Genotypic-phenotypic landscape computation based on first principle and deep learning.

The relationship between genotype and fitness is fundamental to evolution, but quantitatively mapping genotypes to fitness has remained challenging. We propose the Phenotypic-Embedding theorem (P-E theorem) that bridges genotype-phenotype through an encoder-decoder deep learning framework. Inspired by this, we proposed a more general first principle for correlating genotype-phenotype, and the P-E theorem provides a computable basis for the application of first principle. As an application example of the P-E theorem, we developed the Co-attention based Transformer model to bridge Genotype and Fitness model, a Transformer-based pre-train foundation model with downstream supervised fine-tuning that can accurately simulate the neutral evolution of viruses and predict immune escape mutations. Accordingly, following the calculation path of the P-E theorem, we accurately obtained the basic reproduction number (${R}_0$) of SARS-CoV-2 from first principles, quantitatively linked immune escape to viral fitness and plotted the genotype-fitness landscape. The theoretical system we established provides a general and interpretable method to construct genotype-phenotype landscapes, providing a new paradigm for studying theoretical and computational biology.

Host plant richness explains diversity of ectomycorrhizal fungi: Response to the comment of Tedersoo et al. (2014).

Exploring the relationships between the biodiversity of groups of interacting organisms yields insight into ecosystem stability and function (Hooper et al. ; Wardle ). We demonstrated positive relationships between host plant richness and ectomycorrhizal (EM) fungal diversity both in a field study in subtropical China (Gutianshan) and in a meta-analysis of temperate and tropical studies (Gao et al. ). However, based on re-evaluation of our data sets, Tedersoo et al. () argue that the observed positive correlation between EM fungal richness and EM plant richness at Gutianshan and also in our metastudies was based mainly from (i) a sampling design with inconsistent species pool and (ii) poor data compilation for the meta-analysis. Accordingly, we checked our data sets and repeated the analysis performed by Tedersoo et al. (). In contrast to Tedersoo et al. (), our re-analysis still confirms a positive effect of plant richness on EM fungal diversity in Gutianshan, temperate and tropical ecosystems, respectively.

Characterization of 40 single nucleotide polymorphism (SNP) via Tm-shift assay in the mud crab (Scylla paramamosain).

In this study, single nucleotide polymorphism (SNP) were identified, confirmed and genotyped in the mud crab (Scylla paramamosain) using Tm-shift assay. High quality sequences (13, 311 bp long) were obtained by re-sequencing that contained 91 SNPs, with a density of one SNP every 146 bp. Of all 91 SNPs, 40 were successfully genotyped and characterized using 30 wild specimens by Tm-shift assay. The minor allele frequency per locus ranged from 0.017 to 0.500. The observed and expected heterozygosity, and polymorphism information content (PIC) ranged from 0.000 to 0.600, from 0.033 to 0.509, and from 0.033 to 0.375, respectively, with an average of 0.142, 0.239 and 0.198 per locus. Seventeen SNPs were significantly deviated from Hardy-Weinberg equilibrium. No significant linkage disequilibrium between pairs of loci was detected after sequential Bonferroni correction (P > 0.00125). Seventeen SNPs were related with known function genes. This study provided new molecular markers for investigation of population genetic diversity, construction of genetic linkage maps and molecular marker-assisted selection in this important crustacean species.

Single-cell 5' RNA sequencing of camelid peripheral B cells provides insights into cellular basis of heavy-chain antibody production.

Camelids produce both conventional tetrameric antibodies (Abs) and dimeric heavy-chain antibodies (HCAbs). Although B cells that generate these two types of Abs exhibit distinct B cell receptors (BCRs), whether these two B cell populations differ in their phenotypes and developmental processes remains unclear. Here, we performed single-cell 5' RNA profiling of peripheral blood mononuclear cell samples from Bactrian camels before and after immunization. We characterized the functional subtypes and differentiation trajectories of circulating B cells in camels, and reconstructed single-cell BCR sequences. We found that in contrast to humans, the proportion of T-bet+ B cells was high among camelid peripheral B cells. Several marker genes of human B cell subtypes, including CD27 and IGHD, were expressed at low levels in the corresponding camel B cell subtypes. Camelid B cells expressing variable genes of HACbs (VHH) were widely present in various functional subtypes and showed highly overlapping differentiation trajectories with B cells expressing variable genes of conventional Abs (VH). After immunization, the transcriptional changes in VHH+ and VH+ B cells were largely consistent. Through structure modeling, we identified a variety of scaffold types among the reconstructed VHH sequences. Our study provides insights into the cellular context of HCAb production in camels and lays the foundation for developing single-B cell-based camelid single-domain Ab screening.

Benefits of 12-month peer support for diabetes self management sustained at 18 months.

AIMS: To evaluate sustainability of peer support (PS) benefits in diabetes management. METHODS: Supporting a Peer Leader program through Community Health Centers (CHCs) included trainings and consultations from baseline to 12 months. Evaluation at baseline, 12-month, and 18-month follow-up included primary outcome, HbA1c, and other outcomes of SBP, DBP, LDLc, PHQ-8, diabetes distress, and EQ-5D. RESULTS: 1284 participants with type 2 diabetes mellitus were recruited from 9 CHCs. Mean (SD) for age = 68.00 (7.55) years, 43.07 % male, mean (SD) for diabetes duration = 11.79 (7.34) years. Across 18-months, linear mixed model analyses controlling for confounders found the least square mean (SE) of HbA1c improved significantly from 7.62 % (0.06 %) to 7.53 % (0.06 %) for all, and from 9.25 % (0.09 %) to 8.52 % (0.11 %) among those ≥8 % at baseline. Parallel improvements were found among all for SBP, DBP, PHQ-8, diabetes distress, and, among those elevated at baseline for all outcomes. EQ-5D showed significant but modest increase from baseline to 18 months. No significant reversals between 12 and 18 months were found except for LDLc. Supporting robustness of findings, patterns were similar across age, diabetes duration, and gender. CONCLUSIONS: Relative to the fundamentally progressive nature of diabetes, it is striking that improvements associated with PS were generally sustained after program support ended.

A deep learning system for predicting time to progression of diabetic retinopathy.

Diabetic retinopathy (DR) is the leading cause of preventable blindness worldwide. The risk of DR progression is highly variable among different individuals, making it difficult to predict risk and personalize screening intervals. We developed and validated a deep learning system (DeepDR Plus) to predict time to DR progression within 5 years solely from fundus images. First, we used 717,308 fundus images from 179,327 participants with diabetes to pretrain the system. Subsequently, we trained and validated the system with a multiethnic dataset comprising 118,868 images from 29,868 participants with diabetes. For predicting time to DR progression, the system achieved concordance indexes of 0.754-0.846 and integrated Brier scores of 0.153-0.241 for all times up to 5 years. Furthermore, we validated the system in real-world cohorts of participants with diabetes. The integration with clinical workflow could potentially extend the mean screening interval from 12 months to 31.97 months, and the percentage of participants recommended to be screened at 1-5 years was 30.62%, 20.00%, 19.63%, 11.85% and 17.89%, respectively, while delayed detection of progression to vision-threatening DR was 0.18%. Altogether, the DeepDR Plus system could predict individualized risk and time to DR progression over 5 years, potentially allowing personalized screening intervals.

Host plant genus-level diversity is the best predictor of ectomycorrhizal fungal diversity in a Chinese subtropical forest.

Microbial diversity is generally far higher than plant diversity, but the relationship between microbial diversity and plant diversity remains enigmatic. To shed light on this problem, we examined the diversity of a key guild of root-associated microbes,that is, ectomycorrhizal (EM) fungi along a plant diversity gradient in a Chinese subtropical forest. The results indicated that EM fungal diversity was positively correlated with host plant diversity. Furthermore, this relationship was best predicted by host genus-level diversity, rather than species-level diversity or family-level diversity. The generality of this finding was extended beyond our study system through the analyses of 100 additional studies of EM fungal communities from tropical and temperate forests.Here as well, EM fungal lineage composition was significantly affected by EM plant diversity levels, and some EM fungal lineages were co-associated with some host plant genera. These results suggest a general diversity maintenance mechanism for host-specific microbes based on higher order host plant phylogenetic diversity.

Multi-omics of extracellular vesicles: An integrative representation of functional mediators and perspectives on lung disease study.

Extracellular vesicles are secreted by almost all cell types. EVs include a broader component known as exosomes that participate in cell-cell and tissue-tissue communication via carrying diverse biological signals from one cell type or tissue to another. EVs play roles as communication messengers of the intercellular network to mediate different physiological activities or pathological changes. In particular, most EVs are natural carriers of functional cargo such as DNA, RNA, and proteins, and thus they are relevant to advancing personalized targeted therapies in clinical practice. For the application of EVs, novel bioinformatic models and methods based on high-throughput technologies and multi-omics data are required to provide a deeper understanding of their biological and biomedical characteristics. These include qualitative and quantitative representation for identifying cargo markers, local cellular communication inference for tracing the origin and production of EVs, and distant organ communication reconstruction for targeting the influential microenvironment and transferable activators. Thus, this perspective paper introduces EVs in the context of multi-omics and provides an integrative bioinformatic viewpoint of the state of current research on EVs and their applications.

Characterization of heavy-chain antibody gene repertoires in Bactrian camels.

Camelids are the only mammals that can produce functional heavy-chain antibodies (HCAbs). Although HCAbs were discovered over 30 years ago, the antibody gene repertoire of Bactrian camels remains largely underexplored. To characterize the diversity of variable genes of HCAbs (VHHs), germline and rearranged VHH repertoires are constructed. Phylogenetics analysis shows that all camelid VHH genes are derived from a common ancestor and the nucleotide diversity of VHHs is similar across all camelid species. While species-specific hallmark sites are identified, the non-canonical cysteines specific to VHHs are distinct in Bactrian camels and dromedaries compared with alpacas. Though low divergence at the germline repertoire between wild and domestic Bactrian camels, higher expression of VHHs is observed in some wild Bactrian camels than that of domestic ones. This study not only adds our understanding of VHH repertoire diversity across camelids, but also provides useful resources for HCAb engineering.

Community organization guides standardization, adaptability, and innovation: lessons from peer support in the Shanghai Integration Model.

Although there is broad evidence for the value of peer support (PS) in preventing and managing diabetes and other chronic diseases, identifying approaches to stage, scale, and adapt PS interventions is a challenge. Community organization may provide a process for such adaptation of standardized PS and diabetes management to individual communities. This community organization approach was used to develop PS in 12 communities in Shanghai, China. Through a convergent mixed methods design, project records, semi-structured interviews, and an implementation assessment characterized processes of adaptation of standardized materials, examined the extent to which the program was implemented, and identified key success factors and challenges. Findings from both interviews and the implementation assessment indicated that communities adapted standardized intervention components to meet the needs of their communities and assumed responsibility for implementation of different components of the program based on their community's available capacity. Additionally, community innovations occurring as part of the project were reported and standardized for dissemination in future iterations of the program. Key success factors identified included cooperation and collaboration among varied partners within and across communities. Two challenges illustrate the resilience of the community organization model in response to COVID-19 and the need for further adaptation in rural communities. Community organization provided a useful approach to standardization, adaptation, innovation, and reporting of PS interventions for diabetes management.

Effect of changes in anthropometric measurements on the remission and progression of prediabetes: A community-based cohort study.

AIMS: We assessed the impact of changes in body mass index (BMI), body fat percentage (BF%), and waist circumference (WC) on prediabetes among middle-aged and elderly Chinese adults. SUBJECTS, MATERIALS AND METHODS: 2.5-year changes in BMI, BF%, and WC were calculated by subtracting baseline levels from follow-up, based on a cohort of 3,632 participants with prediabetes, and outcomes were defined as remission to normal glucose regulation (NGR), persistence in prediabetes, and progression to newly diagnosed diabetes mellitus (NDM). RESULTS: Among participants with prediabetes, 16.9% returned to NGR and 24.6% progressed to NDM. Changes in BMI, BF%, but not WC were associated with remission and progression of prediabetes (risk ratio per standard deviation increase of BMI: 0.86 [0.79-0.93] and 1.15 [1.08-1.23]; BF%: 0.91 [0.84-0.98] and 1.11 [1.03-1.19]). Among participants with combined impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), only BF% change was significantly associated with remission of prediabetes. CONCLUSION: Short-term management of BMI and BF% should be emphasized to promote the remission and prevent the progression of prediabetes. Moreover, it is of particular clinical importance to monitor BF% among people with combined IFG and IGT.

Sex- and age-specific associations between abdominal fat and non-alcoholic fatty liver disease: a prospective cohort study.

Obesity is closely related to non-alcoholic fatty liver disease (NAFLD). Although sex differences in body fat distribution have been well demonstrated, little is known about the sex-specific associations between adipose tissue and the development of NAFLD. Using community-based cohort data, we evaluated the associations between magnetic resonance imaging-quantified areas of abdominal adipose tissue, including visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), and incident NAFLD in 2830 participants (1205 males and 1625 females) aged 55-70 years. During a 4.6-year median follow-up, the cumulative incidence rates of NAFLD increased with areas of VAT and SAT both in males and females. Further analyses showed that the abovementioned positive associations were stronger in males than in females, especially in participants under 60 years old. In contrast, these sex differences disappeared in those over 60 years old. Furthermore, the risk of developing NAFLD increased nonlinearly with increasing fat area in a sex-specific pattern. Additionally, sex-specific potential mediators, such as insulin resistance, lipid metabolism, inflammation, and adipokines, may exist in the associations between adipose tissue and NAFLD. This study showed that the associations between abdominal fat and the risk of NAFLD were stratified by sex and age, highlighting the potential need for sex- and age-specific management of NAFLD.

Artificial intelligence in diabetes management: Advancements, opportunities, and challenges.

The increasing prevalence of diabetes, high avoidable morbidity and mortality due to diabetes and diabetic complications, and related substantial economic burden make diabetes a significant health challenge worldwide. A shortage of diabetes specialists, uneven distribution of medical resources, low adherence to medications, and improper self-management contribute to poor glycemic control in patients with diabetes. Recent advancements in digital health technologies, especially artificial intelligence (AI), provide a significant opportunity to achieve better efficiency in diabetes care, which may diminish the increase in diabetes-related health-care expenditures. Here, we review the recent progress in the application of AI in the management of diabetes and then discuss the opportunities and challenges of AI application in clinical practice. Furthermore, we explore the possibility of combining and expanding upon existing digital health technologies to develop an AI-assisted digital health-care ecosystem that includes the prevention and management of diabetes.

Effectiveness of quality of care for patients with type 2 diabetes in China: findings from the Shanghai Integration Model (SIM).

This cross-sectional study aimed to investigate the quality of care of diabetes in Shanghai, China. A total of 173 235 patients with type 2 diabetes in 2017 were included in the analysis. Profiles of risk factors and intermediate outcomes were determined. The patients had a mean age of 66.43 ± 8.12 (standard deviation (SD)) years and a mean diabetes duration of 7.95 ± 5.53 (SD) years. The percentage of patients who achieved the target level for HbA1c (< 7.0%) was 48.6%. Patients who achieved the target levels for blood pressure (BP) < 130/80 mmHg and low-density lipoprotein-cholesterol (LDL-c) < 2.6 mmol/L reached 17.5% and 34.0%, respectively. A total of 3.8% achieved all three target levels, and the value increased to 6.8% with an adaptation of the BP target level (< 140/90 mmHg) for those over 65 years. Multivariable analysis identified the factors associated with a great likelihood of achieving all three target levels: male, young age, short diabetes duration, low body mass index, macrovascular complications, no microvascular complications, prescribed with lipid-lowering medication, and no prescription of antihypertensive medication. In conclusion, nearly 50% and one-third of the patients with diabetes met the target levels for HbA1c and LDL-c, respectively, with a low percentage achieving the BP target level. The percentage of patients who achieved all three target levels needs significant improvement.

Association of MAFLD With Diabetes, Chronic Kidney Disease, and Cardiovascular Disease: A 4.6-Year Cohort Study in China.

CONTEXT: In 2020, the terminology of metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace nonalcoholic fatty liver disease (NAFLD). OBJECTIVES: This work aimed to investigate the prevalence and incidence of MAFLD and evaluate its effects on incident extrahepatic diseases. METHODS: A total of 6873 individuals, with a 4.6-year follow-up, were included in this study. Associations of MAFLD and NAFLD with diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD) were examined using logistic regression and Cox proportional hazards models. RESULTS: The prevalence of NAFLD and MAFLD was 40.3% (95% CI, 39.2%-41.5%) and 46.7% (95% CI, 45.6%-47.9%), respectively. Additionally, 321 (4.7%) and 156 (2.3%) participants had MAFLD with excessive alcohol consumption and hepatitis B virus (HBV) infection. During the follow-up period, the incidence of NAFLD and MAFLD was 22.7% (95% CI, 21.3%-24.0%) and 27.0% (95% CI, 25.5%-28.4%). MAFLD was associated with higher risks of incident diabetes (risk ratio [RR] 2.08; 95% CI, 1.72-2.52), CKD (RR 1.64; 95% CI, 1.39-1.94), and CVD (hazard ratio 1.44; 95% CI, 1.15-1.81). Similar associations for NAFLD were observed. Furthermore, the MAFLD subgroups with excessive alcohol consumption (RR 2.49; 95% CI, 1.64-3.78) and HBV infection (RR 1.98; 95% CI, 1.11-3.52) were associated with higher risks of incident diabetes. CONCLUSION: The change from NAFLD to MAFLD did not greatly affect the associations with diabetes, CKD, and CVD. MAFLD further identified those patients of metabolically fatty liver combined with excessive alcohol consumption and HBV infection, who had increased risks of incident diabetes compared with those of non-fatty liver.

A deep learning system for detecting diabetic retinopathy across the disease spectrum.

Retinal screening contributes to early detection of diabetic retinopathy and timely treatment. To facilitate the screening process, we develop a deep learning system, named DeepDR, that can detect early-to-late stages of diabetic retinopathy. DeepDR is trained for real-time image quality assessment, lesion detection and grading using 466,247 fundus images from 121,342 patients with diabetes. Evaluation is performed on a local dataset with 200,136 fundus images from 52,004 patients and three external datasets with a total of 209,322 images. The area under the receiver operating characteristic curves for detecting microaneurysms, cotton-wool spots, hard exudates and hemorrhages are 0.901, 0.941, 0.954 and 0.967, respectively. The grading of diabetic retinopathy as mild, moderate, severe and proliferative achieves area under the curves of 0.943, 0.955, 0.960 and 0.972, respectively. In external validations, the area under the curves for grading range from 0.916 to 0.970, which further supports the system is efficient for diabetic retinopathy grading.

Peer support in Shanghai's Commitment to diabetes and chronic disease self-management: program development, program expansion, and policy.

Identifying organizational settings for sustainable, scalable implementation of peer support (PS) is a challenge. Development, initial evaluation, and community expansion of PS for populations with diabetes staged in the context of the Shanghai Integration Model integrating primary and specialty care for diabetes. Development Phase with 9 Community Health Centers (CHCs) leading to Community Expansion Phase with additional 12 communities. Development Phase peer leaders (PLs) co-led meetings on diabetes management, led neighborhood activities, and followed up with individuals and families. Among 1,284 participants, changes in HbA1c, other clinical markers, and diabetes distress were significant (ps from 0.001 to 0.041), pronounced among those with elevated levels, for example, HbA1c reduction from 9.09% to 8.50% among those ≥8% at baseline (p < 0.001). Ratings of Implementation were associated with reduced HbA1c and diabetes distress and increased neighborhood support. In particular, linking with community resources and utilization of neighborhood Residential Committees were associated with improved HbA1c, indicating the value of PS programs including community resources. Thus, the Community Expansion Phase includes district- and community-level health staff, Community Self Management Groups, and Residential Committees along with CHCs in 12 communities, all of which have implemented activities during the first 6 months. PS programs are feasible and appear to add value among populations with diabetes in community settings such as Shanghai. Recognition by the Shanghai government has included PS as a key strategy for achieving self-management of chronic disease in its 2030 health goals.

Conformational transitions of immobilized DNA chains driven by pH with electrochemical output.

A pH-driven DNA sway rod is prepared by immobilizing thiolated DNA, mercaptohexanol, and cysteine on a gold electrode surface. As pH changes around the pI of cysteine, contrary electrostatic effect is produced between the negative DNA and amphoteric cysteine, which actuates reversible conformational transitions, such as sway of the DNA molecules, rodlike chain-to-globule, and so forth. The nanoscale motion can be detected by commonly used electrochemical technique and reversible electrochemical signal may be observed.

[Effectiveness comparison between proximal femoral nail anti-rotation and proximal femoral locking compression plate for intertrochanteric fracture in elderly patients combined with hemiplegia due to cerebral infarction].

Objective: To investigate the difference in the effectiveness between proximal femoral nail anti-rotation (PFNA) and proximal femoral locking compression plate (PFLCP) for intertrochanteric fracture in elderly patients combined with hemiplegia due to cerebral infarction. Methods: The clinical data of 67 cases of intertrochanteric femoral fractures combined with hemiplegia due to cerebral infarction between October 2013 and January 2017 were retrospectively analyzed. Among them, 32 cases were treated with PFNA internal fixation (PFNA group), and 35 cases were treated with PFLCP internal fixation (PFLCP group). There was no significant difference in gender, age, injury side, modified Evans classification of fracture, preoperative medical disease, and interval from injury to operation between 2 groups ( P>0.05). The operation time, intraoperative blood loss, postoperative bed time, incidence of perioperative complications, time of fracture healing, and hip Harris score at 6 months and 1 year after operation were recorded and compared. Results: Both groups were followed up 12-24 months with an average of 14 months. Compared with the PFLCP group, the PFNA group had shorter operation time, less intraoperative blood loss, and shorter bed time, and the differences were significant ( P<0.05). X-ray films showed that the fractures healed in both groups. The fracture healing time of the PFNA group was shorter than that of the PFLCP group, but the difference was not significant ( t=0.743, P=0.460). During hospitalization, there were 3 cases of pulmonary infection, 2 cases of deep venous thrombosis of lower limbs, and 1 case of urinary tract infection in the PFNA group; and the incidence of perioperative complications was 18.8% (6/32). There were 4 cases of pulmonary infection, 6 cases of deep venous thrombosis of lower limbs, 1 case of recurrent cerebral infarction, and 1 case of stress ulcer in the PFLCP group; and the incidence of perioperative complications was 34.3% (12/35). There was no significant difference in the incidence of perioperative complications between 2 groups ( χ2=2.053, P=0.152). At 6 months after operation, the Harris total score and individual scores in the PFNA group were higher than those in the PFLCP group ( P<0.05). At 1 year after operation, there was no significant difference in the Harris total score and pain score, life ability score, and walking ability score between the PFNA group and the PFLCP group ( P>0.05); However, the joint deformity and activity score of the PFNA group was significantly better than that of the PFLCP group ( t=4.112, P=0.000). Conclusion: For intertrochanteric fracture in elderly patients with cerebral infarction hemiplegia, the PFNA has shorter operative time, less intraoperative blood loss, shorter bed time after operation, and better short-term hip function when compared with the PFLCP.

The complete mitochondrial genome of Eleotris oxycephala (Perciformes: Eleotridae).

In the present study, we obtained the complete mitochondrial genome sequence of Eleotris oxycephala, which was 16 527 bp in length. This genome consisted of 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes and a putative control region. Of the 37 genes, 28 were encoded by heavy strand, while nine were encoded by light strand. The overall base composition of this mitogenome was 28.21% for A, 16.81% for G, 24.75% for T, 30.23% for C, respectively, with a slight higher A + T content (52.96%). The phylogenetic analysis based on 13 concatenated protein-coding genes suggested that E. oxycephala as a sister species to Eleotris acanthopoma was clustered in family Eleotridae. This complete mitochondrial genome sequence of E. oxycephala should be helpful for the studies on population genetic structure, molecular evolution and phylogeny of E. oxycephala and related species.