As green, sustainable, and environmentally friendly material processing processes using biological cells or enzymes to achieve substance conversion, bioprocesses play an increasingly important role in biomanufacturing. It is difficult to optimize bioprocesses because of the complex relationship at multiple levels and multiple scales. The knowledge of mesoscale behaviors is the key to understanding the dynamics of bioprocesses and to sort out the complex relationships of parameter variations in the spatial-temporal domain. Mesoscale numerical simulation paves a way for understanding these phenomena, and the integration of artificial intelligence (AI) and mesoscale simulation offers new vitality into the optimization of bioprocesses. This article reviews the progress in mesoscale simulation and AI optimization of bioprocesses and discusses the possible development directions, aiming to promote the development of this field.
Artificial Intelligence ; Biotechnology/trends* ; Computer Simulation

Alternative splicing (AS) serves as a fundamental regulatory mechanism in gene expression, contributing to proteomic diversity by generating an array of mRNA isoforms from precursor mRNA via distinct splice site combinations. In light of the limited therapeutic options currently available, the exploration of AS as a target for drug development is of paramount importance. This review offers an exhaustive analysis of the biological functions and underlying molecular mechanisms associated with various AS-induced splice variants, RNA-binding proteins, and cis-elements, highlighting their significance as clinical biomarkers. We place particular emphasis on the current therapeutic applications of AS in an array of lung diseases, including but not limited to lung cancer, cystic fibrosis, silicosis, acute respiratory distress syndrome, pneumonia, asthma, chronic obstructive pulmonary diseases, pulmonary arterial hypertension, and idiopathic pulmonary fibrosis. The review delves into the role of AS events in the diagnosis and treatment of lung diseases, focusing on the regulatory influence of splicing factors and RNA-binding proteins, while also enumerating the mutated components implicated in AS misregulation. Consequently, a comprehensive understanding of the intricate mechanisms governing these splicing events could potentially offer novel avenues for the development of splicing-targeted therapeutics and diagnostic tools for the prevention and treatment of lung diseases.

Objective To investigate the effect and mechanisms of celecoxib on right heart function in mice with acute high-altitude hypoxia exposure.Methods Male C57BL/6J mice(7 weeks old)were housed in a hypobaric chamber simulating an altitude of 5 800 m for 2 d to establish an animal model of acute hypobaric hypoxia.①Eighteen mice were randomly assigned to plain+saline(P+S),high-altitude hypoxia exposure+saline(H+S),and high-altitude hypoxia exposure+celecoxib(H+Cel).Body weight and routine blood indicators were measured,and cardiac ultrasound examination were performed for heart rate(HR),pulmonary artery acceleration time to ejection time ratio(AT/ET),tricuspid annular plane systolic excursion(TAPSE),tricuspid annular systolic velocity(S'),and left ventricular ejection fraction(LVEF)and fractional shortening(FS).Targeted metabolomic profiling was applied to detect the cardiac arachidonic acid(AA)metabolite levels.The contents of 12,13-dihydroxy-9Z-octadecenoic acid(12,13-diHOME)in the heart,liver,brown adipose tissue,and plasma were quantified by ELISA.② Eighteen mice were randomly assigned into plain+saline(P+S),high-altitude hypoxia exposure+saline(H+S)and high-altitude hypoxia exposure+12,13-diHOME(H+di)groups.Body weight,routine blood tests,and echocardiography were performed as above.③ Thirty-two mice were randomly divided into high-altitude hypoxia exposure+saline(H+S),high-altitude hypoxia exposure+celecoxib(H+Cel),high-altitude hypoxia exposure+soluble epoxide hydrolase inhibitor(sEHI)(H+sEHI),and high-altitude hypoxia exposure+sEHI+celecoxib(H+sEHI+Cel)groups.Body weight,routine blood tests,and echocardiography were performed as above.Cardiac and plasma contents of 12,13-diHOME and epoxyeicosatrienoic acids(EETs)were measured by ELISA.Results ① Compared to the P+S group,the H+S group exhibited significantly reduction of cardiac 12,13-diHOME level(P<0.001),increased counts of white blood cells(WBC)and neutrophils(P<0.01)and decreased TAPSE,S'and AT/ET both at resting state and under stress(P<0.01,P<0.001).Compared to the H+S group,the H+Cel group exhibited significantly increase of cardiac 12,13-diHOME level(P<0.05),reduced WBC and lymphocyte counts(P<0.01,P<0.05)and improved TAPSE and S'levels at resting state and under stress(P<0.01,P<0.001).② Compared to the H+S group,the H+di group demonstrated significantly improvement of TAPSE at basal and under stress(P<0.001)and a trend towards improved TAPSE at resting state(P=0.0532),but no obvious differences was observed in WBC and neutrophil counts between the H+di group and the H+S group.③ Compared to the H+Cel group,both the H+sEHI and H+sEHI+Cel groups exhibited significantly reduction of cardiac 12,13-diHOME level(P<0.01,P<0.05)though no statistical changes in cardiac function indicators.Compared to the H+S group,WBC counts and lymphocyte were decreased,and serum EETs level was incrased in the H+Cel group,H+sEHI group and H+sEHI+Cel group(P<0.01,P<0.001).Conclusion Celecoxib can elevate cardiac level of 12,13-diHOME and improves right heart function in mice after acute high-altitude hypoxia exposure through the CYP450-sEH metabolic pathway.

Zhizichi Tang （栀子豉汤）， first recorded in Treatise on Febrile and Miscellaneous Diseases （《伤寒杂病论》） by ZHANG Zhongjing， a medical sage during the Han dynasty， is one of the classical prescriptions in traditional Chinese medicine （TCM）. It plays an important role in the clinical practice of TCM because of its dispersing and transparent characteristics. It is one of the representative parts of “dispersing fire stagnation” and is used mainly for the treatment of various symptoms caused by heat depression in the chest and diaphragm. Pharmacological research has found that it has multiple effects， such as sedative hypnosis and anti-depression， inhibiting oxidative stress and inflammatory responses， regulating the intestinal flora， improving insulin resistance and endocrine metabolism disorders， reducing liver toxicity， and protecting the nerve and heart. Clinical studies have confirmed that its treatment of anxiety， depression， insomnia， and other diseases has few side effects and high safety. Combined with the analysis of TCM syndrome and pharmacological effects， Zhizichi Tang also shows potential in treating other diseases such as heart， lung system， spleen and stomach， liver system， endocrine， and metabolic system diseases. Therefore， the authors， by searching Chinese and foreign literature， especially in recent five years， systematically reviewed and summarized the research progress on Zhizichi Tang in six aspects of TCM syndrome， dosage and administration， chemical composition， pharmacological effects， clinical application， and adverse reactions， aiming to provide a reference for further research and clinical application of Zhizichi Tang.

Objective:To explore the clinical feature and genetic variation of NPHS1 variant-associated nephropathy ( NPHS1-VAN) in Chinese patients. Methods:This study was a case-series analysis. Patients with NPHS1-VAN, who were treated and/or followed in the Department of Pediatrics, Nanfang Hospital, Southern Medical University between 2018 and 2023 were recruited into this study. Genotype, phenotype and their relationship were analyzed. Results:Nine NPHS1-VAN patients from 8 non-consanguineous Chinese families were collected, including 5 males and 4 females. There were 7 cases with an onset age within 3 months and 2 cases with an onset age of 6 months and 13 years, respectively. Seven patients harbored compound heterozygous variants, two had homozygous variants, including 8 missense variations,3 frameshift variants, and 1 splicing site variant. Four patients in 3 families harbored missense variant c.928G>A, two of them experienced spontaneous remission of proteinuria at the age of 1 year and 2 years, respectively, another one had persistent proteinuria and entered end stage renal disease (ESRD) at 11 years old. The other one had an onset age of 6 months with no response to steroids initially. She got complete remission by tacrolimus administered, but relapse frequently and partially responded to steroids later. Two patients of this group died, one of them died of respiratory failure 3 days after birth. Excessive amniotic fluid and fetal edema were acknowledged at 28 weeks of gestational age. He harbored compound heterozygous variants of NPHS1, c.1135C>G (R379G) and c.1339G>A (E447K). His mother previously experienced fetal death at 28 weeks gestational age for her first pregnant and stillborn at 36 weeks of gestational age for her second pregnant, respectively. One patient in this study who harbored homozygous variant of c.1339G>A (E447K) presented with a mild phenotype, onset age was 13 years old and didn't progress to ESRD yet at 21 years. Thus, variant E447K was hypothesized to be weakly pathogenic, while R379G may be strongly pathogenic with a risk of death. Five novel variants were identified in this group of patients, 3 missense variants (c.1135C>G, c.1157A>T, c.3197T>A) and 2 frameshift variants (c.709_710delCT, c.3193delG). Renal biopsy was performed in 4 cases, of whom two were focal segmental glomerular sclerosis and another two were minimal change disease. Conclusions:NPHS1-VAN possesses remarkable clinical and genetic heterogeneity. Five novel variants were identified. Missense variant is the most common variant type and c.928G>A is the most common one in this group of patients, in consistent with previous report in China. Children harbor c.928G>A may have a mild phenotype with possible spontaneous remission and may be response to steroids and calcineurin inhibitor. Variant c.1135C>G (R379G) may have a strong pathogenicity, and patient who harbors this variant may have a severe phenotype.

Creutzfeldt-Jakob disease(CJD)is a rapidly progressive and fatal neurodegenerative disorder caused by prions,with certain infectivity and iatrogenic transmission risks.With the rapid progress and application of new dia-gnostic biomarkers and detection methods,as well as the construction and improvement of surveillance and reporting systems,the detection of CJD in patients domestically and internationally has shown an increasing trend year by year.Due to its long incubation period and heterogeneity of early symptoms,early identification and diagnosis of the disease is difficult,increasing the risk of transmission within medical institutions.Currently,there is a lack of con-sensus on the infection prevention and control of CJD.In order to timely identify and diagnose CJD as well as effec-tively block its transmission in medical institutions,this consensus summarizes 15 clinical concerns and formulates 24 specific recommendations based on the latest domestic and international research findings and clinical evidence,as well as combines with clinical practice,aiming to standardize healthcare-associated infection prevention and control measures for CJD and reduce its transmission risk in medical institutions.

Creutzfeldt-Jakob disease(CJD)is a rapidly progressive and fatal neurodegenerative disorder caused by prions,with certain infectivity and iatrogenic transmission risks.With the rapid progress and application of new dia-gnostic biomarkers and detection methods,as well as the construction and improvement of surveillance and reporting systems,the detection of CJD in patients domestically and internationally has shown an increasing trend year by year.Due to its long incubation period and heterogeneity of early symptoms,early identification and diagnosis of the disease is difficult,increasing the risk of transmission within medical institutions.Currently,there is a lack of con-sensus on the infection prevention and control of CJD.In order to timely identify and diagnose CJD as well as effec-tively block its transmission in medical institutions,this consensus summarizes 15 clinical concerns and formulates 24 specific recommendations based on the latest domestic and international research findings and clinical evidence,as well as combines with clinical practice,aiming to standardize healthcare-associated infection prevention and control measures for CJD and reduce its transmission risk in medical institutions.

Objective:To explore the clinical feature and genetic variation of NPHS1 variant-associated nephropathy ( NPHS1-VAN) in Chinese patients. Methods:This study was a case-series analysis. Patients with NPHS1-VAN, who were treated and/or followed in the Department of Pediatrics, Nanfang Hospital, Southern Medical University between 2018 and 2023 were recruited into this study. Genotype, phenotype and their relationship were analyzed. Results:Nine NPHS1-VAN patients from 8 non-consanguineous Chinese families were collected, including 5 males and 4 females. There were 7 cases with an onset age within 3 months and 2 cases with an onset age of 6 months and 13 years, respectively. Seven patients harbored compound heterozygous variants, two had homozygous variants, including 8 missense variations,3 frameshift variants, and 1 splicing site variant. Four patients in 3 families harbored missense variant c.928G>A, two of them experienced spontaneous remission of proteinuria at the age of 1 year and 2 years, respectively, another one had persistent proteinuria and entered end stage renal disease (ESRD) at 11 years old. The other one had an onset age of 6 months with no response to steroids initially. She got complete remission by tacrolimus administered, but relapse frequently and partially responded to steroids later. Two patients of this group died, one of them died of respiratory failure 3 days after birth. Excessive amniotic fluid and fetal edema were acknowledged at 28 weeks of gestational age. He harbored compound heterozygous variants of NPHS1, c.1135C>G (R379G) and c.1339G>A (E447K). His mother previously experienced fetal death at 28 weeks gestational age for her first pregnant and stillborn at 36 weeks of gestational age for her second pregnant, respectively. One patient in this study who harbored homozygous variant of c.1339G>A (E447K) presented with a mild phenotype, onset age was 13 years old and didn't progress to ESRD yet at 21 years. Thus, variant E447K was hypothesized to be weakly pathogenic, while R379G may be strongly pathogenic with a risk of death. Five novel variants were identified in this group of patients, 3 missense variants (c.1135C>G, c.1157A>T, c.3197T>A) and 2 frameshift variants (c.709_710delCT, c.3193delG). Renal biopsy was performed in 4 cases, of whom two were focal segmental glomerular sclerosis and another two were minimal change disease. Conclusions:NPHS1-VAN possesses remarkable clinical and genetic heterogeneity. Five novel variants were identified. Missense variant is the most common variant type and c.928G>A is the most common one in this group of patients, in consistent with previous report in China. Children harbor c.928G>A may have a mild phenotype with possible spontaneous remission and may be response to steroids and calcineurin inhibitor. Variant c.1135C>G (R379G) may have a strong pathogenicity, and patient who harbors this variant may have a severe phenotype.

Alzheimer's disease is a common central neurodegenerative disease， mainly manifested by cognitive impairment and non-cognitive neuropsychiatric symptoms that severely affect patients' daily life and behavioral functioning. The pathogenesis of Alzheimer's disease is still unclear， and the western medicine currently used to treat Alzheimer's disease is only symptomatic， with a single pathway， limited efficacy， and many side effects. In recent years， with the deepening of research on Alzheimer's disease， the study and application of traditional Chinese medicine （TCM） in the treatment of Alzheimer's disease have gradually increased. Several studies have shown that TCM and its effective components can exert anti-Alzheimer's disease effects by regulating molecular mechanisms such as pathological protein production and aggregation， oxidative stress， neuroinflammation， ferroptosis， mitochondrial dysfunction， neurogenesis and neurotransmission， and brain-gut axis. This paper summarized the research progress of TCM in the treatment of Alzheimer's disease in recent years， so as to provide a reference for further study of the specific mechanism of TCM in the prevention and treatment of Alzheimer's disease and the discovery of effective components of TCM.