados al grupo RSFF (n=37) y al grupo MPF (n=43) según el tipo de colgajo. Después de un año de seguimiento, se observó la supervivencia, la necrosis y ulceración del colgajo, así como la recuperación del dolor y la sensación táctil de ambos grupos. En el último seguimiento, se evaluó la respuesta clínica y se realizaron encuestas de salud de formato corto de 36 ítems (SF-36) y encuestas de satisfacción. Ningún paciente falleció en ninguno de los grupos y un paciente de cada grupo desarrolló necrosis del colgajo. El grupo MPF tuvo una mejor recuperación sensorial y una menor incidencia de ulceración del colgajo (P 0,05). La satisfacción cosmética fue mayor en el grupo MPF que en el grupo RSFF (P<0,05). MPF contribuye a una mejor apariencia, mejor recuperación sensorial y un bajo riesgo de ulceración a largo plazo, mientras que RSFF es adecuado para lesiones con defectos grandes o localizados en la parte lateral del talón.

Silencing ANGPT2 alleviates ulcerative colitis by regulating autophagy-mediated NLRP3 inflammasome inactivation via the mTOR signaling pathway

Ulcerative colitis (UC) is a difficult intestinal disease characterized by inflammation, and its mechanism is complex and diverse. Angiopoietin-like protein 2 (ANGPT2) plays an important regulatory role in inflammatory diseases. However, the role of ANGPT2 in UC has not been reported so far. After exploring the expression level of ANGPT2 in serum of UC patients, the reaction mechanism of ANGPT2 was investigated in dextran sodium sulfate (DSS)-induced UC mice. After ANGPT2 expression was suppressed, the clinical symptoms and pathological changes of UC mice were detected. Colonic infiltration, oxidative stress, and colonic mucosal barrier in UC mice were evaluated utilizing immunohistochemistry, immunofluorescence, and related kits. Finally, western blot was applied for the estimation of mTOR signaling pathway and NLRP3 inflammasome-related proteins. ANGPT2 silencing improved clinical symptoms and pathological changes, alleviated colonic inflammatory infiltration and oxidative stress, and maintained the colonic mucosal barrier in DSS-induced UC mice. The regulatory effect of ANGPT2 on UC disease might occur by regulating the mTOR signaling pathway and thus affecting autophagy-mediated NLRP3 inflammasome inactivation. ANGPT2 silencing alleviated UC by regulating autophagy-mediated NLRP3 inflammasome inactivation via the mTOR signaling pathway.

Ag85B with c-di-AMP as mucosal adjuvant showed immunotherapeutic effects on persistent Mycobacterium tuberculosis infection in mice

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the leading cause of mortality by a single infectious agent in the world. M. tuberculosis infection could also result in clinical chronic infection, known as latent TB infection (LTBI). Compared to the current limited treatment, several subunit vaccines showed immunotherapeutic effects and were included in clinical trials. In this study, a subunit vaccine of Ag85B with a novel mucosal adjuvant c-di-AMP (Ag85B:c-di-AMP) was delivered intranasally to a persistent M. tuberculosis H37Ra infection mouse model, which also presented the asymptomatic characteristics of LTBI. Compared with Ag85B immunization, Ag85B:c-di-AMP vaccination induced stronger humoral immune responses, significantly higher CD4+ T cells recruitment, enhanced Th1/Th2/Th17 profile response in the lung, decreased pathological lesions of the lung, and reduced M. tuberculosis load in mice. Taken together, Ag85B:c-di-AMP mucosal route immunization provided an immunotherapeutic effect on persistent M. tuberculosis H37Ra infection, and c-di-AMP, as a promising potential mucosal adjuvant, could be further used in therapeutic or prophylactic vaccine strategies for persistent M. tuberculosis infection as well as LTBI.

PKMYT1 Promotes Epithelial-Mesenchymal Transition Process in Triple-Negative Breast Cancer by Activating Notch Signaling

ABSTRACT Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that lacks receptors for targeted therapy. Deeper insight into the molecular mechanisms regulating TNBC metastasis is urgently needed. The epithelial-mesenchymal transition process facilitates the metastasis of neighboring epithelial tumor cells. Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the Wee family of protein kinases, is upregulated in BC, and its high expression predicts poor prognosis in BC patients. Notch signaling activation is a pathognomonic feature of TNBC. PKMYT1 has been found to induce EMT in non-small cell lung cancer by activating Notch signaling. However, whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling remains unknown. Objectives: The objective of this study was to investigate whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling. Methods: Fifty cases of surgically resected BC samples (tumor and adjacent non-tumor tissue samples) were collected from patients diagnosed with BC. We measured the expression of PKMYT1 in clinical samples with real-time quantitative polymerase chain reaction (RT-qPCR). For in vitro analysis, RT-qPCR and Western blotting were conducted to evaluate PKMYT1 expression in TNBC cells. Then, the viability, migration, and invasion of TNBC cells were detected by cell counting kit-8 assays, wound healing assays, and Transwell assays. The EMT event was examined by evaluating the levels of EMT-associated proteins. For in vivo analysis, xenograft models in nude mice were established to explore PKMYT1 roles. E-cadherin and Ki67 expression in xenograft models were estimated by immunohistochemistry staining. Hematoxylin and eosin staining was performed to assess tumor metastasis. The underlying mechanisms by which PKMYT1 affected the malignant phenotypes of TNBC cells were explored by Western blotting measuring the pathway-associated proteins. Results: PKMYT1 was upregulated in BC tissues and cells, and its knockdown prevented cell proliferation, migration, invasion, and EMT event in TNBC. Mechanistically, Notch signaling was inactivated by PKMYT1 depletion, and Notch activation abolished the PKMYT1 silencing-induced inhibition in the malignant phenotypes of TNBC cells. For in vivo analysis, PKMYT1 knockdown inhibited tumorigenesis and metastasis of TNBC. Conclusion: PKMYT1 promotes EMT, proliferation, migration, and invasion of TNBC cells and facilitates tumor growth and metastasis by activating Notch signaling.

Acute sarcoidosis Löfgren Syndrome treated by Chinese medicinal formula based on Syndrome Differentiation: a case - based review / Tratamiento de síndrome de Löfgren de sarcoidosis con fórmula medicinal china basada en diferenciación de síndrome: una revisión basada en casos

Löfgren syndrome (LS) is a unique acute manifestation of sarcoidosis and characterized by erythema nodosum, bilateral hilar lymphadenectasis, and/or bilateral ankle arthritis or periarthritis. A 37 - year - old female patient with LS presented with fever accompanied by multiple joint swelling and pain, nodular skin erythema, and bilateral hilar lymphadenectasis. The patient had received treatment involving non - steroidal anti - inflammatory drugs and glucocorticoids in other hospitals, but the effects were poor, and the conditions reemerged. The LS duration has lasted for more than 3 months. Following traditional Chinese medicine (TCM) treatment, syndrome differentiation as well as giving patients oral Chinese medicine decoction, the symptoms of the patient were rapidly relieved within one week and did not recur during a six - month follow - up period. This case is the first clinical report of acute sarcoidosis LS treated using T CM and reflects the significant advantages of this form of therapy in emergency treatment

El síndrome de Löfgren (LS) es una manifest ación única y aguda de sarcoidosis, caracterizada por eritrema nodoso, linfadenectasis hilar bilateral, y/o a r tritis de tobillo bilateral o periartritis. Una paciente de 37 años de sexo femenino con LS se presentó con fiebre, acompañada de inflamación y do lor múltiple de articulaciones, eritrema nodular cutáneo, y linfadenectasis hilar bilateral. La paciente recibió un tratamiento que consistió en antiinflamatorios no esteroidales y glucocorticoides en otros hospitales, pero los efectos fueron leves y las c ondiciones reemergieron. El LS ha durado más de tres meses. Siguiendo el tratamiento de medicina tradicional china (MTC), la diferenciación de síndrome, así como darles a los pacientes una decocción de medicina china por vía oral, los síntomas de la pacien te rápidamente fueron aliviados en el curso de una semana y no recidivaron durante los seis meses de un seguimiento. El caso es el primer reporte clínico de tratamiento de sarcoidosis aguda asociada a LS usando TCM y refleja las significativas ventajas de esta forma de terapia en el tratamiento de emergencia.

Signal mining and analysis of adverse drug event signals of darolutamide / 中国药房

OBJECTIVE To explore and analyze the adverse drug event （ADE） signals of darolutamide and provide a reference for its clinical safe use. METHODS ADEs related to darotamide were collected based on the US FDA adverse event reporting system （FAERS） database from the third quarter of 2019 to the third quarter of 2022. Data mining and analysis were conducted by the report odds ratio （ROR） and proportional reporting ratio （PRR） methods. RESULTS A total of 565 ADE reports related to darolutamide were extracted， 356 ADE reports about darolutamide as the primary suspected drug were included， 38 ADE signals with darolutamide as the primary suspected drug were excavated， involving 15 system organ class （SOC）， mainly concentrated in patients over 65 years old. The SOC of darotamide ADE signal mainly focused on various examinations， systemic diseases and various reactions at the administration site， benign/malignant tumors or those with unknown nature （including cystic and polypoid）， kidney and urinary system diseases. A total of 13 ADE signals not mentioned in the instructions included increased prostate-specific antigen， dysphagia， cognitive impairment， erectile dysfunction， rhabdomyolysis， gynecomastia and decreased platelet count， etc. CONCLUSIONS When using darolutamide， in addition to ADE in the drug instruction， we should pay close attention to potential ADE， such as increased prostate-specific antigen， rhabdomyolysis， gynecomastia and decreased platelet count， so as to avoid drug withdrawal or organ damage caused by ADE.

AZD1775 and anti-PD-1 antibody synergistically sensitize hepatoma to radiotherapy / 中华医学杂志(英文版)

BACKGROUND@#Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma.@*METHODS@#The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro . A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8 + T cells in TME were analyzed by flow cytometry.@*RESULTS@#Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro . AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1 + /CD8 + T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ) + or Ki67 + CD8 T cells and decreasing the levels of CD8 + Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8 + T cells proliferation, and weakening CD8 + T cells depletion.@*CONCLUSIONS@#This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8 + T cells in TME.

Effects of higher femoral tunnels on clinical outcomes, MRI, and second-look findings in double-bundle anterior cruciate ligament reconstruction with a minimal 5-year follow-up / 中华医学杂志(英文版)

BACKGROUND@#To perform anatomical anterior cruciate ligament reconstruction (ACLR), tunnels should be placed relatively higher in the femoral anterior cruciate ligament (ACL) footprint based on the findings of direct and indirect femoral insertion. But the clinical results of higher femoral tunnels (HFT) in double-bundle ACLR (DB-ACLR) remain unclear. The purpose was to investigate the clinical results of HFT and lower femoral tunnels (LFT) in DB-ACLR.@*METHODS@#From September 2014 to February 2016, 83 patients who underwent DB-ACLR and met the inclusion and exclusion criteria were divided into HFT-ACLR (group 1, n = 37) and LFT-ACLR (group 2, n = 46) according to the position of femoral tunnels. Preoperatively and at the final follow-up, clinical scores were evaluated with International Knee Documentation Committee (IKDC), Tegner activity, and Lysholm score. The stability of the knee was evaluated with KT-2000, Lachman test, and pivot-shift test. Cartilage degeneration grades of the International Cartilage Repair Society (ICRS) were evaluated on magnetic resonance imaging (MRI). Graft tension, continuity, and synovialization were evaluated by second-look arthroscopy. Return-to-sports was assessed at the final follow-up.@*RESULTS@#Significantly better improvement were found for KT-2000, Lachman test, and pivot-shift test postoperatively in group 1 ( P >0.05). Posterolateral bundles (PL) showed significantly better results in second-look arthroscopy regarding graft tension, continuity, and synovialization ( P <0.05), but not in anteromedial bundles in group 1. At the final follow-up, cartilage worsening was observed in groups 1 and 2, but it did not reach a stastistically significant difference ( P >0.05). No statistically significant differences were found in IKDC subjective score, Tegner activity, and Lysholm score between the two groups. Higher return-to-sports rate was found in group 1 with 86.8% (32/37) vs. 65.2% (30/46) in group 2 ( P = 0.027).@*CONCLUSION@#The HFT-ACLR group showed better stability results, better PL, and higher return-to-sports rate compared to the LFT-ACLR group.

Correlation between Combined Urinary Metal Exposure and Grip Strength under Three Statistical Models: A Cross-sectional Study in Rural Guangxi / 生物医学与环境科学（英文）

OBJECTIVE@#This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength.@*METHODS@#We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength.@*RESULTS@#In the multimetal linear regression, Cu (β = -2.119), As (β = -1.318), Sr (β = -2.480), Ba (β = 0.781), Fe (β = 1.130) and Mn (β = -0.404) were significantly correlated with grip strength ( P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95% confidence interval: -1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn ( P interactions of 0.003 and 0.018, respectively).@*CONCLUSION@#In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.

The Uptake and Distribution Evidence of Nano- and Microplastics in vivo after a Single High Dose of Oral Exposure / 生物医学与环境科学（英文）

OBJECTIVE@#Tissue uptake and distribution of nano-/microplastics was studied at a single high dose by gavage in vivo.@*METHODS@#Fluorescent microspheres (100 nm, 3 μm, and 10 μm) were given once at a dose of 200 mg/(kg∙body weight). The fluorescence intensity (FI) in observed organs was measured using the IVIS Spectrum at 0.5, 1, 2, and 4 h after administration. Histopathology was performed to corroborate these findings.@*RESULTS@#In the 100 nm group, the FI of the stomach and small intestine were highest at 0.5 h, and the FI of the large intestine, excrement, lung, kidney, liver, and skeletal muscles were highest at 4 h compared with the control group ( P < 0.05). In the 3 μm group, the FI only increased in the lung at 2 h ( P < 0.05). In the 10 μm group, the FI increased in the large intestine and excrement at 2 h, and in the kidney at 4 h ( P < 0.05). The presence of nano-/microplastics in tissues was further verified by histopathology. The peak time of nanoplastic absorption in blood was confirmed.@*CONCLUSION@#Nanoplastics translocated rapidly to observed organs/tissues through blood circulation; however, only small amounts of MPs could penetrate the organs.

Neuronomodulation of Excitable Neurons / 神经科学通报·英文版

Neuronomodulation refers to the modulation of neural conduction and synaptic transmission (i.e., the conduction process involved in synaptic transmission) of excitable neurons via changes in the membrane potential in response to chemical substances, from spillover neurotransmitters to paracrine or endocrine hormones circulating in the blood. Neuronomodulation can be direct or indirect, depending on the transduction pathways from the ligand binding site to the ion pore, either on the same molecule, i.e. the ion channel, or through an intermediate step on different molecules. The major players in direct neuronomodulation are ligand-gated or voltage-gated ion channels. The key process of direct neuronomodulation is the binding and chemoactivation of ligand-gated or voltage-gated ion channels, either orthosterically or allosterically, by various ligands. Indirect neuronomodulation involves metabotropic receptor-mediated slow potentials, where steroid hormones, cytokines, and chemokines can implement these actions. Elucidating neuronomodulation is of great significance for understanding the physiological mechanisms of brain function, and the occurrence and treatment of diseases.

Multisensory Conflict Impairs Cortico-Muscular Network Connectivity and Postural Stability: Insights from Partial Directed Coherence Analysis / 神经科学通报·英文版

Sensory conflict impacts postural control, yet its effect on cortico-muscular interaction remains underexplored. We aimed to investigate sensory conflict's influence on the cortico-muscular network and postural stability. We used a rotating platform and virtual reality to present subjects with congruent and incongruent sensory input, recorded EEG (electroencephalogram) and EMG (electromyogram) data, and constructed a directed connectivity network. The results suggest that, compared to sensory congruence, during sensory conflict: (1) connectivity among the sensorimotor, visual, and posterior parietal cortex generally decreases, (2) cortical control over the muscles is weakened, (3) feedback from muscles to the cortex is strengthened, and (4) the range of body sway increases and its complexity decreases. These results underline the intricate effects of sensory conflict on cortico-muscular networks. During the sensory conflict, the brain adaptively decreases the integration of conflicting information. Without this integrated information, cortical control over muscles may be lessened, whereas the muscle feedback may be enhanced in compensation.

Biallelic variants in RBM42 cause a multisystem disorder with neurological, facial, cardiac, and musculoskeletal involvement

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.

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Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice. Unfortunately, current pharmacological treatments for neuropathic pain lack clinical efficacy and often lead to harmful adverse reactions. As G protein-coupled receptors (GPCRs) are widely distributed throughout the body, including the pain transmission pathway and descending inhibition pathway, the development of novel neuropathic pain treatments based on GPCRs allosteric modulation theory is gaining momentum. Extensive research has shown that allosteric modulators targeting GPCRs on the pain pathway can effectively alleviate symptoms of neuropathic pain while reducing or eliminating adverse effects. This review aims to provide a comprehensive summary of the progress made in GPCRs allosteric modulators in the treatment of neuropathic pain, and discuss the potential benefits and adverse factors of this treatment. We will also concentrate on the development of biased agonists of GPCRs, and based on important examples of biased agonist development in recent years, we will describe universal strategies for designing structure-based biased agonists. It is foreseeable that, with the continuous improvement of GPCRs allosteric modulation and biased agonist theory, effective GPCRs allosteric drugs will eventually be available for the treatment of neuropathic pain with acceptable safety.

The ERF transcription factor LTF1 activates DIR1 to control stereoselective synthesis of antiviral lignans and stress defense in Isatis indigotica roots

Lignans are a powerful weapon for plants to resist stresses and have diverse bioactive functions to protect human health. Elucidating the mechanisms of stereoselective biosynthesis and response to stresses of lignans is important for the guidance of plant improvement. Here, we identified the complete pathway to stereoselectively synthesize antiviral (-)-lariciresinol glucosides in Isatis indigotica roots, which consists of three-step sequential stereoselective enzymes DIR1/2, PLR, and UGT71B2. DIR1 was further identified as the key gene in respoJanuary 2024nse to stresses and was able to trigger stress defenses by mediating the elevation in lignan content. Mechanistically, the phytohormone-responsive ERF transcription factor LTF1 colocalized with DIR1 in the cell periphery of the vascular regions in mature roots and helped resist biotic and abiotic stresses by directly regulating the expression of DIR1. These systematic results suggest that DIR1 as the first common step of the lignan pathway cooperates with PLR and UGT71B2 to stereoselectively synthesize (-)-lariciresinol derived antiviral lignans in I. indigotica roots and is also a part of the LTF1-mediated regulatory network to resist stresses. In conclusion, the LTF1-DIR1 module is an ideal engineering target to improve plant Defenses while increasing the content of valuable lignans in plants.

Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent

Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel "trilogy of drug repurposing" strategy that comprises function-based, target-focused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self-established heart failure mice models with and without tumor-bearing. Collectively, the present study validated the practicability of the "trilogy of drug repurposing" strategy in the development of bi-functional co-therapy agents.

Construction of Chinese Herbal Medicine Traceability System Based on Influencing Factors of Chinese Herbal Medicine Quality / 中国实验方剂学杂志

As a Chinese saying goes， "good Chinese medicinal material makes good medicine"， the quality of Chinese herbal medicines is related to the development prospect of Chinese medicine industry in China. With the rapid development of new technologies such as traceability methods and monitoring instruments， it is imperative to integrate and innovate traditional Chinese herbal medicines with new-generation information technology in view of the quality problems existing in the current production and circulation of Chinese herbal medicines， and it is of great significance for the construction of traceability system to ensure the quality and safety of Chinese herbal medicines and to promote the industry of Chinese herbal medicines to move towards high-quality development. This paper reviews the development history of the traceability system of Chinese herbal medicines in China， takes the influencing factors of the quality of Chinese herbal medicines as the entry point， and proposes that the construction of the traceability system should satisfy the traceability requirements of the characteristics of Chinese herbal medicines and their traditional medication experience. By analyzing the influencing factors of the quality of Chinese herbal medicines， it is pointed out that focusing on the influencing factors to build a traceability system is of great significance for targeting the problematic links at a later stage and exploring the interrelationship between environmental factors and the quality of Chinese herbal medicines. Based on the previous explorations， the author summarizes the system framework， functional modules and practical applications of the traceability system of Chinese herbal medicines， and looks forward to the development of a traceability system with risk early warning function and expert decision-making function in its functional development. Finally， based on the factors affecting the quality of Chinese herbal medicines， the author puts forward several thoughts on construction of the traceability system， and makes an in-depth analysis and puts forward a solution for the current situation that a unified， standardized and universal traceability system has not yet been built， with a view to providing ideas and references for the construction of traceability system of Chinese herbal medicines.