Neutralizing antibodies have been designed to specifically target and bind to the receptor binding domain (RBD) of spike (S) protein to block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus from attaching to angiotensin converting enzyme 2 (ACE2). This study reports a distinctive nanobody, designated as VHH21, that directly catalyzes the S-trimer into an irreversible transition state through postfusion conformational changes. Derived from camels immunized with multiple antigens, a set of nanobodies with high affinity for the S1 protein displays abilities to neutralize pseudovirion infections with a broad resistance to variants of concern of SARS-CoV-2, including SARS-CoV and BatRaTG13. Importantly, a super-resolution screening and analysis platform based on visual fluorescence probes was designed and applied to monitor single proteins and protein subunits. A spontaneously occurring dimeric form of VHH21 was obtained to rapidly destroy the S-trimer. Structural analysis via cryogenic electron microscopy revealed that VHH21 targets specific conserved epitopes on the S protein, distinct from the ACE2 binding site on the RBD, which destabilizes the fusion process. This research highlights the potential of VHH21 as an abzyme-like nanobody (nanoabzyme) possessing broad-spectrum binding capabilities and highly effective anti-viral properties and offers a promising strategy for combating coronavirus outbreaks.
Single-Domain Antibodies/immunology* ; Spike Glycoprotein, Coronavirus/metabolism* ; SARS-CoV-2/immunology* ; Animals ; Humans ; Antibodies, Neutralizing/immunology* ; Camelus ; COVID-19/immunology* ; Antibodies, Viral/immunology* ; Angiotensin-Converting Enzyme 2

Objective:To analyze the current status of clinical trials of Chinese materia medica for the purpose of registration in China; To provide reference for the research and development of new TCM drugs.Methods:Clinical trials of Chinese materia medica/natural medicine registered in Drug Clinical Trial Registration and Information Disclosure Platform were retrieved from inception to December 31, 2024. Excel 2019 software was used to input and analyze the data such as the number of registered clinical trials, date of first publication, study status, field of indication, trial phases, sponsors, group leader, and design types.Results:A total of 1 137 Chinese materia medica clinical trials had been registered, accounting for 4.12% of the total number registered on the platform. Phase Ⅱ clinical trials accounted for the highest proportion (58.8%), and 99.7% of clinical trials conducted domestically. The sponsors were predominantly domestically pharmaceutical enterprises. These 1 137 clinical trials of Chinese materia medica clinical trials involved 752 drug categories, 28 dosage forms, and 796 varieties (the same class of drugs had different drug dosage forms), with capsules being the most common. The indications primarily focused on respiratory, digestive, cardio-cerebrovascular, neuropsychiatric, gynecological diseases. The group leader of clinical trials was distributed in 28 provinces, among which the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine as the group leader, undertook the most clinical trials of TCM. 89.9% of the clinical trials adopted the randomized controlled trial design, and only 31.9% of the clinical trials purchased insurance for the subjects.Conclusion:The research and development of new TCM drugs has entered a phase of vigorous development. Further efforts are still needed in establishing systematic guidelines for Chinese materia medica clinical trials, accelerating the internationalization of TCM, exploring innovative dosage forms and indications, and strengthening the protection of participants' rights.

BackgroundInvasive vagus nerve stimulation therapy has been approved for the adjunctive treatment of treatment-resistant depression， which may contribute to the anti-inflammatory properties of vagus nerve stimulation （VNS）， whereas the efficacy of non-invasive transcutaneous cervical vagus nerve stimulation （tcVNS） in treating major depressive disorder （MDD） and its impact on plasma inflammatory factors remain unclear. ObjectiveTo observe the effect of escitaloprom combined with tcVNS on the status of depression， anxiety and sleep quality as well as the plasma levels of interleukin-6 （IL-6） and interleukin-10 （IL-10） in MDD patients， in order to provide references for the recovery and treatment of MDD patients. MethodsFrom August 21， 2019 to April 17， 2024， 45 patients who met the diagnostic criteria for MDD in the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） were recruited from the psychosomatic outpatient clinic of the First Affiliated Hospital of Air Force Military Medical University. Subjects were divided into study group （n=23） and control group （n=22） using random number table method. All patients were treated with escitalopram. On this basis， study group added a 30-minute tcVNS therapy once a day for 4 weeks. While control group was given corresponding sham stimulation， and the duration of each stimulation lasted 30 seconds. Before and after 4 weeks of treatment， Hamilton Depression Scale-17 item （HAMD-17） was used to assess depressive symptoms， and HAMD-17 anxiety/somatization subfactor and insomnia subfactor were used to assess patients' anxiety/somatization symptoms and sleep quality. Levels of plasma IL-6 and IL-10 were measured by enzyme-linked immunosorbent assay （ELISA）. ResultsThe generalized estimating equation model yielded a significant time effect for HAMD-17 total score， anxiety/somatization subfactor score and insomnia subfactor score in both groups （Wald χ²=315.226， 495.481， 82.420， P<0.01）. After 4 weeks of treatment， HAMD-17 total score and anxiety/somatization subfactor score of study group were lower than those of control group， with statistically significant differences （Wald χ²=4.967， 32.543， P<0.05 or 0.01）， while no statistically significant difference was found in the insomnia subfactor score between two groups （Wald χ²=0.819， P=0.366）. Significant time effects were reported on plasma IL-6 and IL-10 levels in both groups （Wald χ²=21.792， 5.242， P<0.05 or 0.01）. Compared with baseline data， a reduction in plasma IL-6 levels was detected in both groups （Wald χ²=22.015， 6.803， P<0.01）， and an increase in plasma IL-10 levels was reported in study group （Wald χ²=5.118， P=0.024） after 4 weeks of treatment. ConclusionEscitalopram combined with tcVNS therapy is effective in improving depressive symptoms， anxiety/somatization symptoms and sleep quality in patients with MDD. Additionally， it helps reduce plasma IL-6 levels and increase IL-10 levels. ［Funded by Shaanxi Provincial Key Research and Development Program-General Project （number， 2023-YBSF-185）， www.clinicaltrials.gov number， NCT04037111］

[Objective]To investigate the chemical compositions,antioxidant and anti-inflammatory activities of Jiangshan Polygonatum sibiricum alcoholic extract(PSAE)in vitro.[Methods]The chemical compositions of PSAE were identified by ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q/TOF-MSE),its antioxidant activity was studied,and in vitro experiments were conducted to determine its effect on lipopolysaccharide(LPS)-induced THP-1 cells.Molecular docking was further used to validate the results.[Results]PSAE contained 17 chemical compositions,including 5 flavonoids,5 saponins,3 lignans,1 phenolic acid,1 steroid and 2 other compositions.In vitro experiments showed that PSAE possessed great antioxidant activity.Besides,PSAE could increase the viability of LPS-induced THP-1 cells,significantly decrease the levels of tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β)in cell supernatants and the expression of NOD-like receptor thermal protein domain associated protein 3(NLRP3),apoptosis-associated speck-like protein containing CARD(ASC)and cysteinyl aspartate specific proteinase-1(Caspase-1).Molecular docking results showed that 16 of the 17 chemical compositions detected in PSAE had good docking activities with the core targets of NLRP3,ASC and Caspase-1.[Conclusion]PSAE has great antioxidant and anti-inflammatory activities,and the main active compositions may be flavonoids and saponins.

AIM:To understand the efficacy and safety of amikacin(AMK)for the treatment of car-bapenem-resistant Klebsiella pneumoniae pneu-moniae(CRKP)in preterm infants and to establish a management process for the use of amikacin in preterm infants.METHODS:CRKP-infected preterm infants treated with amikacin between January 2019 and December 2021 were retrospectively ana-lyzed,and parametric data paired t-tests were used to assess the efficacy and safety of amikacin for the included infectious and safety indicators,and to es-tablish a management process for amikacin use in preterm infants.RESULTS:Eight cases of CRKP in-fection were included,with the main diagnosis of pneumonia and sepsis.eight preterm infants were screened for the AMK ototoxicity gene mitochon-drial gene MT-RNR1(MT-RNR1 1494C＞T and MT-RNR11555A＞G)before amikacin treatment,and none of them were found to have the gene variant.after receiving amikacin sulphate injection treat-ment for 7 days,the indicators of infectivity were improved,and was statistically significant(P＜0.01).No clinical ototoxicity or nephrotoxicity was ob-served in the children before or after treatment.CONCLUSION:Aminoglycosides are still the main antibiotics used for the empirical treatment of sus-pected infections in preterm infants,especially drug-resistant bacterial infections.Despite the risk of ototoxicity and nephrotoxicity,we provide man-agement procedures and recommendations for neonatal treatment with amikacin to reduce the risk of ototoxicity and nephrotoxicity in AMK.

AIM:To understand the efficacy and safety of amikacin(AMK)for the treatment of car-bapenem-resistant Klebsiella pneumoniae pneu-moniae(CRKP)in preterm infants and to establish a management process for the use of amikacin in preterm infants.METHODS:CRKP-infected preterm infants treated with amikacin between January 2019 and December 2021 were retrospectively ana-lyzed,and parametric data paired t-tests were used to assess the efficacy and safety of amikacin for the included infectious and safety indicators,and to es-tablish a management process for amikacin use in preterm infants.RESULTS:Eight cases of CRKP in-fection were included,with the main diagnosis of pneumonia and sepsis.eight preterm infants were screened for the AMK ototoxicity gene mitochon-drial gene MT-RNR1(MT-RNR1 1494C＞T and MT-RNR11555A＞G)before amikacin treatment,and none of them were found to have the gene variant.after receiving amikacin sulphate injection treat-ment for 7 days,the indicators of infectivity were improved,and was statistically significant(P＜0.01).No clinical ototoxicity or nephrotoxicity was ob-served in the children before or after treatment.CONCLUSION:Aminoglycosides are still the main antibiotics used for the empirical treatment of sus-pected infections in preterm infants,especially drug-resistant bacterial infections.Despite the risk of ototoxicity and nephrotoxicity,we provide man-agement procedures and recommendations for neonatal treatment with amikacin to reduce the risk of ototoxicity and nephrotoxicity in AMK.

Objective:To investigate clinical and histopathological features of adult erythema nodosum (EN) .Methods:Clinical data were collected from 54 adult inpatients with histopathologically confirmed EN in Department of Dermatology and Venereology, the First Affiliated Hospital of Wannan Medical College from November 2019 to July 2022, and analyzed retrospectively.Results:Among the 54 EN patients, there were 6 males and 48 females, their ages were 42.50 ± 11.68 years (range, 18 - 73 years), and their disease course ranged from 1 day to 10 years; 30 patients (55.56%) were diagnosed with idiopathic EN, and 24 (44.44%) with secondary EN. The most common etiological factor in secondary EN was infection (17 cases), including respiratory tract infection (9 cases), tuberculosis infection (6 cases), upper respiratory tract infection comorbid with active hepatitis B virus infection (2 cases) ; the following common etiological factor was connective tissue disease (7 cases), including Behcet′s syndrome (4 cases), Sj?gren′s syndrome (1 case), and undifferentiated connective tissue diseases (2 cases). The patients′ ages were significantly younger in the secondary EN group (38.33 ± 12.15 years) than in the idiopathic EN group (46.17 ± 10.20 years, t = 2.58, P = 0.013). All patients had skin lesions on their lower limbs, lesions were limited to both lower limbs in 24 patients with idiopathic EN and 12 with secondary EN, and the proportion of patients with lesions limited to both lower limbs was significantly lower in the secondary EN group than in the idiopathic EN group ( χ2 = 5.44, P = 0.020). Compared with the idiopathic EN group, the secondary EN group showed significantly increased white blood cell counts ([7.56 ± 2.46] × 10 9/L vs. [6.04 ± 1.60] × 10 9/L, t = 2.62, P < 0.05) and C-reaction protein levels (34.34 ± 46.48 mg/L vs. 11.45 ± 18.13 mg/L, t = 2.28, P < 0.05). In the idiopathic EN group, 23 patients mainly showed histopathological features of septal panniculitis, while 17 patients in the secondary EN group mainly showed histopathological features of mixed panniculitis or lobular panniculitis, and the proportion of patients with histopathological features of mixed panniculitis or lobular panniculitis was significantly higher in the secondary EN group than in the idiopathic EN group ( χ2 = 12.18, P < 0.001) . Conclusion:EN was more common in female adults; idiopathic EN was the most common type, and secondary EN may be a cutaneous sign of systemic diseases; for EN patients at a relatively young age, with lesions involving both lower limbs or more sites, higher white blood cell counts and C-reaction protein levels, and histopathological manifestations of lobular panniculitis, systemic examinations were required to rule out underlying causes.

Objective:To explore the efficacy, safety and possible brain network mechanisms of individualized targeted robot assisted Stanford accelerated intelligent neuromodulation therapy (SAINT).Methods:This was a small-sample, open-label study including 15 depressed patients with suicidal ideation. All participants were treated with SAINT in combination with SNRIs. The stimulation target was localized to the region of the left dorsolateral prefrontal cortex (DLPFC) that showed the most negative functional connectivity with the subgenual anterior cingulate cortex (sgACC) based on fMRI data. Stimulation sessions were delivered hourly. Ten sessions were applied per day (18, 000 pulses/day) for 5 consecutive days (90, 000 pulses in total). Stimulation was delivered at 90% resting motor threshold. The changes of functional connectivity of brain networks in various brain regions before and after treatment were compared and analyzed by rest software and functional connectivity analysis based on seed points. The Beck Suicidal Ideation Scale Chinese Version (BSI-CV), HAMD 17, and MADRS were used to assess the suicidal ideation and depressive symptoms at baseline, post treatment, 15 days after treatment, and 30 days after treatment. Statistical analysis was performed using repeated measurements of ANOVA and paired t-tests. Results:(1) After 5-day treatment, individual′s BSI-CV score decreased significantly ( F=38.77, P<0.01), and their average score decreased by 11.80±1.17 (95 %CI=8.19-15.41), with a response rate of 86.67%. SAINT was well tolerated, and there were no significant side effects on individual′s cognitive function. (2) After treatment, patient′s MADRS score decreased significantly at all follow-up assessments ( F=306.97, P<0.01), and the average score decreased by 22.53±1.10 (95 %CI=19.15-25.91) after 5-day treatment, with a response rate of 93.33%. After 15 days and 30 days, the remission and response rates of treatment were 53.33%, 100.00%, 93.33% and 100.00%, respectively. (3) The functional network connectivity after individualized targeted robot assisted SAINT therapy showed significant improvement between sgACC, frontal lobe, temporal lobe, and parietal lobe. Conclusion:Individualized targeted robot assisted SAINT therapy showed satisfactory efficacy and safety in the reduction of suicidal ideation and depressive symptoms, and also improve the functional network connectivity of the injured brain network. Meanwhile, large-sample, randomized, and double-blind controlled studies are warranted to confirm the findings of the current study.

Objective:To investigate the influencing factors of hyperuricemia(HUA) and explore early intervention of metabolic diseases.Methods:A total of 70 523 participants were selected from the database of check-ups in 2016. Univariate analysis and logistic regression analysis were used to identify related factors of HUA. Correspondence analysis was performed for the aggregation of different levels of uric acid(UA) and related factors. The mediating effect of mean blood pressure(MBP) between abnormal metabolic indicators and abnormal renal function was tested.Results:The age, sex, occupation, body mass index(BMI), systolic blood pressure, diastolic blood pressure, blood urea nitrogen(BUN), creatinine(Cr), estimated glomerular filtration rate(eGFR), fasting plasma glucose(FPG), total cholesterol(TC), triacylglycerol(TG), high density lipoprotein-cholesterol(HDL-C), low density lipoprotein-cholesterol, plasma viscosity were significantly related to HUA( P<0.001). Logistic regression analysis showed that youth, male, hypertension, TC, TG, and Cr were risk factors for HUA, while HDL-C was a protective factor for HUA( P<0.001). Correspondence analysis showed that during the gradual increase of UA, TC was the first to appear abnormal, followed by hypertension and TG, and the increase of Cr appeared last. Mediating effect showed that in changes of UA, the mediating effects of MBP on TC, TG, and HDL-C were 36.35%, 12.63%, and 9.41%, respectively. In changes of eGFR, the mediating effects of MBP on TC, TG and HDL-C were 30.20%, 27.70%, and 6.13%, respectively. Conclusions:UA is positively correlated with blood pressure, TC, and TG, and inversely with HDL-C. TC and TG have an impact on renal impairment, in which MBP plays a mediating role.

Objective:To investigate the clinical manifestation, pathological types, treatment and prognosis of primary tracheobronchial tumors in children.Methods:We retrospectively studied the primary tracheobronchial tumors patients who diagnosed from May 2009 to Jan 2021 in Guangzhou Women and Children Medical Center. The clinical manifestations, pathological types, therapeutic methods and prognosis were analyzed.Results:There were 15 patients identified as the primary tracheobronchial tumors, including synovial sarcoma (1 case), pulmonary inflammatory myofibroblastic tumor(IMT 4 cases), mucoepidermoid carcinoma(7 cases), infantile hemangioma (1 case), Ewing's sarcoma (1 case). Respiratory symptoms are the most complaint at the time of diagnosis including 15 patients with cough, 2 with hemoptysis, and 1 with dyspnea. Endoscopic treatment of tracheobronchial tumors was performed under extracorporeal membrane oxygenation (ECMO) support in 1 patient. Sleeve lobectomy was performed in 3 patients, lobectomies in 6, and local tumor resections in 4 patients including 2 patients suffered second surgery due to tumor recurrence.Conclusion:The clinical manifestations of the primary tracheobronchial tumors in children are nonspecific. Complete resection led to excellent outcome.