Drofenine as a Kv2.1 inhibitor alleviated AD-like pathology in mice through A β/Kv2.1/microglial NLRP3/neuronal tau axis / 中国药理学与毒理学杂志

OBJECTIVE Alzheimer disease(AD)is a neurodegenerative disease with clinical hallmarks of pro-gressive cognitive impairment.Synergistic effects of Aβ-tau cascade reaction are tightly implicated in AD patholo-gy,and microglial NLRP3 inflammasome activation drives neuronal tauopathy through microglia and neurons cross-talk.However,the underlying mechanism of how Aβ medi-ates NLRP3 inflammasome remains unclear.Shab related potassium channel member 1(Kv2.1)as a voltage gated po-tassium channel widely distributed in the central nervous system and plays an important role in regulating the out-ward potassium flow in neurons and glial cells.In current work,we aimed to explore the underlying mechanism of Kv2.1 in regulating Aβ/NLRP3 inflammasome/tau axis by using a determined Kv2.1 inhibitor drofenine(Dfe).METHODS Cell-based assays including Western blot-ting and immunofluorescence staining against primary microglia or neurons were carried out to expound the role of Kv2.1 channel in NLRP3 inflammasome activa-tion and subsequent neuronal tau hyperphosphorylation.For animal studies,new object recognition,Y-maze and Morris water maze were performed to evaluate the ame-lioration of Kv2.1 inhibition through either Kv2.1 inhibitor Dfe treatment or adeno-associated virus AAV-ePHP-si-Kv2.1injectionon5×FADADmodel mice.Assays of histol-ogy and immunostaining of tissue sections and Western blotting of brain tissues were performed to verify the con-clusion of cellular assays.RESULTS We reported that oligomeric Aβ(o-Aβ)bound to microglial Kv2.1 and pro-moted Kv2.1-dependent potassium leakage to activate NLRP3 inflammasome through JNK/NF-κB pathway sub-sequently resulting in neuronal tauopathy.Treatment of either Kv2.1 inhibitor Dfe or AAV-ePHP-si-Kv2.1 for brain-specific Kv2.1 knockdown deprived o-A β of its capability in inducing microglial NLRP3 inflammasome activation and neuronal tau hyperphosphorylation,while improved the cognitive impairment of 5×FAD AD model mice.CONCLUSION Our results have highly addressed that Kv2.1 channel is required for o-Aβ driving NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Kv2.1 inhibition is a prom-ising therapeutical strategy for AD and Dfe as a Kv2.1 inhibitor shows potential in the treatment of this disease.

Entity extraction and graph construction based on Chinese medical text / 中国药科大学学报

@#Knowledge graph technology has promoted the progress of new drug research and development, but domestic research starts late and domain knowledge is mostly stored in text, resulting in low rate of knowledge graph reuse.Based on multi-source and heterogeneous medical texts, this paper designed a Chinese named entity recognition model based on Bert-wwm-ext pre-training model and also integrated cascade thought, which reduced the complexity of traditional single classification and further improved the efficiency of text recognition.The experimental results showed that the model achieved the best performance with an F1-score of 0.903, a precision of 89.2%, and a recall rate of 91.5% on the self-built dataset.At the same time, the model was applied to the public dataset CCKS2019, and the results showed that the model had better performance and recognition effect.Using this model, this paper constructed a Chinese medical knowledge graph, involving 13 530 entities, 10 939 attributes and 39 247 relationships of them in total.The Chinese medical entity extraction and graph construction method proposed in this paper is expected to help researchers accelerate the new discovery of medical knowledge, and shorten the process of new drug discovery.

Research progress on application of multi-enzyme-catalyzed cascade reactions in enzymatic synthesis of natural products / 中国中药杂志

As a biocatalyst, enzyme has the advantages of high catalytic efficiency, strong reaction selectivity, specific target products, mild reaction conditions, and environmental friendliness, and serves as an important tool for the synthesis of complex organic molecules. With the continuous development of gene sequencing technology, molecular biology, genetic manipulation, and other technologies, the diversity of enzymes increases steadily and the reactions that can be catalyzed are also gradually diversified. In the process of enzyme-catalyzed synthesis, the majority of common enzymatic reactions can be achieved by single enzyme catalysis, while many complex reactions often require the participation of two or more enzymes. Therefore, the combination of multiple enzymes together to construct the multi-enzyme cascade reactions has become a research hotspot in the field of biochemistry. Nowadays, the biosynthetic pathways of more natural products with complex structures have been clarified, and secondary metabolic enzymes with novel catalytic activities have been identified, discovered, and combined in enzymatic synthesis of natural/unnatural molecules with diverse structures. This study summarized a series of examples of multi-enzyme-catalyzed cascades and highlighted the application of cascade catalysis methods in the synthesis of carbohydrates, nucleosides, flavonoids, terpenes, alkaloids, and chiral molecules. Furthermore, the existing problems and solutions of multi-enzyme-catalyzed cascade method were discussed, and the future development direction was prospected.

Sequential delivery of PD-1/PD-L1 blockade peptide and IDO inhibitor for immunosuppressive microenvironment remodeling via an MMP-2 responsive dual-targeting liposome

Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy. Herein, a kind of tumor cascade-targeted responsive liposome (NLG919@Lip-pep1) is developed by conjugating polypeptide inhibitor of PD-1 signal pathway (AUNP-12), which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2 (MMP-2) cleavable peptide (GPLGVRGD). This targeted liposome is prepared through a mature preparation process, and indoleamine-2,3-dioxygenase (IDO) inhibitor NLG919 was encapsulated into it. Moreover, mediated by the enhanced permeability and retention effect (EPR effect) and AUNP-12, NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues. At the same time, the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12, thus realizing the precise block of PD-1 signal pathway, and restoring the activity of T cells. The exposure of secondary targeting module II VRGDC-NLG919@Lip mediated tumor cells targeting, and further relieved the immunosuppressive microenvironment. Overall, this study offers a potentially appealing paradigm of a high efficiency, low toxicity, and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer, which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.

A Spacetime Odyssey of Neural Progenitors to Generate Neuronal Diversity / 神经科学通报·英文版

To understand how the nervous system develops from a small pool of progenitors during early embryonic development, it is fundamentally important to identify the diversity of neuronal subtypes, decode the origin of neuronal diversity, and uncover the principles governing neuronal specification across different regions. Recent single-cell analyses have systematically identified neuronal diversity at unprecedented scale and speed, leaving the deconstruction of spatiotemporal mechanisms for generating neuronal diversity an imperative and paramount challenge. In this review, we highlight three distinct strategies deployed by neural progenitors to produce diverse neuronal subtypes, including predetermined, stochastic, and cascade diversifying models, and elaborate how these strategies are implemented in distinct regions such as the neocortex, spinal cord, retina, and hypothalamus. Importantly, the identity of neural progenitors is defined by their spatial position and temporal patterning factors, and each type of progenitor cell gives rise to distinguishable cohorts of neuronal subtypes. Microenvironmental cues, spontaneous activity, and connectional pattern further reshape and diversify the fate of unspecialized neurons in particular regions. The illumination of how neuronal diversity is generated will pave the way for producing specific brain organoids to model human disease and desired neuronal subtypes for cell therapy, as well as understanding the organization of functional neural circuits and the evolution of the nervous system.

Prescribing Cascade � What, When, How and the Ways to Mitigate

Rational prescribing is essential for adequate patient compliance and proper therapeutic outcome. Often medicines are prescribed randomly to take care of the drug induced adverse reactions without changing the culprit drug or modifying it抯 dose, rather commonly by adding another drug towards amelioration of the presenting complain, ignoring it抯 drug related occurrence. This 慞rescribing Cascade� turns out to be a vicious cycle by promoting polypharmacy thus leading to it抯 adverse consequences. This can happen to any person at any age but elderly population are more vulnerable because of their age related physiological changes and co-morbidities. There are several ways to curb the vicious cycle down like anticholinergic burden assessment, selecting the right drug for the right person, medication reconciliation etc.

Indian Academy of Pediatrics Consensus Guidelines on Prevention and Management of Suicidal Behavior in Adolescents

Justification: Suicide is an important cause of adolescent mortality and morbidity in India. As pediatricians are often the first point of contact for adolescents and their families in the healthcare system, they need guidelines to screen, assess, manage and prevent adolescent suicidal behavior to ensure survival, health and mental well-being of this vulnerable population. Objectives: To formulate guidelines to aid pediatricians for prevention and management of adolescent suicidal behavior. Process: Indian Academy of Pediatrics, in association with Adolescent Health Academy, formed a multidisciplinary committee of subject experts in June, 2019 to formulate guidelines for adolescent suicide prevention and management. After a review of current scientific literature and preparation of draft guidelines, a national consultative meeting was organized on 16 August, 2019 for detailed discussions and deliberations. This was followed by refining of draft guidelines, and discussions over e-mail where suggestions were incorporated and the final document was approved. Guidelines: Pediatricians should screen for mental distress, mental disorders and suicidal and para-suicidal (non-suicidal self-injury) behavior during adolescent health visits. Those with suicidal behavior should be referred to a psychiatrist after providing emergency healthcare, risk assessment, immediate counselling and formulation of a safety plan. Pediatricians should partner with the community and policymakers for primary and secondary prevention of adolescent suicide.

Criterios predictores en el diagnóstico de la hipercolesterolemia familiar / Predictive criteria in the diagnosis of familial hypercholesterolemia

Introducción: La hipercolesterolemia familiar es una enfermedad con alta prevalencia, no tratada acorta la esperanza de vida, por lo que el diagnóstico a edades tempranas resulta fundamental. Las pruebas genéticas constituyen el gold standard para el diagnóstico de hipercolesterolemia familiar, sin embargo, la no disponibilidad del test genético no debe constituir un impedimento para la adecuada conducta en estos casos. Objetivo: Identificar criterios clínicos predictores en el diagnóstico por pesquisa de la hipercolesterolemia familiar. Métodos: Se realizó un estudio descriptivo prospectivo a partir de una muestra de 393 pacientes (casos índices) de HF en el Hospital Clínico Quirúrgico Hermanos Ameijeiras; durante el período 2008-2018. Resultados: En la pesquisa familiar fueron identificados 177 (15,66 por ciento) nuevos casos de hipercolesterolemia familiar, de ellos se clasifican como casos positivos 35 (19,77 por ciento), casos probables 58 (32,77 por ciento) y casos posibles 84 (47,46 por ciento). Las categorías del estrato Make early diagnosis to prevent early death MEDPED y la edad del caso índice resultaron ser las variables clínicas de interés con mayor probabilidad para identificar nuevos casos de hipercolesterolemia familiar. Conclusiones: los criterios clínicos estandarizados de la escala make early diagnosis to prevent early death P y la edad del caso índice resultaron ser indicadores predictivos de gran valor para identificar y estratificar casos con variantes fenotípicas de hipercolesterolemia familiar(AU)

Introduction: Familial hypercholesterolemia is a disease with high prevalence; it shortens life expectancy if it is not treated, so early diagnosis is essential. Genetic tests are the gold standard for the diagnosis of familial hypercholesterolemia, however, the unavailability of the genetic test should not be an obstacle to proper conduct in these cases. Objective: To identify predictive clinical criteria in the diagnosis by screening of familial hypercholesterolemia. Methods: A prospective descriptive study was carried out from a sample of 393 patients (index cases) of FH at Hermanos Ameijeiras Surgical Clinical Hospital from 2008 to 2018. Results: In the family investigation, 177 (15.66 percent) new cases of familial hypercholesterolemia were identified, 35 of them (19.77 percent) are classified as positive cases, 58 (32.77 percent) as probable cases and 84 as possible cases (47.46 percent)The stratum categories of Make Early Diagnosis to Prevent Early Death (MEDPED) and the age of the index case turned out to be the clinical variables of interest with the greatest probability to identify new cases of familial hypercholesterolemia. Conclusions: The standardized clinical criteria of the make early diagnosis to prevent early death P scale and the age of the index case turned out to be highly valuable predictive indicators to identify and stratify cases with phenotypic variants of familial hypercholesterolemia(AU)

Implementación de una estrategia de revinculación a la atención en pacientes con infección crónica por el virus de la hepatitis C en el Hospital Central de las Fuerzas Armadas de Uruguay. Resultados preliminares

Resumen: Introducción: La infección crónica por el virus de la hepatitis C (VHC) es responsable de 400.000 muertes al año, asociadas fundamentalmente al desarrollo de cirrosis y carcinoma hepatocelular. El advenimiento de los nuevos antivirales de acción directa ha marcado un punto de inflexión en el tratamiento del VHC, llevando a casi 100% la curación de los pacientes tratados. En tal sentido, la OMS se ha fijado como objetivos para el año 2030, reducir un 90% las nuevas infecciones por el VHC y un 65% la mortalidad asociada a este virus, para lo cual es necesario el desarrollo de estrategias activas de diagnóstico y vinculación a la atención y tratamiento. El objetivo del trabajo es realizar un diagnóstico de situación de los pacientes infectados por el VHC en el Hospital Central de las Fuerzas Armadas (HCFFAA), e implementar y evaluar una estrategia secuencial de revinculación a la atención. Metodología: Se construyó la cascada de tratamiento mediante una estimación de los pacientes portadores de infección crónica por VHC basada en la prevalencia local y la revisión de historias clínicas de los pacientes asistidos en el servicio de Hepatología y Trasplante Hepático del HCFFAA. Se implementó una estrategia para contactar a los pacientes con infección por VHC de forma secuencial, buscando re-establecer el vínculo de estos con el servicio de salud, asegurando el acceso a la estadificación de la enfermedad hepática y al tratamiento antiviral. Resultados: La prevalencia global estimada de personas con infección crónica por VHC fue de 1.008 personas. De 135 pacientes con serología positiva, 113 tenían ARN confirmatorio, 76 habían recibido tratamiento y 70 habían alcanzado respuesta virológica sostenida. La implementación de la estrategia logró un aumento en la prescripción del tratamiento del 67% a 76% de los pacientes con infección crónica por VHC confirmada. Conclusiones: La implementación de la estrategia de revinculación fue exitosa, con un aumento de la prescripción del tratamiento antiviral en los pacientes candidatos a tratamiento. La búsqueda activa de los pacientes infectados no diagnosticados mediante el cribado es el siguiente paso para alcanzar los objetivos de erradicación.

Abstract: Introduction: Chronic infection by the hepatitis C virus (HCV) is responsible for 400,000 deaths per year, mainly associated with the development of cirrhosis and hepatocellular carcinoma. The advent of new direct-acting antivirals has marked a turning point in the treatment of HCV, leading to almost 100% cure of treated patients. In this sense, the WHO has set as objectives for the year 2030, to reduce new HCV infections by 90% and the mortality associated with this virus by 65%, for which it is necessary to develop active strategies for diagnosis and linkage to care and treatment. The objective of the work is to carry out a diagnosis of the situation of the patients infected by HCV in the Central Hospital of the Armed Forces (HCFFAA), and to implement and evaluate a sequential strategy of re-attachment to care. Methodology: The treatment cascade was constructed by estimating the number of patients with chronic HCV infection based on local prevalence and review of the medical records of patients seen in the Hepatology and Liver Transplant service of the HCFFAA. A strategy was implemented to contact patients with HCV infection sequentially, seeking to re-establish their link with the health service, ensuring access to liver disease staging and antiviral treatment. Results: The estimated global prevalence of people with chronic HCV infection was 1,008 people. Of 135 patients with positive serology, 113 had confirmatory RNA, 76 had received treatment, and 70 had achieved sustained virologic response. The implementation of the strategy achieved an increase in the prescription of treatment from 67% to 76% of patients with confirmed chronic HCV infection. Conclusions: The implementation of the rebinding strategy was successful, with an increase in the prescription of antiviral treatment in patients who are candidates for treatment. Active search for undiagnosed infected patients through screening is the next step to achieve eradication goals.

Resumo: Introdução: A infecção crônica pelo vírus da hepatite C (HCV) é responsável por 400.000 óbitos por ano, principalmente associada ao desenvolvimento de cirrose e carcinoma hepatocelular. O advento de novos antivirais de ação direta marcou um ponto de virada no tratamento do HCV, levando à cura de quase 100% dos pacientes tratados. Nesse sentido, a OMS estabeleceu como objetivos para o ano de 2030, reduzir em 90% as novas infecções por HCV e a mortalidade associada a este vírus em 65%, para o que é necessário desenvolver estratégias ativas de diagnóstico e vinculação aos cuidados e tratamento. O objetivo do trabalho é realizar um diagnóstico da situação dos pacientes infectados pelo HCV no Hospital Central das Forças Armadas (HCFFAA), e implementar e avaliar uma estratégia sequencial de reinserção aos cuidados. Metodologia: A cascata de tratamento foi construída estimando o número de pacientes com infecção crônica pelo HCV com base na prevalência local e revisão dos prontuários dos pacientes atendidos no serviço de Hepatologia e Transplante de Fígado do HCFFAA. Foi implantada uma estratégia de contato sequencial dos pacientes com infecção pelo HCV, buscando restabelecer o vínculo com o serviço de saúde, garantindo o acesso ao estadiamento da doença hepática e ao tratamento antiviral. Resultados: A prevalência global estimada de pessoas com infecção crônica pelo HCV foi de 1.008 pessoas. Dos 135 pacientes com sorologia positiva, 113 tiveram RNA confirmatório, 76 receberam tratamento e 70 alcançaram resposta virológica sustentada. A implementação da estratégia conseguiu um aumento na prescrição de tratamento de 67% para 76% dos pacientes com infecção crônica pelo HCV confirmada. Conclusões: A implementação da estratégia de religação foi bem sucedida, com aumento da prescrição do tratamento antiviral em pacientes candidatos ao tratamento. A busca ativa de pacientes infectados não diagnosticados por meio de triagem é o próximo passo para atingir as metas de erradicação.

Shortcomings on genetic testing of Familial hypercholesterolemia (FH) in India: Can we collaborate to establish Indian FH registry?

Familial hypercholesterolemia (FH) is a common autosomal dominant disorder that affects ∼1 in 250–500 individuals globally. The only prevalence study in India shows FH in 15% of patients with premature CAD in North Indians. There are only 6 genetic studies in India of the total mutations, 32% are LDLR mutations, 4% are ApoB, 2% are PCSK9 mutations and the mutational spectrum for 37% is unknown. This calls for widespread genetic screening which could help identify definite FH patients. European Atherosclerosis Society-Familial Hypercholesterolemia Studies Collaboration (EAS- FHSC) has taken an initiative to develop a worldwide registry of FH. India is also a part of the collaboration and 3 groups from Mumbai, Delhi and Chennai are actively contributing to this registry. We believe this review might help to understand the Indian scenario of FH and investigators across India can contribute in managing FH in India and further help in the detection, diagnosis and treatment.

Research advances in the role of MAPK cascade in regulation of cell growth, immunity, inflammation, and cancer / 中南大学学报(医学版)

Mitogen-activated protein kinase (MAPK) cascade system is one of the highly conserved signal systems in eukaryotic cells, which participates in the regulation of many biological processes. Under the stimulation of different signals (such as cytokines, neurotransmitters, and hormones), MAPK cascade activates downstream targets and controls a variety of cellular processes, including growth, immunity, inflammation, and stress response. In different cells, the effects of MAPK cascade on cells vary with the stimuli and the duration of stimulation. MAPK cascade induces Th differentiation and participates in T cell receptor signal pathway and B cell receptor signal pathway. MAPK cascades regulate various cellular activities related to the occurrence and development of cancer. A thorough and systematic understanding of the specific regulatory effects of MAPK cascade on various cellular processes will provide theoretical guidance for treating various diseases.

Gather wisdom to overcome barriers: Well-designed nano-drug delivery systems for treating gliomas

Due to the special physiological and pathological characteristics of gliomas, most therapeutic drugs are prevented from entering the brain. To improve the poor prognosis of existing therapies, researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy. Although these strategies can be used clinically to overcome the blood‒brain barrier (BBB), the accurate delivery of drugs to the glioma lesions cannot be ensured. Nano-drug delivery systems (NDDS) have been widely used for precise drug delivery. In recent years, researchers have gathered their wisdom to overcome barriers, so many well-designed NDDS have performed prominently in preclinical studies. These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions, drug release in response to the glioma microenvironment, biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein, and carriers created according to the active ingredients of traditional Chinese medicines. We reviewed these well-designed NDDS in detail. Furthermore, we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy, and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS.

Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure. Recently, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3K/AKT in fibrotic processes is increasingly prominent, with PI3K/AKT inhibitors currently under clinical evaluation in IPF. Therefore, PI3K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.

Point-of-care hepatitis C screening with direct access referral to improve linkage to care among halfway house residents: a pilot randomised study

INTRODUCTION@#Linkage to care among individuals with substance misuse remains a barrier to the elimination of the hepatitis C virus (HCV). We aimed to determine whether point-of-care (PoC) education, screening and staging for liver disease with direct access to hospitals would improve linkage to care among this group. @*METHODS@#All participants were offered PoC education and HCV screening. HCV-positive participants were randomised to standard care (controls) or direct access, which provided a direct pathway to hospitals. Linkage to care was determined by reviewing electronic medical records. Linkage of care cascade was defined as attendance at the specialist clinic, confirmation of viraemia by HCV RNA testing, discussion about HCV treatment and initiation of treatment. @*RESULTS@#351 halfway house residents were screened. The overall HCV prevalence was 30.5% (n = 107), with 69 residents in the control group and 38 in the direct access group. The direct access group had a significantly higher percentage of cases linked to specialist review for confirmatory RNA testing (63.2% vs. 40.6%, p = 0.025), HCV treatment discussion (p = 0.009) and treatment initiation (p = 0.01) compared to the controls. Overall, only 12.6% (n = 13) had treatment initiation during follow-up. PoC HCV screening with direct access referral had significantly higher linkage to HCV treatment initiation (adjusted odds ratio 9.13, p = 0.005) in multivariate analysis. @*CONCLUSION@#PoC HCV screening with direct access improves linkage to care and simplifies the HCV care cascade, leading to improved treatment uptake. PoC education, screening, diagnosis and treatment may be an effective strategy to achieving HCV micro-elimination in this population.

Rational design of the C-terminal Loop region of leucine dehydrogenase and cascade biosynthesis L-2-aminobutyric acid / 生物工程学报

Leucine dehydrogenase (LDH) is the key rate-limiting enzyme in the production of L-2-aminobutyric acid (L-2-ABA). In this study, we modified the C-terminal Loop region of this enzyme to improve the specific enzyme activity and stability for efficient synthesis of L-2-ABA. Using molecular dynamics simulation of LDH, we analyzed the change of root mean square fluctuation (RMSF), rationally designed the Loop region with greatly fluctuated RMSF, and obtained a mutant EsLDHD2 with a specific enzyme activity 23.2% higher than that of the wild type. Since the rate of the threonine deaminase-catalyzed reaction converting L-threonine into 2-ketobutyrate was so fast, the multi-enzyme cascade catalysis system became unbalanced. Therefore, the LDH and the formate dehydrogenase were double copied in a new construct E. coli BL21/pACYCDuet-RM. Compared with E. coli BL21/pACYCDuet-RO, the molar conversion rate of L-2-ABA increased by 74.6%. The whole cell biotransformation conditions were optimized and the optimal pH, temperature and substrate concentration were 7.5, 35 °C and 80 g/L, respectively. Under these conditions, the molar conversion rate was higher than 99%. Finally, 80 g and 40 g L-threonine were consecutively fed into a 1 L reaction mixture under the optimal conversion conditions, producing 97.9 g L-2-ABA. Thus, this strategy provides a green and efficient synthesis of L-2-ABA, and has great industrial application potential.

Efficient cascade biosynthesis of (S)-2-hydroxybutyric acid / 生物工程学报

2-Hydroxybutyric acid (2-HBA) is an important intermediate for synthesizing biodegradable materials and various medicines. Chemically synthesized racemized 2-HBA requires deracemization to obtain optically pure enantiomers for industrial application. In this study, we designed a cascade biosynthesis system in Escherichia coli BL21 by coexpressing L-threonine deaminase (TD), NAD-dependent L-lactate dehydrogenase (LDH) and formate dehydrogenase (FDH) for production of optically pure (S)-2-HBA from bulk chemical L-threonine (L-Thr). To coordinate the production rate and the consumption rate of the intermediate 2-oxobutyric acid in the multi-enzyme cascade catalytic reactions, we explored promoter engineering to regulate the expression levels of TD and FDH, and developed a recombinant strain P21285FDH-T7V7827 with a tunable system to achieve a coordinated multi-enzyme expression. The recombinant strain P21285FDH-T7V7827 was able to efficiently produce (S)-2-HBA with the highest titer of 143 g/L and a molar yield of 97% achieved within 16 hours. This titer was approximately 1.83 times than that of the highest yield reported to date, showing great potential for industrial application. Our results indicated that constructing a multi-enzyme-coordinated expression system in a single cell significantly contributed to the biosynthesis of hydroxyl acids.

Effect of multi-disciplinary transitional nursing on nursing participation, nursing continuity and virus inhibition of AIDS patients / 中国实用护理杂志

Objective:To explore the impact of multidisciplinary transitional nursing on AIDS patients' nursing participation, nursing continuation and virus suppression.Methods:A total of 322 patients with AIDS who were hospitalized in the Infection Department of Dalian Sixth People's Hospital from March 2014 to March 2018 were selected and randomly divided into general nursing group and multidisciplinary transitional nursing group with 161 cases in each group. The demographic and clinical data of each patient were recorded and compared, and the barriers of patients to participate in nursing and medical consultation were recorded. Consulted The patients were consulted about the nursing participation before hospitalization and the times of nursing continuation. After one year of follow-up, the number of cases of nursing participation, nursing continuity and virus suppression were recorded. The differences between the two groups were compared. The patients in the multidisciplinary transitional care group were divided into three subgroups after discharge, and the comparison between the subgroups was made. Multivariate Logistic regression analysis was performed.Results:In the multidisciplinary nursing group, 119 cases (81.51%, 119 / 146) and 105 cases (71.92%, 105 / 146) were involved in nursing and 105 cases (71.92%, 105/146) in the multidisciplinary nursing group, and 100 cases (62.11%, 100/161) and 90 cases (55.90%, 90/161) in the general nursing group 1 year after discharge, respectively. The difference between the two groups was statistically significant ( χ2 value was 14.09, 8.48, P<0.05). There was a significant difference in the number of cases in the multidisciplinary transitional care group without consulting the subgroup, only the medical and nursing consulting subgroup and medical, and the nursing and social support consulting subgroup in nursing participation, nursing continuation and increased viral suppression ( χ2 value was 22.90, 37.21, 23.07, P<0.05). The results of the regression model suggested that patients with medical and nursing consultation only, patients with medical, nursing, and social consultation had OR value of 1.67 and 1.89 compared with patients without consultation. The OR value was 1.35 and 1.76, which were significantly different. Conclusions:Through multidisciplinary transitional nursing, it can significantly improve nursing participation and nursing continuity and can improve virus suppression.

Structural feature of type I CRISPR-Cas system and its application in gene editing / 中国药科大学学报

@#The CRISPR-Cas (clustered regularly interspaced short palindromic repeats and CRISPR-associated) system is an "adaptive immune system" found in the genomes of bacteria and archaea which is mediated by RNA and resists foreign nucleic acid invasion.Take advantage of specific recognition of target nucleic acid, CRISPR-Cas system can efficiently edit their target site or accurately regulate gene expression, and now have been developed into a powerful tool for gene editing.According to the different compositions of the effector complex, the system has been divided into two categories: class 1 (type I, type IV, and type III) and class 2 (type II, type V, and type VI).Class 2 system, like the CRISPR-Cas9, is widely used in basic research due to the earliest discovery and best research.However, class 1 has not been maturely developed and utilized though it makes up 90% of the entire CRISPR-Cas system.In this essay, the classification of subtype, the assembly of Cascade complex, the cleavage and degradation mechanism of Cas3, and the application in gene editing of class 1 type I CRISPR-Cas system will be discussed and summarized to provide new ideas and methods for further mechanism studying and application of this category.

Exhaled breath detection is expected to become a new method for non-invasive screening of lung cancer— Project initiation of "research on the application of human exhaled breath detection technology based on quantum cascade laser in the diagnosis of lung cancer and other diseases" / 中国胸心血管外科临床杂志

@#Being a non-invasive diagnostic technique for molecular biological markers, exhaled breath detection has the most latent capacity and future in the diagnosis and treatment of tumors. The National Key Research and Development Plan named "Strategic Advanced Electronic Materials" in 2020 has laid out the application of exhaled breath detection technology in the medical field, and the scientific research project led by Sichuan Cancer Hospital has been successfully launched. For the moment, as a novel strategy for early detection of lung cancer, exhaled breath detection is being perfected further and popularized or put in clinical practice step by step to reduce the mortality of lung cancer patients.

Emerging nanomedicine-based therapeutics for hematogenous metastatic cascade inhibition: Interfering with the crosstalk between "seed and soil"

Despite considerable progresses in cancer treatment, tumor metastasis is still a thorny issue, which leads to majority of cancer-related deaths. In hematogenous metastasis, the concept of "seed and soil" suggests that the crosstalk between cancer cells (seeds) and premetastatic niche (soil) facilitates tumor metastasis. Considerable efforts have been dedicated to inhibit the tumor metastatic cascade, which is a highly complicated process involving various pathways and biological events. Nonetheless, satisfactory therapeutic outcomes are rarely observed, since it is a great challenge to thwart this multi-phase process. Recent advances in nanotechnology-based drug delivery systems have shown great potential in the field of anti-metastasis, especially compared with conventional treatment methods, which are limited by serious side effects and poor efficacy. In this review, we summarized various factors involved in each phase of the metastatic cascade ranging from the metastasis initiation to colonization. Then we reviewed current approaches of targeting these factors to stifle the metastatic cascade, including modulating primary tumor microenvironment, targeting circulating tumor cells, regulating premetastatic niche and eliminating established metastasis. Additionally, we highlighted the multi-phase targeted drug delivery systems, which hold a better chance to inhibit metastasis. Besides, we demonstrated the limitation and future perspectives of nanomedicine-based anti-metastasis strategies.