Transcriptional precision in photoreceptor development and diseases - Lessons from 25 years of CRX research.

The vertebrate retina is made up of six specialized neuronal cell types and one glia that are generated from a common retinal progenitor. The development of these distinct cell types is programmed by transcription factors that regulate the expression of specific genes essential for cell fate specification and differentiation. Because of the complex nature of transcriptional regulation, understanding transcription factor functions in development and disease is challenging. Research on the Cone-rod homeobox transcription factor CRX provides an excellent model to address these challenges. In this review, we reflect on 25 years of mammalian CRX research and discuss recent progress in elucidating the distinct pathogenic mechanisms of four CRX coding variant classes. We highlight how in vitro biochemical studies of CRX protein functions facilitate understanding CRX regulatory principles in animal models. We conclude with a brief discussion of the emerging systems biology approaches that could accelerate precision medicine for CRX-linked diseases and beyond.

Clinical value-oriented research paradigm about inheritance and innovation development of TCM dominant diseases.

Modern medicine has made remarkable achievements in safeguarding people's life and health, however, it is increasingly found that in the face of complex diseases, selective targeting of single target is often difficult to produce a comprehensive rehabilitation effect, and is prone to induce drug resistance, toxic side effects. Traditional Chinese medicine (TCM) has a long history of clinical application, and its clinical value in the treatment of complex diseases such as cardiovascular and cerebrovascular diseases, digestive diseases, skin diseases, rheumatism and immunity diseases, and adjuvant treatment of tumors has been proven to have obvious advantages. However, its modern research is relatively lagging behind, and in the face of the aging society and the characteristics of the modern disease spectrum, the traditional knowledge-driven research paradigm seems to be stuck in a bottleneck and difficult to make greater breakthroughs. Focusing on the key issues of TCM development in the new era, the clinical value-oriented strategy becomes to be a new research paradigm of TCM inheritance and innovation development, and dominant diseases would be the focus of the TCM inheritance and innovation development, which has been highly valued in recent years by the TCM academia and the relevant national management departments. Based on the clinical value, a series of policies are formulated for the selection and evaluation of the TCM dominant diseases (TCMDD), and exploratory researches about the clinical efficacy characteristics, the modern scientific connotation interpretation were carried out. The clinical value-oriented research paradigm of TCMDD inheritance and innovation development has been initially formed, which is characterized by strong policy support as the guarantee, systematic and standardized selection and evaluation methods as the driving force, scientific and effective research on internal mechanisms as the expansion, and effective clinical guidelines and principles as the transformation, which is of great value in promoting the high-quality development of the industries and undertaking of TCM. In this paper, the main policy support, selection and evaluation methods, therapeutic effect characterization, and modern scientific connotation research strategies of TCMDD in recent years have been comprehensively sorted out, with a view to providing the healthy and benign development of the research on TCMDD.

Identification of novel exonic variants contributing to hereditary breast and ovarian cancer in west Indian population.

Breast and ovarian cancers are the most common cancer types in females worldwide and in India. Patients with these cancers require an early diagnosis which is essential for better prognosis, treatment and improved patient survival. Recently, the utilization of next-generation sequencing (NGS)-based screening has accelerated molecular diagnosis of various cancers. In the present study, we performed whole-exome sequencing (WES) of 30 patients who had a first or second-degree relative with breast or ovarian cancer and are tested negative for BRCA1/2 or other high and moderate-risk genes reported for HBOC. WES data from patients were analyzed and variants were called using bcftools. Functional annotation of variants and variant prioritization was performed by Exomiser. The clinical significance of variants was determined as per ACMG classification using Varsome tool. The functional analysis of genes was determined by STRING analysis and disease association was determined by open target tool. We found novel variants and gene candidates having significant association with HBOC conditions. The genes identified by exomiser (phenotype score > 0.75) are associated with various biological processes such as DNA integrity maintenance, transcription regulation, cell cycle regulation, and apoptosis. Our findings provide novel and prevalent gene variants associated with the HBOC condition in the West Indian population which could be further studied for early diagnosis and better prognosis of HBOC.

Clinical value-oriented research paradigm about inheritance and innovation development of TCM dominant diseases / 中草药·英文版

Modern medicine has made remarkable achievements in safeguarding people's life and health, however, it is increasingly found that in the face of complex diseases, selective targeting of single target is often difficult to produce a comprehensive rehabilitation effect, and is prone to induce drug resistance, toxic side effects. Traditional Chinese medicine (TCM) has a long history of clinical application, and its clinical value in the treatment of complex diseases such as cardiovascular and cerebrovascular diseases, digestive diseases, skin diseases, rheumatism and immunity diseases, and adjuvant treatment of tumors has been proven to have obvious advantages. However, its modern research is relatively lagging behind, and in the face of the aging society and the characteristics of the modern disease spectrum, the traditional knowledge-driven research paradigm seems to be stuck in a bottleneck and difficult to make greater breakthroughs. Focusing on the key issues of TCM development in the new era, the clinical value-oriented strategy becomes to be a new research paradigm of TCM inheritance and innovation development, and dominant diseases would be the focus of the TCM inheritance and innovation development, which has been highly valued in recent years by the TCM academia and the relevant national management departments. Based on the clinical value, a series of policies are formulated for the selection and evaluation of the TCM dominant diseases (TCMDD), and exploratory researches about the clinical efficacy characteristics, the modern scientific connotation interpretation were carried out. The clinical value-oriented research paradigm of TCMDD inheritance and innovation development has been initially formed, which is characterized by strong policy support as the guarantee, systematic and standardized selection and evaluation methods as the driving force, scientific and effective research on internal mechanisms as the expansion, and effective clinical guidelines and principles as the transformation, which is of great value in promoting the high-quality development of the industries and undertaking of TCM. In this paper, the main policy support, selection and evaluation methods, therapeutic effect characterization, and modern scientific connotation research strategies of TCMDD in recent years have been comprehensively sorted out, with a view to providing the healthy and benign development of the research on TCMDD.

Advantages of Chinese Medicine in Treating Dominant Disease： Benign Prostatic Hyperplasia / 中国实验方剂学杂志

China Association of Chinese Medicine organized specialists in andrology of Chinese and western medicine to explore the population and treatment stage of benign prostatic hyperplasia （BPH） with Chinese medicine as the leading therapy. Chinese medicine has great advantages in the treatment of benign prostatic hyperplasia. However， it is necessary to make clear the stage when Chinese medicine or modern medical treatment can be used as the leading therapy， and the conditions under which Chinese and western medicine can be combined to achieve the best treatment efficacy. The specialists agreed Chinese medicine as the leading therapy for the treatment of BPH in the following populations or conditions： the elderly and weak patients with basic diseases， BPH symptoms， and cannot tolerate anesthesia and surgery， the patients with BPH symptoms and cannot tolerate the adverse reactions or the possible adverse reactions of western medicine； the patients with mild ［international prostatic symptom score （IPSS） ≤ 7］ or moderate lower urinary tract symptoms （IPSS ≥ 8） and the quality of life not significantly affected， the patients with bladder detrusor hypofunction， bladder dysfunction and cannot be treated surgically， or with incomplete bladder emptying after surgical treatment； the BPH patients with prostatitis as the main clinical manifestation， the patients with non-acute complications after operation. BPH is one of the dominant diseases in urology and andrology of Chinese medicine， and the symptoms， complications， and prognosis of BPH patients need to be fully considered during the clinical treatment. When Chinese medicine is taken as the leading therapy， it is essential to regularly review the serum level of prostate-specific antigen to exclude the possibility of prostate cancer， and apply Chinese medicine for full treatment course and cycle. At the same time， Chinese and western medicine can be combined to achieve the most effective， convenient， economical， and satisfactory treatment， which can carry forward the advantages of Chinese medicine in treating this disease.

Study on the current status and feasibility of payment reform for TCM dominant diseases from the perspective of clinicians / 中国药房

OBJECTIVE To understan d the c urrent situation and feasibility of payment reform for TCM dominant diseases from the perspective of clinicians ，so as to provide reference for optimizing and improving the reform scheme. METHODS A questionnaire was designed by ourselves ，and a simple random sampling method was used to select clinicians from the pilot hospitals of payment reform for TCM dominant diseases in Guizhou province to conduct a face-to-face questionnaire survey. SPSS 20.0 software was used for statistical analysis. The single-factor analysis and ordered Logistic regression analysis of multi-factor were used to analyze the influential factors of reform feasibility. RESULTS A total of 420 questionnaires were distributed in this survey，and 413 valid questionnaires were recovered ，with an effective rate of 98.3％. Totally 86.0％ of the clinicians thought that it was feasible for the reform to be carried out in their hospitals ，and 81.8％ thought that the selected TCM dominant diseases in the pilot hospitals were reasonable. After the reform was carried out ，61.0％ and 58.8％ of clinicians indicated that the daily number of patients treated in their departments and their willingness to communicate with patients increased ，respectively；60.3％ indicated that the difficulties and obstacles encountered in the reform were the complexity and diversity of TCM diseases ，for the treatment of patients with integrated traditional Chinese and Western medicine ，which was difficult to use a unified disease and surgery code to correctly code ；76.3％ indicated that the greatest advantage of the reform implementation was the improvement of medical quality ，while 54.2％ indicated that the greatest disadvantage was the excessive restriction of doctors ’autonomy. The results of multi-factor ordered Logistic regression analysis showed that changes in treatment services （changes in readmission rate of patient），the reasonableness of the selection of TCM dominant diseases ，and whether to reduce medical costs ，improve doctor-patient relationship ， and promote hierarchical treatment were the influential factors of reform feasibility after the implementation of reform （P＜0.05）. CONCLUSIONS It is feasible to carry out payment reform for TCM dominant diseases in Guizhou province ，but it is still in the exploratery stage ，and there are many factors affecting the feasibility of the reform. It is suggested that in the future ，when promoting in the whole pr ovince and even the whole c ountry，we should pay attention to selecting more and more reasonable dominant diseases for payment reform ， further standardize the diagnosis and treatment behavior of clinicians ， control the unreasonablegrowth of medical expenses ， strengthen communication between clinicians and patients， improve the accurate diagnosis rate of traditional Chinese medicine diseases ，implement hierarchical calculation of dominant diseases ，and promote hierarchical diagnosis and treatment of medical institutions.

The novel loss of function Ile354Val mutation in PPARG causes familial partial lipodystrophy.

AIMS: Familial partial lipodystrophy (FPLD) is a rare autosomal dominant disorder, mostly due to mutations in lamin A (LMNA) or in peroxisome proliferator-activated receptor gamma (PPARG) genes. In the present study, we aimed to identify and functionally characterize the genetic defect underlying FPLD in an Italian family presenting with several affected individuals in three consecutive generations. METHODS: Mutational screening by direct Sanger sequencing has been carried out on both LMNA and PPARG genes. In silico analyses and functional in vitro studies on transfected cell lines have been also performed to evaluate the biological impact of the identified mutation. RESULTS: We identified a novel PPARG missense mutation (i.e., PPARγ2 Ile354Val) segregating with FPLD in the study family. In silico analyses and in vitro experiments showed that probably altering the PPARγ2 ligand binding domain conformation, the Ile354Val aminoacid change leads to a significant reduction (i.e., ~ 30-35%) of transcriptional activity in the mutant receptor, with no evidences of a dominant negative effect on the wild-type receptor. CONCLUSIONS: Our present data extend the spectrum of PPARG mutations responsible for FPLD3 and reinforce the notion that even loss of function mutations affecting transcriptional activity to an extent lower than that observed in the case of haploinsufficiency are able to cause a severe FPLD3 phenotype.

[Analysis on the dominant diseases treated with spreading moxibustion therapy based on randomized controlled trials].

OBJECTIVE: To analyze the indications and dominant diseases of the spreading moxibustion therapy. METHODS: By retrieving 7 databases of both Chinese and English version, such as CNKI, WANFANG, VIP and PubMed, the eligible articles of randomized controlled trials (RCTs) treated with spreading moxibustion therapy were collected. The number of annual publications, the number of each disease system, the indications and dominant diseases involved in the related articles were analyzed statistically, as well as the number of cases and the corresponding clinical effective rates. RESULTS: A total of 182 articles were included, including 40 indications for the spreading moxibustion and covering 9 major disease systems. Specially, the indications in the motor system were maximal in number, accounting for 17.50% (7/40) of the total number of indications. The number of indications in the digestive system was on the second top, accounting for 15.00% (6/40). The dominant diseases were mainly distributed in motor system, respiratory system, nervous system and gynecological system. There were 3 dominant diseases in motor system, i.e. ankylosing spondylitis, back pain and rheumatoid arthritis; 1 dominant disease, i.e. chronic obstructive pulmonary disease in the respiratory system, 1 dominant disease, i.e. primary dysmenorrheal in the gynecological system and 1 dominant disease, i.e. post-stroke paralysis in the nervous system. CONCLUSION: At present, the indications of the spreading moxibustion therapy are widely distributed and the dominant diseases are concentrated, representatively by ankylosing spondylitis. But, the indications and the dominant diseases of spreading moxibustion are changeable dynamically and the disease spectrum of spreading moxibustion needs to be further explored.

Analysis on the dominant diseases treated with spreading moxibustion therapy based on randomized controlled trials / 中国针灸

OBJECTIVE@#To analyze the indications and dominant diseases of the spreading moxibustion therapy.@*METHODS@#By retrieving 7 databases of both Chinese and English version, such as CNKI, WANFANG, VIP and PubMed, the eligible articles of randomized controlled trials (RCTs) treated with spreading moxibustion therapy were collected. The number of annual publications, the number of each disease system, the indications and dominant diseases involved in the related articles were analyzed statistically, as well as the number of cases and the corresponding clinical effective rates.@*RESULTS@#A total of 182 articles were included, including 40 indications for the spreading moxibustion and covering 9 major disease systems. Specially, the indications in the motor system were maximal in number, accounting for 17.50% (7/40) of the total number of indications. The number of indications in the digestive system was on the second top, accounting for 15.00% (6/40). The dominant diseases were mainly distributed in motor system, respiratory system, nervous system and gynecological system. There were 3 dominant diseases in motor system, i.e. ankylosing spondylitis, back pain and rheumatoid arthritis; 1 dominant disease, i.e. chronic obstructive pulmonary disease in the respiratory system, 1 dominant disease, i.e. primary dysmenorrheal in the gynecological system and 1 dominant disease, i.e. post-stroke paralysis in the nervous system.@*CONCLUSION@#At present, the indications of the spreading moxibustion therapy are widely distributed and the dominant diseases are concentrated, representatively by ankylosing spondylitis. But, the indications and the dominant diseases of spreading moxibustion are changeable dynamically and the disease spectrum of spreading moxibustion needs to be further explored.

[Exploring research ideas of mechanism of dominant diseases in traditional Chinese medicine based on evidence-based medicine].

The prescription of clinical curative effect has promoted the formation and development of the dominant diseases in traditional Chinese medicine, but it has been controversial for a long time because its mechanism has not been effectively explained. Breaking the gap between animal/cell research and clinical research, and understanding the mechanism of dominant diseases in traditional Chinese medicine based on evidence-based medicine has become an important breakthrough in this scientific issue. Therefore, based on evidence-based medicine, we established the research concept that "originating from clinic, testing in experiment, returning to clinic". Taking the classic formula (Jinqi Jiangtang formula) treating diabetes as an example to find characteristic markers of diabetes supported by evidence-based medicine from clinic. We used the reverse analysis strategy of the response of characteristic markers to explore the intervention mechanism of Jinqi Jiangtang formula on characteristic markers. Then, we verified the key signaling molecules of the metabolic regulation of the Jinqi Jiangtang formula in clinic. The research ideas and key technologies for the mechanism of treatment of diabetes by Jinqi Jiangtang formula based on evidence-based medicine are formed, and it is expected to provide research reference for explaining the mechanism of dominant diseases in traditional Chinese medicine based on evidence-based medicine.

Study on TCM Dominant Diseases Based on Diagnosis Related Groups Data / 中国中医药信息杂志

Objective To screen TCM dominant diseases from service efficiency, service quality and security by taking a three-A-grade TCM hospital as example.Methods According to the diagnosis related data of the TCM hospital, the common diseases in major disease categories (MDC) were screened out. Average cost of hospitalization, average hospitalization days, antibiotic use rates, blood use rates, and mortality rates were compared with the average level of tertiary general hospitals.Results Totally 27 common diseases were screened out. Three diseases had advantages in terms of service efficiency, security and service quality; 14 diseases had security advantage; 13 diseases had advantage in service quality.Conclusion Compared with three-A-grade general hospitals, most of the common diseases in the hospital has obvious advantages in security and service quality, but the average length of hospitalization in the hospital is longer, and the average cost of most of the common diseases is higher than the general hospital, without advantages in service efficiency.

Exploring research ideas of mechanism of dominant diseases in traditional Chinese medicine based on evidence-based medicine / 中国中药杂志

The prescription of clinical curative effect has promoted the formation and development of the dominant diseases in traditional Chinese medicine, but it has been controversial for a long time because its mechanism has not been effectively explained. Breaking the gap between animal/cell research and clinical research, and understanding the mechanism of dominant diseases in traditional Chinese medicine based on evidence-based medicine has become an important breakthrough in this scientific issue. Therefore, based on evidence-based medicine, we established the research concept that "originating from clinic, testing in experiment, returning to clinic". Taking the classic formula (Jinqi Jiangtang formula) treating diabetes as an example to find characteristic markers of diabetes supported by evidence-based medicine from clinic. We used the reverse analysis strategy of the response of characteristic markers to explore the intervention mechanism of Jinqi Jiangtang formula on characteristic markers. Then, we verified the key signaling molecules of the metabolic regulation of the Jinqi Jiangtang formula in clinic. The research ideas and key technologies for the mechanism of treatment of diabetes by Jinqi Jiangtang formula based on evidence-based medicine are formed, and it is expected to provide research reference for explaining the mechanism of dominant diseases in traditional Chinese medicine based on evidence-based medicine.

A pipeline combining multiple strategies for prioritizing heterozygous variants for the identification of candidate genes in exome datasets.

BACKGROUND: The identification of disease-causing variants in autosomal dominant diseases using exome-sequencing data remains a difficult task in small pedigrees. We combined several strategies to improve filtering and prioritizing of heterozygous variants using exome-sequencing datasets in familial Meniere disease: an in-house Pathogenic Variant (PAVAR) score, the Variant Annotation Analysis and Search Tool (VAAST-Phevor), Exomiser-v2, CADD, and FATHMM. We also validated the method by a benchmarking procedure including causal mutations in synthetic exome datasets. RESULTS: PAVAR and VAAST were able to select the same sets of candidate variants independently of the studied disease. In contrast, Exomiser V2 and VAAST-Phevor had a variable correlation depending on the phenotypic information available for the disease on each family. Nevertheless, all the selected diseases ranked a limited number of concordant variants in the top 10 ranking, using the three systems or other combined algorithm such as CADD or FATHMM. Benchmarking analyses confirmed that the combination of systems with different approaches improves the prediction of candidate variants compared with the use of a single method. The overall efficiency of combined tools ranges between 68 and 71% in the top 10 ranked variants. CONCLUSIONS: Our pipeline prioritizes a short list of heterozygous variants in exome datasets based on the top 10 concordant variants combining multiple systems.

Anesthetic management for oocyte retrieval: An exploratory analysis comparing outcome in in vitro fertilization cycles with and without pre-implantation genetic diagnosis.

PURPOSE: To date, there has been no comparison of outcomes in women undergoing anesthesia for in vitro fertilization (IVF) oocyte retrieval for the purpose of pre-implantation genetic diagnosis (PGD) because of their or their partner's genetic disease relative to the outcome in women requiring IVF because of fertility issues. MATERIALS AND METHODS: A prospective observational study, wherein all demographic and anesthetic management data were collected from IVF and PGD units' records for a 6-month period. Descriptive analyses and parametric tests were employed. RESULTS: There were 307 cases IVF and 76 cases PGD: most (97.4% and 99.7%, respectively) received general anesthesia with propofol and fentanyl ± dipyrone (90.5% and 93.3%, respectively) with no adverse effects. The only statistically significant difference between IVF and PGD groups that was potentially clinically significant was post-procedure recovery time (23.0 ± 20.4 vs. 29.4 ± 35.8 min, respectively; P < 0.0001), but is explainable as greater caution by Anesthesiologists for higher-risk PGD cases having autosomal dominant diseases that may impact anesthesia management (myotonic dystrophy, neurofibromatosis, Marfan's); two of these cases also recovered in the general post-anesthesia care unit, as a precaution for early diagnosis and treatment of potential post-procedural complication. CONCLUSIONS: Results of this first-ever survey of anesthesia for PGD compared with IVF cases imply that propofol-and-fentanyl-based anesthesia is safe and can be recommended, bearing in mind that with patients who have autosomal dominant diseases impacting anesthetic management it is prudent to be more cautious post-recovery.