The genome tagging project (GTP) plays a pivotal role in addressing a critical gap in the understanding of protein functions. Within this framework, we successfully generated a human influenza hemagglutinin-tagged sperm-specific protein 411 (HA-tagged Ssp411) mouse model. This model is instrumental in probing the expression and function of Ssp411. Our research revealed that Ssp411 is expressed in the round spermatids, elongating spermatids, elongated spermatids, and epididymal spermatozoa. The comprehensive examination of the distribution of Ssp411 in these germ cells offers new perspectives on its involvement in spermiogenesis. Nevertheless, rigorous further inquiry is imperative to elucidate the precise mechanistic underpinnings of these functions. Ssp411 is not detectable in metaphase II (MII) oocytes, zygotes, or 2-cell stage embryos, highlighting its intricate role in early embryonic development. These findings not only advance our understanding of the role of Ssp411 in reproductive physiology but also significantly contribute to the overarching goals of the GTP, fostering groundbreaking advancements in the fields of spermiogenesis and reproductive biology.
Animals ; Female ; Humans ; Male ; Mice ; Spermatids/metabolism* ; Spermatogenesis/physiology* ; Spermatozoa/metabolism* ; Thioredoxins/genetics*

This study was conducted retrospectively on a cohort of 68 patients with steroid 5 α-reductase 2 (SRD5A2) deficiency and 46,XY disorders of sex development (DSD). Whole-exon sequencing revealed 28 variants of SRD5A2 , and further analysis identified seven novel mutants. The preponderance of variants was observed in exon 1 and exon 4, specifically within the nicotinamide adenine dinucleotide phosphate (NADPH)-binding region. Among the entire cohort, 53 patients underwent initial surgery at Sichuan Provincial People's Hospital (Chengdu, China). The external genitalia scores (EGS) of these participants varied from 2.0 to 11.0, with a mean of 6.8 (standard deviation [s.d.]: 2.5). Thirty patients consented to hormone testing. Their average testosterone-to-dihydrotestosterone (T/DHT) ratio was 49.3 (s.d.: 23.4). Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome; and their T/DHT ratios were below the diagnostic threshold. Furthermore, assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants. These mechanisms include interference with NADPH binding (c.356G>C, c.365A>G, c.492C>G, and c.662T>G) and destabilization of the protein structure (c.727C>T). The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts. Seven novel variations were identified, and the variant database for the SRD5A2 gene was expanded. These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.
Humans ; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Disorder of Sex Development, 46,XY/blood* ; Male ; Membrane Proteins/genetics* ; Child, Preschool ; Child ; Retrospective Studies ; Adolescent ; Female ; Mutation ; Testosterone/blood* ; Infant ; Dihydrotestosterone/blood*

Acute liver injury (ALI) serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders. The prevention and treatment of ALI is still a serious global challenge. Given the limited therapeutic options for ALI, exploring novel targeted therapeutic agents becomes imperative. The potential therapeutic efficacy of inhibiting RIPK2 is highlighted, as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling. Herein, we propose a CMD-OPT model, a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties. Compound RP20, which targets the ATP binding site, demonstrated excellent kinase specificity, ideal oral pharmacokinetics, and superior therapeutic effects in a model of APAP-induced ALI, positioning RP20 as a promising preclinical candidate. This marks the first application of RIPK2 inhibitors in ALI treatment, opening a novel therapeutic pathway for clinical applications. These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules, showcasing its significant potential in drug discovery.

Objective:To evaluate the efficacy and safety of baricitinib combined with ruxolitinib cream in the treatment of progressive nonsegmental vitiligo.Methods:Clinical data were retrospectively collected from patients with progressive nonsegmental vitiligo in Boao Super Hospital. All the patients were treated with oral baricitinib daily (2 mg/day for patients weighing ≤ 50 kg; 4 mg/day for those > 50 kg) in combination with topical application of ruxolitinib cream twice daily for 24 consecutive weeks. Disease severity was assessed using the facial vitiligo area scoring index (F-VASI) and total body VASI (T-VASI) at baseline, week 12, and week 24. Adverse reactions were monitored throughout the treatment course.Results:Six patients with progressive nonsegmental vitiligo were collected, including 3 males and 3 females, aged 26 - 42 years, with the disease duration ranging from 0.5 to 25 years. At week 12, 3 patients achieved a 50% ~ < 75% improvement in facial vitiligo lesions (F-VASI 50), 1 patient achieved F-VASI 75 (75% ~ < 90% improvement), and 1 patient achieved T-VASI 50; at week 24, 4 patients achieved F-VASI 50, 1 patient achieved F-VASI 75, 1 patient achieved F-VASI 90 (≥ 90% improvement), and 3 patients achieved T-VASI 50. During the treatment, upper respiratory infection occurred in 1 patient, acne in 1 patient, pruritus in 2 patients, elevation of total cholesterol levels in 2 patients, and increase of high-density lipoprotein levels in 2 patients. No severe adverse events were observed during the treatment.Conclusion:The combination therapy with baricitinib and ruxolitinib cream may have potential efficacy and safety in the treatment of progressive nonsegmental vitiligo.

Objective:To summarize the clinicopathologic characteristics of malignant hypertension (MHT) patients with acute kidney injury (AKI) and application of renin-angiotensin-aldosterone system inhibitor (RAASi).Methods:It was a retrospective cohort study. The adult patients with MHT and AKI admitted to Peking University First Hospital from January 1, 2012 to July 14, 2022. The patients were categorized into RAASi group and non-RAASi group based on RAASi administration from AKI onset to discharge. The clinicopathological data between the two groups were compared, and application of RAASi was analyzed.Results:A total of 179 patients were enrolled with age of 31 (26, 37) years and 148 males (82.7%). Ninety-five patients (53.1%) received dialysis treatment. The common causes of MHT were essential hypertension (125 patients, 69.8%), renal hypertension (39 patients, 21.8%) and endocrine hypertension (7 patients, 3.9%). AKI severity distribution showed 41 patients (22.9%) in stage 1, 1 patient (0.5%) in stage 2 and 137 patients (76.5%) in stage 3. Among MHT patients, 94 patients (52.5%) had been treated with RAASi before AKI, and 13 patients (7.3%) discontinued RAASi after AKI. Among 85 patients (47.5%) without receiving RAASi treatment before AKI, 68 new patients (38.0%) received RAASi treatment after AKI, and 40 patients (22.3%) were treated with the support of dialysis. Compared with non-RAASI group ( n=30), proportions of chronic kidney disease ( χ2=6.324, P=0.012) and post-AKI hyperkalemia ( χ2=4.048, P=0.044) in RAASi group ( n=149) were lower, and the proportion of dialysis treatment ( χ2=5.638, P=0.018), admission diastolic blood pressure ( Z=-3.609, P<0.001) and maximum diastolic blood pressure during hospitalization ( Z=-1.978, P=0.048) were higher. There were no statistically significant differences in the rates of target blood pressure control and renal function recovery between the two groups during hospitalization (all P>0.05). During hospitalization, 64 patients received renal biopsies, of which 50 patients (78.1%) had typical MHT vascular lesions such as "onion skin" in renal arterioles. Twenty-seven patients (42.2%) were complicated with glomerular diseases, and IgA nephropathy was the most common type (85.2%, 23/27). The proportions of glomerular ischemia and sclerosis, endothelial cell proliferation and acute renal tubular injury in RAASi group ( n=54) were lower than those in non-RAASi group ( n=10), and proportions of thrombosis and "onion skin" change were higher than those in RAASi group ( n=10), but the differences were not statistically significant (all P>0.05). Renal function recovery occurred in 47 patients (26.3%) by discharge. Among 95 dialysis patients, 26 patients (27.4%) achieved dialysis independence at discharge. Conclusions:MHT patients with AKI exhibit severe renal pathology and short-term poor prognosis. RAASi is primarily prescribed to those with relatively better kidney function or those receiving dialysis support.

Crohn 's disease (CD) is an intestinal inflammatory disease of unknown etiology, the pathophysiological mechanism is still unclear. The enteric nervous system (ENS) is responsible for the autonomous regulation of intestinal function. Therefore, ENS dysfunction may be the core of the pathophysiological mechanism of CD. Here, we review the pathophysiological mechanism by which ENS contributes to the development of CD, with a focus on the role of aberrant histological manifestations of ENS and plexitis in predicting the recurrence of CD following surgery.

Objective:To investigate the risk factors associated with 90-day mortality in critically ill patients receiving continuous renal replacement therapy (CRRT), with a particular focus on the association between hypotension within the first hour of CRRT initiation and 90-day mortality after hospital admission.Methods:This study was a post hoc analysis of a prospective cohort study investigating the impact of colloid versus crystalloid priming solutions on early hemodynamics in critically ill patients undergoing CRRT. The study enrolled intensive care unit patients who received CRRT at West China Hospital of Sichuan University from January 2024 to May 2024. The data were collected including demographic characteristics, laboratory tests, CRRT-related parameters, blood pressure, heart rate, sequential organ failure assessment scores, and vasoactive-inotropic score, etc. The 90-day survival outcome after hospital admission of critically ill patients aged 18-80 years who received continuous veno-venous hemodiafiltration was used as the primary outcome indicator. A Cox proportional hazards model analysis was conducted, and the predictive ability of the model was evaluated along with the test of the proportional hazards assumption. The risk factors associated with the 90-day mortality after hospital admission of critically ill patients receiving CRRT were explored, with a particular focus on whether hypotension occurring within the first hour of CRRT initiation was one of these risk factors.Results:A total of 208 patients were included in this study. Within 90 days after hospital admission, 141 patients (67.8%) died, among whom 102 were male (72.3%) and the median age was 61.0 (50.0, 71.5) years; 67 patients (32.2%) survived, among whom 53 were males (79.1%) and the median age was 56.0 (47.0, 68.0) years. The incidence of hypotension within the first hour of CRRT initiation was significantly higher in the death group than in the survival group [29.8% (42/141) vs. 16.4% (11/67), χ2=4.275, P=0.039]. Moreover, The mortality rate of the group with hypotension within the first hour of CRRT initiation was higher than that of the group without hypotension [79.2% (42/53) vs. 63.9% (99/155), χ2=4.275, P=0.039]. The Kaplan-Meier survival analysis showed that the median survival time of patients without hypotension within the first hour of CRRT initiation [39.0 d (95% CI 23.2-54.8)] was longer than that of patients with hypotension [26.0 d (95% CI 18.9-33.1)], and the 90-day cumulative survival rate after hospital admission of patients without hypotension was significantly higher than that of patients with hypotension (Log-rank test, χ2=5.100, P=0.024). Univariate and multivariate Cox proportional hazards analyses demonstrated that serum albumin ( HR=0.964, 95% CI 0.933-0.997, P=0.030), sequential organ failure assessment score ( HR=1.064, 95% CI 1.012-1.118, P=0.015), and the use of mechanical ventilation ( HR=8.272, 95% CI 1.145-59.743, P=0.036) were significantly associated with 90-day mortality in critically ill patients undergoing CRRT. In contrast, the vasoactive-inotropic score ( HR=1.004, 95% CI 0.999-1.008, P=0.079) and the presence of hypotension within the first hour of CRRT initiation ( HR=1.236, 95% CI 0.833-1.835, P=0.293) were not significantly associated with 90-day mortality in critically ill patients undergoing CRRT. The consistency index of this model was 0.654 (95% CI 0.617-0.691), the area under the receiver operating characteristic curve was 0.724 (95% CI 0.658-0.800), and the calibration curve showed that the predicted values of the model were well fitted to the actual observations, suggesting that the predictive effect of this model was relatively ideal. Conclusions:In critically ill patients undergoing CRRT, the occurrence of hypotension within the first hour of CRRT initiation was not significantly associated with 90-day mortality after hospital admission. Lower serum albumin levels, higher sequential organ failure assessment scores, and the use of mechanical ventilation may be the risk factors for 90-day mortality in this population.

Objective:To investigate the serum sodium level and its fluctuation in patients with hospitalized acquired acute kidney injury (AKI) and explore their impacts on in-hospital mortality.Methods:It was a single-center retrospective study. The adult patients developing hospital-acquired AKI and receiving at least twice serum sodium tests admitted to Peking University First Hospital from January 1, 2018, to December 31, 2020 were included. Dysnatremia included hyponatremia (< 135 mmol/L) and hypernatremia (>145 mmol/L). The patients were divided into hyponatremia group, normal serum sodium group and hypernatremia group, and the differences of clinical data among the three groups were compared. The fluctuation of serum sodium level was evaluated by coefficient of variation. A restricted cubic spline was applied to investigate the association between serum sodium level at AKI onset and mortality. Poisson regression analysis was used to explore the mortality risk of dysnatremia at AKI onset, dysnatremia at admission, and coefficient of variation of serum sodium, respectively.Results:Among the enrolled 1 475 AKI patients, the age was 66.0 (55.0, 78.0) years, and 850 patients (57.6%) were males. The estimated glomerular filtration rate was 77.3 (50.4, 97.6) ml·min -1·(1.73 m 2) -1. The time from admission to AKI onset was 8 (4, 15) days. The incidence of hyponatremia and hypernatremia at admission were 19.6% (289/1 475) and 2.6% (39/1 475), respectively, while the incidence at AKI onset was 24.0% (354/1 475) and 12.7% (188/1 475), respectively. There was statistically significant difference in terms of age, the initial classification distribution of AKI, serum sodium at admission, serum sodium at the occurrence of AKI, the lowest serum sodium at hospitalization, the highest serum sodium at hospitalization, the coefficient of variation of serum sodium, and the proportions of heart failure, stroke, disseminated intravascular coagulation, sepsis, acute respiratory distress syndrome, shock, prerenal causes, circle diuretics and aldosterone antagonists among hyponatremia group, normal serum sodium group and hypernatremia group (all P<0.05). The restricted cubic spline analysis showed a "U"-shaped correlation between serum sodium level at AKI onset and in-hospital mortality. Poisson regression analysis showed that after adjusting for age, gender, number of chronic comorbidities, initial classification of AKI, basal estimated glomerular filtration rate and number of acute disease state, with normal serum sodium as the reference, hyponatremia ( RR=1.56, 95% CI 1.14-2.13) and hypernatremia ( RR=1.71, 95% CI 1.23-2.39) at AKI onset were correlated with an increased risk of in-hospital mortality. Hyponatremia at admission was correlated with an increased risk of in-hospital mortality ( RR=2.13, 95% CI 1.62-2.79), while there was no statistically significant association between hypernatremia and in-hospital mortality ( RR=1.22, 95% CI 0.62-2.44). After further adjusting serum sodium levels at admission and at the occurrence of AKI, the coefficient of variation of serum sodium level was still correlated with an increased risk of in-hospital mortality ( RR=1.23, 95% CI 1.14-1.33). Conclusions:Dysnatremia is common in patients with hospital-acquired AKI. The serum sodium level at AKI onset is correlated with in-hospital death in a "U" shape. Dysnatremia and serum sodium fluctuation are associated with an increased risk of in-hospital mortality.

Objective:To evaluate the safety and efficacy of early precise lower limb weight-bearing functional rehabilitation after open reduction and internal fixation of ankle fractures.Methods:A restropective multi-center study was conducted to enroll the eligible 120 patients with malleolar fracture who received the same surgical treatment from March 2023 to December 2023 at the trauma centers in 7 tertiary hospitals according to the inclusion criteria. They were assigned into a study group ( n=60) for precise lower limb weight-bearing functional rehabilitation with the assistance of intelligent lower limb walking rehabilitation crutches and a control group ( n=60) for conventional weight-bearing functional rehabilitation which was gradually increased according to their own feelings under the protection of a walking boot. All the 60 patients in the study group completed their final follow-ups. They were 25 males and 35 females, with an age of (43.8±16.6) years and a body mass index of (25.3±2.3) kg/m 2. Only 51 patients in the control group completed their final follow-ups. They were 27 males and 24 females, with an age of (45.1±16.4) years and a body mass index of (24.7±2.3) kg/m 2. When their incisions healed and their sutures were removed 2 weeks after operation, the patients were guided to start lower limb weight-bearing functional rehabilitation, and exercises for foot and ankle joint mobility and lower limb muscles. The end point of follow-up was 12 weeks after operation. The 2 groups were compared in terms of the crutch-off rates, thigh circumferences, calf circumferences, dorsiflexions, plantarflexions, ankle swellings, American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot scores, and visual analog scale (VAS) pain scores at 6 and 12 weeks after operation. The complications were also recorded in the 2 groups. Results:No statistically significant differences were observed in the baseline characteristics between the 2 groups, indicating comparability ( P>0.05). At 6 and 12 weeks after operation, the crutch-off rates [41.7% (25/60) and 100.0% (60/60)], dorsiflexions (69.3%±21.6% and 82.9%±26.3%) and AOFAS ankle-hindfoot scores [(68.5±7.6) points and (96.9±3.7) points] in the study group were significantly better than those in the control group [13.7% (7/51) and 39.2% (20/51), 61.5%±16.5% and 72.0%±14.3%, (61.9±9.3) points and (90.1±7.2) points] ( P<0.05). At 6 weeks after operation, the thigh circumference (97.4%±1.9%), calf circumference (97.3%±1.9%), and plantarflexion (76.6%±19.8%) in the study group were significantly higher than those in the control group (95.9%±2.5%, 94.6%±3.2%, and 63.9%±16.9%) ( P<0.05). There were no significant differences between the 2 groups in ankle swelling at 6 or 12 weeks after operation, or thigh or calf circumference, plantarflexion, or VAS pain score at 12 weeks after operation ( P>0.05). No wound complications, secondary fracture displacement, or loosening of internal fixation occurred in either group during the follow-up period. There were no cases of nonunion or delayed union. Conclusions:Early lower limb weight-bearing functional rehabilitation after open reduction and internal fixation of ankle fractures demonstrates good safety. Precise weight-bearing rehabilitation accelerates functional recovery of the ankle, enabling earlier return to normal daily activities.

Purpose To investigate correlation of ADP ribosylation-like factor 6 interacting protein 4(ARL6IP4)expression with the pathological characteristics and clinical prognosis in primary colon cancer.Methods The ARL6IP4 mRNA expression in tumor and adjacent normal tissues of 133 colon cancer patients was analyzed by RT-qPCR,and its relationship with tumor location,pathological TNM stage,and 3-year survival prognosis was assessed.Additionally,ARL6IP4 protein expression was analyzed by immunohistochemistry in 30 cases,of which 16 cases were analyzed by immunofluorescence.Results The colon cancer presented significantly higher mRNA and protein levels of ARL6IP4 than adjacent normal tissues(t=4.221,P=5.200 × 10-5;t=7.421,P=3.537 × 10-8).The relative ex-pression level of ARL6IP4 mRNA in colon cancer was positively correlated with pathological TNM stage,N stage and M stage(P＜0.05),and negatively correlated with 3-year cumulative survival probability(P＜0.01).Additionally,sig-moid colon cancer presented significantly higher ARL6IP4 expression than other colon cancers,and at the cellular lev-el,ARL6IP4 was predominantly expressed in the cell nucleus.Conclusion The ARL6IP4 expression in colon cancer is higher than that in adjacent normal tissues,which is closely related to tumor metastasis and clinical prognosis.