Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Sensorineural hearing loss (SNHL), the most commonly-occurring form of hearing loss, is caused mainly by injury to or the loss of hair cells and spiral ganglion neurons in the cochlea. Numerous environmental and physiological factors have been shown to cause acquired SNHL, such as ototoxic drugs, noise exposure, aging, infections, and diseases. Several programmed cell death (PCD) pathways have been reported to be involved in SNHL, especially some novel PCD pathways that have only recently been reported, such as ferroptosis, necroptosis, and pyroptosis. Here we summarize these PCD pathways and their roles and mechanisms in SNHL, aiming to provide new insights and potential therapeutic strategies for SNHL by targeting these PCD pathways.
Humans ; Hearing Loss, Sensorineural/metabolism* ; Necroptosis/drug effects* ; Pyroptosis/drug effects* ; Ferroptosis/drug effects* ; Animals

As a potential vectored vaccine,Newcastle disease virus(NDV)has been subject to various studies for vaccine development,while relatively little research has outlined the immunomodulatory effect of the virus in antigen presentation.To elucidate the key inhibitory factor in regulating the interaction of infected dendritic cells(DCs)and T cells,DCs were pretreated with the NDV vaccine strain LaSota as an inhibitor and stimulated with lipopolysaccharide(LPS)for further detection by enzyme-linked immunosorbent assay(ELISA),flow cytometry,immunoblotting,and quantitative real-time polymerase chain reaction(qRT-PCR).The results revealed that NDV infection resulted in the inhibition of interleukin(IL)-12p40 in DCs through a p38 mitogen-activated protein kinase(MAPK)-dependent manner,thus inhibiting the synthesis of IL-12p70,leading to the reduction in T cell proliferation and the secretion of interferon-γ(IFN-γ),tumor necrosis factor-α(TNF-α),and IL-6 induced by DCs.Consequently,downregulated cytokines accelerated the infection and viral transmission from DCs to T cells.Furthermore,several other strains of NDV also exhibited inhibitory activity.The current study reveals that NDV can modulate the intensity of the innate?adaptive immune cell crosstalk critically toward viral invasion improvement,highlighting a novel mechanism of virus-induced immunosuppression and providing new perspectives on the improvement of NDV-vectored vaccine.

Objective:To evaluate the influencing factors and predictive value of renal function recovery in elderly patients with heart failure(HF)and acute renal injury(AKI)after intermittent veno-venous hemofiltration(IVVH)using critical care ultrasound.Methods:The clinical data of elderly patients with heart failure(NYHF grade Ⅲ~Ⅳ)complicated with acute kidney injury(stage 2~stage 3)who underwent intravenous veno-venous hemofiltration(IVVH)in the critical care unit(CCU)of our hospital were retrospectively analyzed.The demographic information of the patients and the changes in clinical biochemical and critical care ultrasound monitoring parameters before and after 7 days of IVVH were recorded.Based on the recovery of renal function, the patients were divided into two groups: a renal function recovery group and a renal function non-recovery group.Logistic regression and Receiver Operating Characteristic Curve(ROC)curve analysis were performed to determine the predictive value of various influencing factors on the recovery of renal function in patients.Results:A total of 178 patients were enrolled in this study.After starting IVVH treatment, renal function recovered in 143 cases at 30 days, and in 138 cases at 90 days.However, renal function did not recover in 35 cases at 30 days, and in 40 cases at 90 days.The proportion of NYHF Ⅲ patients、the proportion of diabetic patients、the decrease of Beta 2-microglobulin(β2-MC)、the decrease of Cystain C(CysC)、the increase of venous transit time index(VTI)、the increase of Cardiac Output(CO)and the decrease in renal blood flow resistance index(RI)in the recovery groups at both 30 days and 90 days was significantly higher than that in the non-recovery group(all P<0.05).The total treatment time of IVVH in the recovery group was significantly shorter than that in the non-recovery group, with 30 days and 90 days( P<0.05).Logistic analysis revealed that the total treatment time of IVVH( OR=1.067, P<0.001), VTI( OR=0.652, P=0.024), CO( OR=0.037, P<0.001), and RI(OR<0.001, P=0.010)of the interlobar artery were identified as independent factors influencing the recovery of renal function in AKI patients at 30 days and 90 days after IVVH treatment.The ROC curve demonstrated the predictive value of various independent influencing factors for 30-day renal function recovery.The area under the curve(AUC)for VTI was 0.610(95% CI: 0.513-0.707), for CO it was 0.760(95% CI: 0.656-0.864), and for RI it was 0.694(95% CI: 0.589-0.799).Similarly, the ROC curve showed the predictive value of these factors for renal function recovery at 90 days.The AUC for VTI was 0.654(95% CI: 0.564-0.744), for CO it was 0.697(95% CI: 0.605-0.789), and for interlobar artery RI it was 0.605(95% CI: 0.495-0.715). Conclusions:The venous transit time index(VTI), cardiac output(CO), and renal interlobar artery RI, monitored by critical care ultrasound, are independent factors that can be used to evaluate the recovery of renal function in elderly patients with HF and AKI after IVVH treatment.Additionally, the changes in these parameters within 7 days after IVVH treatment have a high predictive value for the improvement of renal function in elderly patients after 30 days and 90 days.

Objective:To investigate the volume management of intermittent veno-venous hemofiltration (IVVH) guided by critical care ultrasound in the treatment of acute kidney injury (AKI) in patients with heart failure (HF).Methods:A total of 216 patients with HF and AKI treated with IVVH in the coronary care unit (CCU) of the Third Central Hospital of Tianjin from April 2019 to June 2022 were selected as the study subjects, the patients were randomly divided into conventional guidance group (107 cases) and ultrasound guidance group (109 cases). According to the recovery of renal function, IVVH was performed 12 hours every day or 12 hours every other day. The conventional guidance group selected the conventional method to formulate IVVH prescription, and the ultrasound guidance group used critical care ultrasound to adjust the treatment parameters of IVVH on the basis of the conventional guidance group. Respiratory variation index (RVI) of inferior vena cava (IVC), right left ventricular end-diastolic transverse area ratio, early diastolic peak mitral flow velocity/mitral annulus velocity peak (E/E'), aortic flow velocity time integral (VTI), cardiac output (CO), bilateral lung ultrasound B-line range, bilateral renal interlobar arteries resistance index (RI) were recorded before and 3, 6, 9 hours after each treatment. The net dehydration rate was adjusted in real time according to the comprehensive results. Urine volume, serum creatinine (SCr), estimated glomerular filtration rate (eGFR), blood B-type brain natriuretic peptide (BNP), β 2-microglobulin (β 2-MG) and cystatin C (Cys C) levels of patients in both groups were monitored before and 3, 7 and 10 days after initial treatment, and renal function recovery and clinical prognostic indexes of patients in both groups were recorded. Results:The dehydration rate of the ultrasound guidance group was slow at the beginning of IVVH, and gradually increased after 6 hours, and the overall dehydration rate was significantly slower than that of the conventional guidance group. In the ultrasound guidance group using critical care ultrasound, the RVI gradually increased, the right left ventricular end-diastolic area ratio gradually decreased, the E/E' ratio gradually decreased, and the range of B-line of bilateral lungs gradually decreased, RI of bilateral renal interlobar arteries decreased. At 3, 7 and 10 days after the first IVVH, renal function related indexes in both groups were significantly improved compared with before treatment, and the decline rate of β 2-MG and Cys C in the ultrasound guidance group was faster than that in the conventional guidance group at early (3 days) [β 2-MG (mg/L): 3.69±1.31 vs. 3.99±1.45, Cys C (mg/L): 2.91±0.95 vs. 3.14±0.96, both P < 0.05], urine volume, SCr and eGFR at 7 days were also significantly improved compared with the conventional guidance group [24-hour urine volume (mL): 1 128.23±153.92 vs. 1 015.01±114.18, SCr (μmol/L): 145.86±32.25 vs. 155.64±28.42, eGFR (mL/min): 50.26±11.24 vs. 46.51±10.61, all P < 0.05]. The time of SCr recovery, the time of reaching polyuria, the total time of IVVH treatment, the time of non-invasive mechanical ventilation and the time of living in CCU in the ultrasound guidance group were shorter than those in the conventional guidance group. The incidences of hypotension, long-term RRT, incidence of major cardiovascular adverse event (MACE) and at 28-day mortality were all lower than those in the conventional guidance group. Kaplan-Meier survival curve showed that the 28-day cumulative survival rate in the ultrasound guidance group was significantly lower than that in the conventional guidance group (Log-Rank test: χ 2 = 3.903, P = 0.048). Conclusion:The strategy of IVVH guided by critical care ultrasound in the treatment of HF with AKI has unique advantages.

Objective To evaluate the efficacy of testa triticum tricum purif combined with polyethylene glycol electrolyte powder for bowel preparation before colonoscopy in patients with constipation. Methods A total of 190 patients with constipation who underwent colonoscopy were randomized into 2 groups. The study group(n=93)were given testa triticum tricum purif and polyethylene glycol electrolyte powder,whereas the control group(n=97)were given polyethylene glycol electrolyte powder only.The bowel cleanness,adenoma detection rate,and incidence of adverse events during bowel preparation were compared. Results The bowel preparation score(7.31±1.14 VS 6.06±1.22,P=0.000)and effective rate(95.70%VS 69.07%, P=0.000)in the study group was significantly higher than that in the control group. The incidence of adverse events in the study group was lower than that in the control group(5.38% VS 17.53%, P=0.009). There was no significant difference in the adenoma detection rate between the two groups (36.56% VS 26.80%, P=0.148). Conclusion Testa triticum tricum purif combined with polyethylene glycol electrolyte powder is superior to conventional method of polyethylene glycol electrolyte powder alone for colonoscopy bowel preparation in patients with constipation.

Objective To explore the value of OTSC( over-the-scope-clip) for upper digestive tract perforation. Methods Thirteen patients with old and fresh upper digestive tract perforation, treated with an OTSC clip at the Department of Digestive Endoscopy from May 2015 to June 2016, were enrolled. All OTSCs were 11/6t, and all procedures were performed by experienced endoscopists. Results Seven cases of fresh perforation were iatrogenic after treatment for gastric submucosal tumor. Six cases of old perforation included 2 cases of spontaneous esophageal rupture, 2 fistula after operations for esophageal foreign body, 1 fistula after the operation for gastric stromal tumor, and 1 anastomotic fistula after esophagectomy. Eight cases of perforation occurred in stomach and 5 in esophageal. Fresh lesion sizes were from 4 to 30 mm ( average 15. 3 mm), old lesion sizes from 5 to 10 mm(average 7. 8 mm). OTSC′s release time in fresh lesions was 6-27 min(average 15. 1 min), that in old 15-80 min(average 42. 3 min) with significant difference. Technical success rate was 100％(13/13),clinical success rate in fresh lesions was 100％(7/7),and 50％ (3/6) in old lesions. No patient had special treatment or complication. Conclusion OTSC is useful and safe for the treatment of upper digestive tract perforation, which is superior for fresh perforation than for the old. The perfect time to release OTSC for old perforation is when there is no obvious fibrosis caused by inflammation. The success rate is higher when the lesion size is smaller than 30 mm. Self-releasing of OTSC is rare. The necessity and the timing to take them out still needs further study.

Objective To evaluate the efficacy of combined application of lactitol oral solution and polyethylene glycol electrolyte (PEG) powder compared with conventional method in bowel preparation before colonoscopy. Methods 205 patients who underwent colonoscopy were randomly divided into experimental group and control group. The experimental group (n = 102) were given lactitol and polyethylene glycol electrolyte powder, whereas the patients in control group (n = 103) were given polyethylene glycol electrolyte powder only. The visibility and adverse effects during colonoscopy were observed. Results The cleaning satisfaction rate was not statistically significant between the two groups. The proportion of cleanliness to grade 1 in experimental group was higher than that in control group. The incidence of adverse effects in experimental group was lower, and there was no effect on sleeping night. The compliance and tolerance of hospitalized patients were significantly improved. Conclusion Lactitol combined with polyethylene glycol electrolyte (peg) powder is safe, effective, with low incidence of adverse effect for bowel preparation in hospitalized patients.

Objective To investigate the ethical needs for nursing of patients with urinary surgery and discuss the interventions related to nursing ethics.Methods Totally 247 patients who received urinary surgery from February 2013 to February 2015 were selected by purposive sampling method. Then their ethical needs for nursing were investigated by our self-designed questionnaires. Finally,targeted interventions of nursing ethics were proposed to meet their most pressing needs found in the study.Results The top three ethical needs for nursing of patients with urinary surgery were disease rehabilitation (4.88±0.59),privacy protection (4.48±0.52) and health education (3.60±0.48);the differences in ethical needs for nursing between patients with different sexes,ages,marital status and literacy were of statistical significance (P<0.05).Conclusions Unmarried and highly educated females under 18 years old have the highest ethical needs for nursing. Nursing intervention should take the individual variation into consideration and satisfy patients′ ethical needs with differentiated ethical nursing interventions,so as to build a harmonious relationship between doctors and patients,and help patients to restore their health soon.

Objective To observe the difference of retinal vessel oxygen saturation in glaucoma and normal eyes.Methods A cross sectional study design was performed.Fifty eyes of 30 glaucoma patients (glaucoma group) and 41 eyes of 27 age-and sex-matched healthy subjects (control group) were included.Retinal vessel oxygen saturation was measured with a spectrophotometric retinal oximeter in darkness and visual fields were obtained by Humphrey filed analyzer.The glaucoma eyes were divided into two groups:mean defect (MD) ＜6 dB (28 eyes) and MD≥6 dB (22 eyes) according to mean defect of visual field.Results Retinal arteriolar oxygen saturation values in glaucoma group and control group were (94.52 ±6.51) ％ and (93.47±6.30) ％ respectively.No statistical difference was found in retinal oxygen saturation in arterioles (H =-0.949,P =0.343).Retinal venous oxygen saturation values in glaucoma group and control group were (57.57 ± 7.96)％ and (52.60 ± 7.70) ％ respectively.The retinal venous oxygen saturation values in glaucoma group was higher than that in control group (H=-3.318,P=0.001).The retinal arteriovenous difference in glaucoma group and control group were (36.59± 4.69)％ and (42.41 ±6.73) ％ respectively.The retinal arteriovenous difference in glaucoma group was lower than that in control group (H=-4.148,P＜0.01).The retinal arteriolar oxygen saturation values in glaucoma eyes with MD＜6 dB and MD≥6 dB were (93.38 ± 6.33)％ and (95.71 ± 6.54)％ respectively,with no statistical difference (H=-1.857,P=0.063).Retinal venous oxygen saturation values in glaucoma eyes with MD＜6 dB and MD≥6 dB were (54.83 ± 6.10) ％ and (6 1.07 ± 8.79) ％ respectively.The retinal venous oxygen saturation values in MD≥ 6 dB glaucoma eyes was higher than that in MD＜ 6 dB glaucoma eyes (H =-2.599,P=0.009).The retinal arteriovenous difference in glaucoma eyes with MD＜6 dB and MD≥6 dB were (38.12± 4.34) ％ and (34.64 ± 4.49) ％ respectively.The retinal arteriovenous difference in MD≥6 dB glaucoma eyes was lower than that in MD＜6 dB glaucoma eyes (H=-2.463,P＜0.05).Conclusions Compared with healthy eyes,there is no change in the retinal arteriolar oxygen saturation,but the retinal venous oxygen saturation is higher and the retinal arteriovenous difference is lower.This feature is more obvious in MD≥6 dB glaucoma eyes.